Apparatus and methods for ocular injection

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

PATENT TITLE No. 372859

<td>Title(s):</td><td>CLEARSIDE BIOMEDICAL, INC.</td>

<td>Home:</td><td>1220 Old Alpharetta Road, Suite 300, Alpharetta, Georgia, 53000, USA</td>

Name: DEVICE AND METHODS FOR OCULAR INJECTION.

<td>Classification:</td><td>CIP: A61F9/00; A61M5/00; A61M5/31; A61M5/34; A61M5/46; A61M37/00 CPC: A61F9/0017; A61M5/00; A61M5/31; A61M5/34; A61M5/46; A61M37/0015</td>

<td>Inventor(s):</td><td>RAFAEL VICTOR ANDINO; VLADIMIR ZARNITSYN; CHRISTOPHER JOHN BROOKS; JESSE YOO; TRENT JOHN KAHUATE; JUSTIN WILLIAM ARSENAULT; DAVID JACKSON TRETTIN; ANDREW KENT BAUER; STEPHANIE ELAINE LEWIS APPLICATION</td>

Number: International Filing Date:

MX/a/2015/015282 May 2, 2014

PRIORITY*

<td>Country:</td><td>Date:</td><td>Number:</td>

<td>US</td><td>May 3, 2013</td><td> 61/819,048</td>

<td>US</td><td>May 3, 2013</td><td> 61/819,052</td>

Validity: Twenty years

Expiration Date: May 2, 2034

Date of Issue: July 7, 2020

The reference patent is granted on the basis of articles 1^either, 2^either Section V, 6^either Section III, and 59 of the Industrial Property Law.

Pursuant to Article 23 of the Industrial Property Law, this patent is valid for twenty years, non-renewable, starting from the date of filing of the international application, and is subject to payment of the fee to maintain the rights.

The undersigned of this title does so on the basis of the provisions of articles 6^either Section III, 7^either BIS 2 and 59 of the Industrial Property Law; articles 1^either, 3^either Section V, paragraph a), sub-paragraph iii), 4^either and 12° sections I and III of the Regulations of the Mexican Institute of Industrial Property; articles 1^either, 3^either, 4^either, 5^either Section V, paragraph a), sub-paragraph iii), 16, sections I and III, and 30 of the Organic Statute of the Mexican Institute of Industrial Property; 1^either, 3^either and 5^either Section a) and the penultimate paragraph of the Agreement that delegates powers to the Deputy General Directors, Coordinator, Divisional Directors, Heads of Regional Offices, Divisional Deputy Directors, Departmental Coordinators and other subordinates of the Mexican Institute of Industrial Property .

This document is signed with an advanced electronic signature (FIEL), pursuant to Article 7 BIS 2 of the Industrial Property Law; Article 3 of its Regulations; and Articles 1, Section III, 2, Section V, 26 BIS, and 26 TER of the Agreement Establishing the Guidelines for the Use of the Electronic Payments and Services Portal (PASE) of the Mexican Institute of Industrial Property (Instituto Mexicano de Propiedad Industrial) in the procedures indicated.

DIVISIONAL DEPUTY DIRECTOR OF PATENT SUBSIDY EXAMINATION, MECHANICAL, ELECTRICAL, INDUSTRIAL DESIGN AND UTILITY MODEL AREAS

Pedro David Fragoso Lopez

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MX/2020/31666 www.gob.mx/impi

Arenal No. 550, Santa María Tepepan Town, Mexico City, CP 16020. CDMX

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ECONOMY

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Continued Priorities

Country: Date: Number:

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US May 2013 February 2014 March 2014

61/827,371

61/944,214

61/953,147 www.gob.mx/ímpi

Arenal No. 550, Santa María Tepepan Town, Mexico City, CP 16020. CDMX

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

DEVICES AND METHODS FOR OCULAR INJECTION

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to, and the benefit of, U.S. Provisional Patent Application No. 61/953,147, entitled Apparatus and Methods for Ocular Injection, filed March 14, 2014, U.S. Provisional Patent Application No. 61/944,214, entitled Apparatus and Methods for Controlling Insertion Depth of a Needle, filed February 25, 2014, U.S. Provisional Patent Application No. 61 /827,371, entitled Apparatus and Methods for Ocular Injection, filed on May 24, 2013, U.S. Provisional Patent Application No. 61/819,052, entitled Apparatus and Methods for Delivering a Drug to Ocular Tissue, filed on May 3, 2013, and U.S. Provisional Patent Application No. 61/819,048, entitled Apparatus and Methods for Controlling Needle Insertion Depth, filed May 3, 2013, the disclosures of each of which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

The modalities described herein are

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Mexican Institute of Industrial Property refers, in general, to the field of ophthalmic therapies and more particularly, to the use of a microneedle for the delivery and/or removal of a substance, such as a fluid therapeutic agent, into and/or from ocular tissues for treatment of the eye.

Although needles are used in transdermal and infraocular drug delivery, there remains a need for improved microneedle devices and methods, particularly for the delivery of substances (e.g., drugs) to the posterior region of the eye. Many inflammatory and proliferative diseases in the posterior region (or other regions) of the eye require long-term pharmacological treatment. Examples of such diseases include macular degeneration, diabetic retinopathy, and uveitis. 15 It is often difficult to deliver effective doses of a drug to the back of the eye using conventional delivery methods such as topical application or intravitreal administration (IVT), which has low efficacy, and systemic administration, which often causes significant side effects. For example, while eye drops are useful in treating conditions affecting the outer surface of the eye or tissues in the front of the eye, eye drops are often not sufficiently transported to the back of the eye, as may be required for the treatment of eye problems.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY treatment of some of the retinal diseases listed above.

Although there have been advances in the past decade regarding the use of systemically delivered substances, there are obstacles to widespread adoption of such methods. For example, in certain situations, direct injection into the eye (e.g., into the vitreous humor) using conventional 27-gauge or 30-gauge needles and syringes can be effective. Direct injection, however, can be associated with significant safety risks, and specialists often require professional training to effectively perform such methods. However, in some cases, targeted injection of a therapeutic agent is desirable.

In such cases, however, the relatively small anatomical structures of the eye often result in significant challenges in placing a needle into a target location using known devices and methods, especially as they pertain to placing the distal end of the needle at the desired depth within the eye.

In addition, IVT administration may have side effects such as increased infraocular pressure or faster onset of cataract formation.

In addition, many known methods of direct injection of a drug into the eye include inserting a needle or

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Mexican Institute of Industrial Property (MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY) a cannula at an acute angle relative to a surface of the eye, which can make controlling the depth of insertion challenging. For example, some such methods include controlling the angular orientation of the needle so that the injected substance exits the needle in a particular location. However, some known methods for injecting substances into ocular tissue include using complicated display systems or sensors to control the placement of the needle or cannula.

1Q Known devices for ocular injection do not provide a mechanism for adjusting the needle length so that the needle can be inserted into the eye at the desired depth. Known systems also do not provide a reliable mechanism for determining when the needle tip is in the desired location, e.g., the suprachoroidal space (SCS) of the eye. Such disadvantages of known systems and methods are exacerbated by the size and thickness of the various layers included in the eye, which can vary substantially from one person to another. For example, the thickness of the conjunctiva and sclera can be substantially different, and their true value cannot be easily determined using standard techniques. Furthermore, the thickness of these layers can also be different in different portions of the eye and at different times of the day in the same eye and location.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Therefore, using known systems and methods, it can be challenging to determine and/or adjust the length of the needle to puncture the eye so that the needle tip is at a desired depth, e.g., the SCS. A needle that is too short may not penetrate the sclera, and one that is too long may penetrate beyond the SCS and damage the retina of the eye. Furthermore, known systems do not provide a convenient way to detect the position of the needle tip within the eye.

Due to the sensitivities associated with infraocular injection (e.g., tissue sensitivity, potential impact on infraocular pressure, and the like), many known systems involve manual injection. More specifically, many known devices and methods involve the user manually applying force (e.g., pushing through a plunger with their thumb or fingers) to expel a fluid (e.g., a drug) into the eye. Due to the small size of the needle and/or the characteristics of the injected drug, some of these devices and methods involve the use of higher levels of force than users are comfortable with. For example, some studies have shown that users generally do not want to apply more than 2 N of force against the eye during ocular injection. Consequently, in certain situations a user may not be able to

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY appropriately supply the medication using known systems and methods due to their reluctance to apply force to completely expel the medication.

However, injection into different target layers of the eye can cause variability in the amount of force required for needle insertion and/or injection of the medication. Different layers of the eye may have different densities. For example, the sclera generally has a higher density than the conjunctiva or the SCS. Differences in the density of the target region or layer can produce different back pressures against the needle exit, i.e., the needle tip from which the fluid emerges. Thus, injection into a relatively dense ocular material such as the sclera 15 requires more back pressure to expel the drug from the needle than is required when injecting a drug into the SCS.

Additionally, the injection force to expel the medication also depends on the density and viscosity of the liquid medication, needle length, and needle diameter. Injecting certain medications into the eye using the desired needles (e.g., 27 gauge, 30 gauge, or even smaller) may require more force than many practitioners feel comfortable applying.

Infraocular injection can also lead to

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Mexican Institute of Industrial Property leaks of infraocular fluids (e.g., vitreous humor and aqueous humor) or the drug from a delivery passage formed by the needle that penetrates the ocular tissue. For example, if the drug is delivered to the sclera instead of the target layer of ocular tissue, e.g., the SCS, the high back pressure of the sclera can force the drug to leak from the insertion site. Known systems do not provide a convenient way to prevent leakage from the insertion site, which can lead to discomfort and loss of medication.

This can prolong treatment as well as increase the costs associated with treatment.

Thus, there is a need for improved devices and methods, which can assist in determining whether the needle is at the correct depth, can facilitate injection of the medication into the ocular tissue, and/or can prevent leakage of ocular fluids and/or medication from the insertion site.

BRIEF DESCRIPTION OF THE INVENTION

The modalities described herein relate generally to the field of ophthalmic therapies and more particularly to the use of a microneedle for the delivery and/or removal of a substance, such as a fluid therapeutic agent, into and/or from ocular tissues for the

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY eye treatment.

In some embodiments, an apparatus includes a housing configured to be coupled to a medication container. The medication container is configured to be coupled to a needle. An injection assembly is disposed within the housing and includes an energy storage member and a drive rod. A distal end portion of the drive rod is configured to be disposed within the medication container. The energy storage member is configured to produce a force at a proximal end portion of the drive rod. The force is sufficient to move the distal end portion of the drive rod within the drug container to transmit at least a portion of a substance from the drug container through the needle when a distal tip of the needle is disposed within a first region at a target location. Furthermore, the force is insufficient to move the distal end portion of the drive rod 20 within the drug container when the distal tip of the needle is disposed within a second region of the target location. In some embodiments, the first region of the target location has a first density and the second region of the target location 25 has a second density, greater than the first

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Mexican Institute of Industrial Property density. In some embodiments, the first region of the target location produces a first back pressure, and the second region of the target location produces a second back pressure, greater than the first back pressure.

In some embodiments, an apparatus includes a housing configured to receive a portion of a medication container, and an adjustment member. A proximal end portion of the adjustment member is configured to be coupled to the medication container. A distal end portion of the adjustment member is coupled to a needle. The adjustment member is movably disposed within the housing such that when the adjustment member is rotated relative to the housing, the needle moves through a plurality of discrete increments along a longitudinal axis of the housing. In some embodiments, the adjustment member defines a lumen configured to place the drug container in fluid communication with the needle.

In some embodiments, an apparatus includes a hub configured to be coupled to a medical injector. The hub defines a passageway configured to receive a needle therethrough. The hub has a convex distal end surface that is configured to contact a target surface of a target tissue when a substance is transported through the needle into the target tissue.

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In some embodiments, the distal end surface includes a sealing portion configured to define a substantially fluid-tight seal with the target surface when the distal end surface is not in contact with the target surface. In such embodiments, the sealing portion may be symmetrical about the centerline of the passageway.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is a cross-sectional view of an illustration of the human eye.

Figure 2 is a cross-sectional view of a portion of the human eye of Figure 1 taken along line 2-2.

Figures 3 and 4 are cross-sectional views of a portion of the human eye of Figure 1 taken along line 3-3, illustrating the suprachoroidal space without and with, respectively, the presence of a fluid.

Figure 5 is a schematic illustration of an apparatus including a housing and an injection assembly in a first configuration, in accordance with one embodiment.

Figure 6 shows the apparatus of Figure 5 in a second configuration, in accordance with one embodiment.

Figure 7 is a perspective view of a

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY system for delivering a medication to an eye, in accordance with a modality.

Figure 8 is an exploded view of the system shown in Figure 7.

Figure 9 is a perspective view of a system for delivering a medicament to an eye including an injector assembly, in accordance with one embodiment.

Figure 10 shows the system of Figure 9 with a first portion of a housing removed to show the injector assembly.

Figure 11 shows an exploded view of the system in Figure 10.

Figure 12A shows a side view, Figure 12B shows a front view, and Figure 12C shows a top view of a drive member included in the system of Figure 9.

Figure 13A shows a side view, Figure 13B shows a front view, and Figure 13C shows a top view of a pawl included in the system of Figure 9.

Figure 14A shows a side view of an actuator included in the system of Figure 9. Figure 14B shows a side cross-sectional view of the actuator of Figure 14A taken along line 25 14B-14B.

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Figure 15 shows a side view of a guide rod included in the system of Figure 9.

Figures 16A-E show side views of the system of Figure 9 with a first portion of the housing removed, the system is shown in various states of operation.

Figure 17 shows a flow diagram of a method for determining the insertion depth into a target tissue of a needle included in a drug delivery device using an injection assembly, in accordance with one embodiment.

Figure 18 shows a flow diagram of a method for assisting a user in determining the insertion depth into a target tissue of a needle 15 included in a drug delivery device, and assisting the user in delivering medication using an injection assembly, in accordance with one embodiment.

Figure 19 shows a schematic illustration of a medical injector including an adjustment member in a first configuration, in accordance with one embodiment.

Figure 20 shows the medical injector of Figure 19 in a second configuration.

Figure 21 shows a perspective view of a system for delivering a medicament to an eye including a needle assembly, in accordance with one embodiment.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Figure 22 shows an exploded view of the needle assembly included in the system of Figure 21,

Figure 23A shows a top view, Figure 23B shows a side view, and Figure 23C shows a side cross-sectional view (taken along line 23C-23C) of a housing of the needle assembly of Figure 22.

Figure 24A shows a side view and Figure 24B shows a top view of a plunger included in the needle assembly of Figure 22.

Figure 25 shows a perspective view of an adjustment member, a lead screw, and a piercing member included in the needle assembly of Figure 22.

Figure 26A shows a side view of the adjustment member included in the needle assembly of Figure 22. Figure 26B shows a side cross-section of the adjustment member of Figure 26A taken along line 26B-26B.

Figure 27A shows a side view of the lead screw included in the needle assembly of Figure 22. Figure 27B shows a cross-sectional view of the lead screw of Figure 27A taken along line 27B-27B.

Figure 28Ά shows a side view and Figure

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

28B shows a front view of a bushing included in the needle assembly of Figure 22. Figure 28C shows a cross-sectional view of the bushing of Figure 28A taken along line 28C-28C.

Figure 29 shows a side view of a locking pin included in the needle assembly of Figure 22.

Figure 30A shows a side view and Figure 30B shows a front view of a tab engaged with the locking pin included in the needle assembly of Figure 22, Figure 30C shows a cross-sectional view of the tab of Figure 30A taken along line 30C-30C.

Figure 31Ά shows a side view and Figure 15 31B shows a front view of a hub included in the needle assembly of Figure 22, in accordance with one embodiment. Figure 31C shows a cross-sectional view of the hub of Figure 31A taken along line 31C-31C.

Figure 32 shows a perspective view of the needle assembly of Figure 22.

Figure 33 shows a side cross-sectional view of the needle assembly of Figure 32 taken along line 33-33.

Figure 34 is a cross-sectional view of

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY a portion of a supply device in accordance with a modality.

Figure 35 is an elongated portion of the eye identified in Figure 1 as region Z and the portion of the delivery device of Figure 34 in use, in a first configuration.

Figure 36 is the elongated portion of the eye identified in Figure 1 as region Z and the portion of the delivery device of Figure 34 in use, in a second configuration.

Figure 37 is a cross-sectional view of a portion of a delivery device in accordance with one embodiment.

Figure 38 is a cross-sectional view of a portion of a delivery device in accordance with one embodiment.

Figure 39 shows a schematic illustration of a system for delivering a medicament to an eye including a hub including a sealing portion, in accordance with one embodiment.

Figure 40A shows a distal end surface of a hub included in the system of Figure 39 in contact with a conjunctiva of an eye and a piercing member included in the system of Figure 39 inserted into the sclera of the eye. Figure 40B shows the distal end surface of a hub included in the system of Figure 39 in contact with a conjunctiva of an eye and a piercing member included in the system of Figure 39 inserted into the sclera of the eye.

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INDUSTRIAL distal of the cube compressing the conjunctiva, Figure 40C shows the cube further compressing the conjunctiva, and the distal end of the piercing member is disposed in proximity to a suprachoroidal space of the eye and is delivering a medicament to the suprachoroidal space, such that the sealing portion forms a substantially fluid-tight seal with the conjunctiva. Figure 40D shows an angle Θ formed between a center line of a supply passage formed by insertion of the piercing member into the sclera of the eye and a tangent of the surface line to the conjunctiva.

Figure 41A shows a finite element analysis (FEA) model of the cube of Figure 40A-D, pressed against the conjunctiva of an eye with a force IN. Figure 41B shows an enlarged view of a portion shown by arrow 4IB shown in Figure 41A.

Figure 42A shows a side view and Figure 42B shows a front view of a hub including a convex distal end, in accordance with one embodiment, the

Figure 42C shows a cross-sectional view of the cube of Figure 42A taken along line 42C-42C.

Figure 43A shows a side view and Figure 43B shows a front view of a hub including a convex distal end, in accordance with one embodiment.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Figure 43C shows a cross-sectional view of the cube of Figure 43A taken along line 43C-43C.

Figure 44A-B shows schematic illustrations of a cube included in a drug delivery system in a first configuration and a second configuration respectively, in accordance with one embodiment.

Figures 45A and 45B are schematic illustrations of a portion of a delivery device in accordance with one embodiment.

Figures 46 and 47 are perspective views of a portion of a delivery device in accordance with one embodiment.

Figure 48 is a perspective view of a portion of a delivery device in accordance with one embodiment.

Figure 4 9 is a perspective view of a portion of a delivery device in accordance with one embodiment.

Figure 50 is a perspective view of a portion of a delivery device in accordance with one embodiment.

Figure 51 is a perspective view of a portion of a delivery device in accordance with one embodiment.

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Figure 52 is a perspective view of a portion of a delivery device in accordance with one embodiment.

Figure 53 is a perspective view of a portion of a delivery device in accordance with one embodiment.

Figure 54 is a perspective view of a portion of a delivery device being used to facilitate an ocular injection, in accordance with one embodiment.

Figure 55 is a cross-sectional view of the portion of the delivery device shown in Figure 54.

Figure 56 shows a perspective view of a 15 supply device, in accordance with one embodiment.

Figure 57 shows an exploded view of the delivery device shown in Figure 56.

Figure 58 shows a perspective view of an actuator rod included in the delivery device of Figure 56.

Figure 59 shows a top perspective view of a plunger included in the delivery device of Figure 56.

Figure 60 shows a bottom perspective view 25 of the plunger of Figure 59.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Figure 61 shows a top perspective view of an actuator included in the delivery device of Figure 56.

Figure 62 shows a side cross-sectional view of the actuator of Figure 61, taken along line 62-62 shown in Figure 61.

Figure 63 shows a top perspective view of a drug containment chamber included in the delivery device of Figure 56.

Figure 64 shows a bottom perspective view of the drug containment chamber of Figure 63.

Figure 65 shows a side cross-sectional view of the drug containment chamber of Figure 63 taken along line 65-65 shown in Figure 63.

Figure 66 shows a top perspective view of a cube included in the delivery device of Figure 56.

Figure 67 shows a side cross-sectional view of the cube of Figure 66 taken along line 67-67 shown in Figure 66.

Figure 68 shows a top perspective view of a cap included in the delivery device of Figure 56.

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Figure 69 shows a side cross-sectional view of the cover of Figure 68 taken along line 69-69 shown in Figure 68.

Figures 70 and 71 show side cross-sectional views of the fuel supply device.

Figure 56 in a first configuration and a second configuration, respectively.

Figure 72 shows a perspective view of an injection marker that may be included in a gi.iminist-.ro system, in accordance with one embodiment.

Figure 73 shows the injection marker of the

Figure 72 being used to mark an injection site on an eye.

Figure 74 shows a perspective view of a delivery device and an extraction member configured to be coupled to the delivery device, in accordance with one embodiment.

Figure 75 shows a perspective view of the supply device of Figure 7 4 with the extraction member coupled thereto.

Figure 76 shows a side cross-sectional view of the extraction member of Figure

74.

Figure 77 shows a perspective view of the delivery device of Figure 75 and a vial of

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY medicine, the extraction member configured to be coupled to the vial.

Figure 78 shows a side cross-sectional view of the extraction member and vial of Figure 77 in an uncoupled configuration.

Figure 79 shows the extraction member of the delivery device of Figure 77 coupled to the vial.

Figure 80 shows a side cross-sectional view of the extraction member and vial of Figure 79 in a coupled configuration.

Figure 81 shows a system for delivering a medicament to an eye, in accordance with an embodiment, in a first configuration.

Figure 82 shows an enlarged view of a portion of the system of Figure 81 shown by arrow 82 in Figure 81.

Figure 83 shows a perspective view of the system of Figure 81 in a second configuration.

Figures 84Ά-B show a schematic illustration of a delivery device including a mechanism for adjusting the length of an insertion depth of a needle included in the delivery device in a first configuration and a second configuration respectively, in accordance with an embodiment.

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Figures 85A-B show a schematic illustration of a delivery device including an injection assisting assembly in a first configuration and a second configuration respectively, in accordance with one embodiment.

Figure 86 shows a schematic illustration of a delivery device including an adjustment member, in accordance with one embodiment.

Figure 87 shows a schematic illustration of a delivery device including an injection assembly, in accordance with one embodiment.

Figure 88 shows a schematic illustration of a portion of a delivery device including an adjustment member, in accordance with one embodiment.

Figures 89A-B show schematic illustrations of a portion of a delivery device including an adjustment member in a first configuration and a second configuration respectively, in accordance with one embodiment.

2Q Figures 90A-C show schematic illustrations of a delivery device including a needle assembly in a first, second, and third configuration, in accordance with one embodiment.

Figure 91 shows a schematic illustration of a delivery device including a needle assembly.

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INDUSTRIAL and an adjustment member, in accordance with a modality.

Figure 92A shows a perspective view and Figure 92B shows a side cross-sectional view of a delivery device including a hub, in accordance with one embodiment.

Figure 93A shows a perspective view of a delivery device including a hub, in accordance with one embodiment. Figures 93B-C show side cross-sectional views of the delivery device of Figure 93A in a first configuration and a second configuration.

Figure 94A-B shows schematic illustrations of a needle configured to communicate light inserted a first distance into ocular tissues and a second distance into the ocular tissue respectively, in accordance with one embodiment.

Figure 95 shows a speculum configured to position an ocular injection delivery device within an eye, in accordance with one embodiment.

Figure 96 shows a speculum that includes markings for sizing an eye, in accordance with a modality.

Figure 97 shows a speculum including a mount configured to receive a mounting portion included in a delivery device and position the delivery device for ocular injection within a

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INDUSTRIAL eye, in accordance with a modality.

Figure 98A shows a perspective view of a one-piece speculum, and Figure 98B shows the speculum of Figure 98A disposed in an eye and a delivery device coupled thereto, in accordance with one embodiment.

Figure 99 shows a flow diagram of a method for injecting a substance into an eye using a medical injector including a hub such that a convex distal end of the hub forms a seal with a target surface to fluidly isolate a delivery passage, in accordance with one embodiment.

DETAILED DESCRIPTION OF THE INVENTION

The embodiments described herein relate to systems and devices for delivering a fluid (e.g., a drug) to or extracting a fluid into the sclera of an eye. Furthermore, embodiments described herein relate to systems, devices, and methods for assisting in inserting a delivery member, e.g., a needle or microneedle, into the eye, and/or assisting in injecting a drug into a target ocular tissue. Embodiments described herein also relate to systems, devices, and methods for controlling the depth of insertion of a delivery member, such as, for example, a microneedle, into the eye to deliver an agent.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY therapeutic to, for example, a posterior region of the eye (for example, via the suprachoroidal space). Embodiments described herein also relate to systems, devices and methods for forming a substantially fluid-tight seal around a delivery passageway formed by insertion of a delivery member, e.g., a microneedle, into the eye to prevent leakage of ocular substance and/or fluid from the insertion site.

₁₀ In some embodiments, the microneedles included in the embodiments described herein include a bevel, which allows for ease of penetration into the sclera and/or suprachoroidal space with minimal collateral damage. However, in some embodiments, the microneedles 15 described herein may define a narrow lumen (e.g., gauge size greater than or equal to 30 gauge, 32 gauge, 34 gauge, 36 gauge, etc.) to allow suprachoroidal drug delivery while minimizing the diameter of the needle path caused by microneedle insertion. In some embodiments, the lumen and bevel aspect ratio of the microneedles described herein is distinct from the standard 27 gauge and 30 gauge needles now commonly used for infraocular injection. For example, the microneedles included in the embodiments described herein may be

<img file="MX372859B_D0028.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY any of those described in the Publication of

International Patent Application No. WO2014/036009, entitled, Apparatus and Methods for Delivering Drug Using Microneedles filed on August 27, 2013, the disclosure of which is incorporated by reference herein in its entirety (hereinafter referred to as PCT application 009).

In some embodiments, an apparatus includes a housing configured to be coupled to a medication container. The medication container is configured to be coupled to a needle. An injection assembly is disposed within the housing and includes an energy storage member and a drive rod. A distal end portion of the drive rod is configured to be disposed within the medication container. The energy storage member is configured to produce a force at a proximal end portion of the drive rod. The force is sufficient to move the distal end portion of the drive rod within the drug container to transmit at least a portion of a substance from the drug container through the needle when a distal tip of the needle is disposed within a first region at a target location. Furthermore, the force is insufficient to move the distal end portion of the

<img file="MX372859B_D0029.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY drive rod within the drug container when the distal tip of the needle is disposed within a second region of the target location, in some embodiments, the first region of the target location has a first density and the second region of the target location has a second density, greater than the first density. In some embodiments, the first region of the target location produces a first back pressure and the second region of the target location produces a second back pressure, greater than the first back pressure.

In some embodiments, an apparatus includes a housing configured to receive at least a portion of a medicament container. The medicament container is configured to be coupled to a needle. An injection assembly is disposed within the housing. The injection assembly includes an energy storage member, an actuating rod, and a release member. A portion of the distal end of the drive rod is configured to be disposed within 20 of the medication container. The release member is configured to maintain a position of the drive rod relative to the housing when the release member is in a first position such that movement of the housing relative to the drug container moves the distal end portion of the drive rod within the drug container. The release member is configured to release the drive rod when it moves from the first position to a second position such that a force produced by the energy storage member moves the distal end portion of the drive rod relative to the housing within the medicament container. This delivers at least a portion of a substance from the medicament container through the needle. In some embodiments, the force is sufficient to move the distal end portion of the drive rod within the drug container when a distal tip of the needle is disposed within a first region at a target location. The force, however, is insufficient to move the distal end portion of the drive rod within the drug container when the distal tip of the needle is disposed within a second region of the target location.

In some embodiments, a method includes inserting a distal tip of a needle of a medical injector, which includes a drug container and an injection assembly, a first distance into a target tissue. The drug container is in fluid communication with the needle. The injection assembly includes a

<img file="MX372859B_D0030.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY drive rod and an energy storage member that is configured to produce a force on a portion of the proximal end of the drive rod. The method further includes releasing the drive rod 5 from the injection assembly to allow a portion of the distal end of the drive rod to move within the drug container in response to the force. Finally, the method includes inserting, after releasing, the distal tip of the medical injector needle a second distance into the target tissue if the distal end portion of the drive rod moves less than a threshold injection distance within the drug container in response to the force, the second distance greater than the first distance. In some embodiments, the distal end portion of the drive rod moves a first injection distance within the medicament container in response to the force. In such embodiments, the method may further include moving the injection assembly relative to the medicament container to move the distal end portion of the drive rod a second injection distance, greater than the first injection distance, within the medicament container.

In some embodiments, an apparatus includes a housing configured to receive a portion of the

<img file="MX372859B_D0031.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY medication container and an adjustment member. A proximal end portion of the adjustment member is configured to be coupled to the medication container. A distal end portion of the adjustment member is coupled to a needle. The adjustment member is movably disposed within the housing such that when the adjustment member is rotated relative to the housing, the needle moves through a plurality of discrete increments along a longitudinal axis of the housing. In some embodiments, the adjustment member defines a lumen configured to position the drug container in fluid communication with the needle.

In some embodiments, an apparatus includes a housing configured to receive a portion of a medication container and an adjustment member. A proximal end portion of the adjustment member is configured to be coupled to the medication container. A distal end portion of the adjustment member is coupled to a needle. The adjustment member defines a plurality of detents 20 such that a projection of the housing is configured to be removably disposed within each detent from the plurality of detents when the adjustment member is moved relative to the housing to move the needle relative to the housing through a plurality 25 of discrete increments. In some embodiments, the projection

<img file="MX372859B_D0032.tif" />

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Mexican Institute of Industrial Property may be a bearing movably coupled within the Anto aiojami. In such embodiments, the bearing is configured to be removably disposed within each of the plurality of retainers when the adjustment member moves relative to the housing to move the needle through the plurality of discrete increments. In addition, the apparatus may also include a biasing member configured to hold the bearing within one of the plurality of retainers.

In some embodiments, an apparatus includes a hub configured to be coupled to a medical injector. The hub defines a passageway configured to receive a needle therethrough. The hub has a convex distal end surface, which is configured to contact a target surface of a target tissue when a substance is transported through the needle into the target tissue. In some embodiments, the distal end surface includes a sealing portion configured to define a substantially fluid-tight seal with the target surface when the distal end surface is not in contact with the target surface.

In some embodiments, a method includes inserting a portion of the distal end of a medical injector needle into a target tissue to define a delivery passage within the target tissue. This is followed by

<img file="MX372859B_D0033.tif" />

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Mexican Institute of Industrial Property placement of a convex distal end surface of a medical injector hub into contact with a target surface of the target tissue to fluidly isolate the delivery passageway. The method then includes transmitting, 5 minutes after placement, a substance into the target tissue via the needle. In some embodiments, the target tissue is an eye and the target surface is the conjunctiva of the eye. In some embodiments, the delivery passageway extends through a sclera of the eye and transmitting includes transmitting the substance into at least one of a suprachoroidal space or inferior portion of the sclera. In such embodiments, the method may further include adjusting, prior to transmitting, a length of the needle extending from the distal end surface of the hub.

In some embodiments, a method includes inserting a portion of the distal end of a medical injector needle into a target tissue to define a delivery passage within the target tissue. The insertion is performed such that a centerline of the needle is substantially normal to a target surface of the target tissue. This is followed by placing a distal end surface of a hub of the medical injector in contact with a target surface of the target tissue to fluidly isolate the delivery passage. The method then includes transmitting, after placement, a substance

<img file="MX372859B_D0034.tif" />

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Mexican Institute of Industrial Property into the target tissue by means of the needle. In some embodiments, delivery is performed such that a centerline of the delivery passage and a tangent from the surface line to the target surface define an entry angle of between about 75 degrees and about 105 degrees.

As used herein, the singular form "a one" includes plural referents unless the context clearly dictates otherwise. Thus, for example, the term "a member" is intended to mean a single member or a combination of members; "a material" is intended to mean one or more materials, or a combination thereof.

As used herein, the words proximal 15 and distal refer to the direction closest to, and farthest from, respectively, an operator (e.g., surgeon, physician, nurse, technician, etc.), who might insert the medical device into the patient, with the tip end (i.e., distal end!) of the device inserted into a first body of the patient. Thus, for example, the end of a microneedle described herein first inserted into the patient's body could be the distal end, while the opposite end of the microneedle (e.g., the end of the medical device is manipulated by the operator)

<img file="MX372859B_D0035.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY could be the next end of the microneedle.

As used herein, a series may refer to multiple features or a single feature with multiple parts. For example, when referring to a series of walls, the series of walls may be considered one wall with distinct portions, or the series of walls may be considered multiple walls.

As used in I^to Present, the terms around and approximately generally mean more or less 10% of the stated value. For example, approximately 0.5 could include 0.45 and 0.55, approximately 10 could include 9 to 11, approximately 1000 could include 900 to 1100.

As used herein, the terms delivery member, puncture member, and piercing member are used interchangeably to refer to an article configured to pierce tissue layers and deliver a substance to a target tissue layer, e.g., a needle, or a microneedle.

As used herein, the terms drug container and drug containment chamber are used interchangeably to refer to an article configured to contain a volume of a substance, e.g., a drug.

<img file="MX372859B_D0036.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

The term fluid tight is understood to encompass both a hermetic seal (i.e., a seal that is impermeable to gas) as well as a seal that is impermeable to liquid. The term substantially when used in conjunction with fluid tight, gas tight, and/or liquid tight, is intended to convey such that, while total fluid tightness is desirable, some minimal leakage due to manufacturing tolerances, or other practical considerations (such as, for example, pressure applied to the seal and/or within the fluid), may occur even in a substantially fluid tight seal. Thus, a substantially fluid-tight seal includes a seal that prevents the passage of a fluid (including gases, liquids and/or suspensions) therethrough when the seal is maintained at a constant position and at fluid pressures of less than about 0.35 kgf/cm² (5 psig), less than about 0.7 kgf/cm (10 psig), less than about 1.41 kgf/cm² (20 psig), less than approximately 2.11 kgf/cm² (30 psig), less than 20 approximately 3.52 kgf/cm² (50 psig), less than approximately 5.27 kgf/cm² (75 psig), less than approximately 7.03 kgf/cm² (100 psig) and all values between these. Similarly, a substantially liquid-tight seal includes a seal that prevents the passage of a liquid (e.g., a liquid medicament) through the liquid.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY of this when the seal is held in a constant position and exposed to liquid pressures of less than approximately 0.35 kgf/cm² (5 psig), less than approximately 0.7 kgf/cm²(10 psig), less than approximately 1.41 kgf/cm² (20 psig), 5 less than approximately 2.11 kgf/cm² (30 psig), less than approximately 3.52 kgf/cm² (50 psig), less than approximately 5.27 kgf/cm² (75 psig), less than approximately 7.03 kgf/cm² (100 psig) and all values between these.

The modalities and methods described herein can be used to treat, deliver substances to, and/or aspirate substances from, various target tissues in the eye. For reference, Figures 1-4 are various views of a human eye 19 (with Figures 2-4 being cross-sectional views). While specific regions are identified, those skilled in the art will recognize that the foregoing identified regions do not constitute the entirety of the eye 10, preferably the identified regions are presented as a simplified example suitable for discussion of the embodiments herein.

The eye 10 includes both an anterior segment 12 (the portion of the eye in front of and including the lens) and a posterior segment 14 (the portion of the eye behind the lens). The anterior segment 12 is joined by the cornea 16 and the lens 18, while the posterior segment 14 is joined by the eye 16.

<img file="MX372859B_D0038.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY joined by the sclera 20 and the lens 18. The anterior segment 12 is further subdivided into the anterior chamber 22, between the iris 24 and the cornea 16, and the posterior chamber 26, between the lens 18 and the iris 2.4. The cornea 16 and the sclera 20 collectively form a limbus 38 at the point at which they overlap. The exposed portion of the sclera 20 in the anterior segment 12 of the eye is protected by a clear membrane referred to as the conjunctiva 45 (see e.g., Figures 2 and 3). Underlying the sclera 20 is the choroid 10 28 and the retina 27, collectively referred to as retinochoroidal tissue. A vitreous humor 30 (also referred to as the vitreous) is disposed between a ciliary body 32 (which includes a ciliary muscle and a ciliary process) and the retina 27. The anterior portion of the retina 27 forms an ora serrata 15 34. The loose connective tissue, or potential space, between the choroid 28 and the sclera 20 is referred to as the suprachoroid. Figure 2 illustrates the cornea 16, which is composed of the epithelium 40, Bowman's layer 41, the stroma 42, Descemet's membrane 43, and the endothelium 44. Figure 20 3 illustrates the sclera 20 with the surrounding Tenon's capsule 4 6 or conjunctiva 45, suprachoroidal space 36, choroid 28, and retina 27, with substantially no tissue and/or fluid separation in the suprachoroidal space 36 (i.e., in this configuration, the space is a potential suprachoroidal space 25). As shown in Figure 3, the sclera 20

<img file="MX372859B_D0039.tif" />

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Mexican Institute of Industrial Property has a thickness of between approximately 500 pm and 700 pm. Figure 4 illustrates the sclera 20 with the surrounding Tenon's capsule 46 or conjunctiva 45, suprachoroidal space 36, choroid 28, and retina 27, with fluid 50 in the suprachoroidal space 36.

As used herein, the term suprachoroidal space, or SCS which is synonymous with suprachoroid, or suprachoroid, describes the space (or volume) and/or potential space (or potential volume) in the region of the eye 10 10 disposed between the sclera 20 and choroid 28. This region is composed primarily of closely packed layers of long, pigmented processes derived from each of the two adjacent tissues; however, a space may develop in this region due to fluid or other material accumulating in the suprachoroidal space and adjacent tissues. The suprachoroidal space may be enlarged by fluid accumulation in some eye disease states or due to trauma or surgical intervention. In some embodiments, fluid accumulation is intentionally created by the delivery, injection, and/or infusion of a drug formulation into the suprachoroid to further create and/or expand the suprachoroidal space 36 (i.e., by disposition of a drug formulation therein). This volume may serve as a pathway for oveoscleral outflow (i.e., a natural process).

<img file="MX372859B_D0040.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY of the eye to move fluid from one region of the eye to the other through it) and can become a space in cases of choroidal detachment of the sclera.

The dotted line in Figure 1 represents the equator of the eye 10. In some modalities_t the insertion site of any of the microneedles and/or methods described herein is between the equator and the limbus 38 (i.e., in the anterior portion 12 of the eye 10). For example, in some embodiments, the insertion site is between approximately two millimeters and 10 millimeters (mm) posterior to the limbus 38. In other embodiments, the microneedle insertion site is at approximately the equator of the eye 10. In still other embodiments, the insertion site is posterior to the equator of the eye 10. In this manner, a drug formulation may be introduced (e.g., via the microneedle) into the suprachoroidal space 36 at the insertion site and may flow through the suprachoroidal space 36 away from the insertion site during an infusion event (e.g., during injection).

In some embodiments, an ocular injection system may include a drug container, at least a portion of which is disposed in a housing including an injection assembly. The injection assembly may facilitate delivery of a substance disposed in a drug container to a target tissue, e.g.,

<img file="MX372859B_D0041.tif" />

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Mexican Institute of Industrial Property, for example, the SCS. For example, Figures 5-6 show a system 100, in accordance with one embodiment. The system 100 includes a housing 110, an injection assembly 111, a drug container 130, and a needle 140, in a first configuration and a second configuration, respectively. The system 100 may be configured to deliver a medicament to a region and/or layer at a target location, e.g., an eye of a patient, (e.g., to the SCS of the eye), as described herein.

The housing 110 is configured to be coupled to the medicament container 130, and the medicament container 130 is configured to be coupled to the needle 140. For example, in some embodiments, at least a portion of the medicament container 130 may be disposed within an internal volume defined by the housing 110. In some embodiments, the medicament container 130 may be slidably disposed within the housing 110. Housing 110 may be a monolithic housing or may include two or more portions which may be joined together to form housing 110. As shown, housing 110 defines an internal volume within which injection assembly 111 is disposed. Mounting features, for example, saddles, notches, grooves, grooves, guide rods, slots, or any other mounting features

<img file="MX372859B_D0042.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY suitable may be arranged in the interval volume defined by the housing 110 configured to secure at least a portion of the components included in the injection assembly 111.

The injection assembly 111 includes an energy storage member 146 and an actuating rod 120. In some embodiments, the energy storage member 146 may be a spring, e.g., coil spring, compression, extension, spring washers, Belleville washers, tapered, any other type of spring. In other embodiments, the energy storage member 146 may include a container of compressed gas, or a container containing a propellant. The energy storage member 146 is operatively coupled to a proximal end portion 122 of the drive rod 120, and produces a force on the proximal end portion 122 of the drive rod 120.

A distal end portion 124 of the actuation rod 120 is disposed within the medicament container 130. The distal end portion 124 may be coupled to and/or in contact with a plunger 128 which is in fluid communication with a substance M (e.g., a VEGF inhibitor such as, for example, VEGF, a VEGF inhibitor, a combination thereof, or any other medicament described herein) disposed within a

<img file="MX372859B_D0043.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY internal volume defined by the drug container 130. The distal end portion 124 of the drive rod 120 is configured to be displaced within the internal volume defined by the drug container 130, for example, due to the force produced by the energy storage member 146, as described herein. In this manner, the drive rod 120 may move the plunger 128 within the medicament container 130 to draw in or expel substance M from the distal tip 142 of the needle 140, as described herein. The side walls of the plunger 128 may be configured to contact the side walls of the medicament container 130 such that the plunger 128 forms a substantially fluid tight seal with the side wall of the medicament container 130, for example, to prevent leakage of substance M. The plunger 128 may be made of an inert and/or biocompatible material which is rigid but soft. Exemplary materials include rubber, silicone, plastic, polymers, or any other suitable material or combination thereof. In some embodiments, plunger 128 may be formed monolithically with actuator rod 120.

The needle 140 may be coupled to the medication container 130 using any suitable coupling features, e.g., Luer connectors, threads,

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY snap fit, latch, lock, friction fit, or any other suitable coupling feature. Needle 140 may include any suitable needle described herein, for example, a microneedle 5 (e.g., a 27 gauge, 30 gauge, or even smaller needles). The distal tip 142 of the needle 140 may define a sharp point such that the needle 140 is configured to pierce a target location T, for example, a body tissue (e.g., ocular tissue), thus, the distal tip 142 may be disposed within a first region R1 and/or a second region R2 of the target location T, as described herein. The needle 140 defines a lumen 141, which is in fluid communication with the substance M disposed within the internal volume 15 defined by the drug container 130. In this manner, the needle 140 is configured to establish fluid communication between the drug container 130 and the target location T, for example, the first region R1 of the target location T, as described herein. In some embodiments, the first region R1 of the target location T may have a first density and the second region R2 may have a second density, which is greater than the first density. In some embodiments, the first region R1 of the target location T produces a first back pressure at the distal tip 142 of the needle 140, and the second region R2 produces a second back pressure at the distal tip 142 of the needle 140, which is greater than the first back pressure. In other words, the first region R1 of the target location T produces a first pressure that resists and/or opposes flow from the distal tip 142 of the needle 140.

142 of the needle 140, and the second region R2 produces a second pressure that resists and/or opposes the flow of the distal tip 142 of the needle 140, which is greater than the first pressure.

In some embodiments, the target location T may be an eye such that the first region R1 is a suprachoroidal space of the eye, and the second region R2 is a sclera of the eye.

The force produced at the proximal end portion 122 of the drive rod 120 by the energy storage member 146 may be sufficient to move the distal end portion 124 of the drive rod 120 within the drug container 130 to transmit at least a portion of the substance M from the drug container 130 through the needle 140 when the distal tip 142 of the needle 140 is disposed within the first region R1 (e.g., an SCS of the eye) from the target location T. In addition, the force may be insufficient to move the distal end portion 124 of the drive rod 120 from within the drug container 130 when the distal tip 142 of the needle 140

<img file="MX372859B_D0044.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY is disposed within the second region R2 (e.g., the sclera of the eye) of the target location T. In other words, the injection assembly 111 may be configured to assist a user in delivering at least a portion of the substance M to the region R1, while being configured or calibrated to limit and/or prevent delivery to the region R2. In some embodiments, the injection assembly 111 may be configured to inform the user when the distal tip 142 of the needle 140 is in the target region of the target location T, e.g., region R1, so that the substance M may be delivered to the target region with high confidence.

Further expanding, Figure 5 shows the apparatus 100 in the first configuration in which the distal tip 15 142 of the needle 140 is disposed in the second region R2.

When the apparatus is actuated, the energy storage member 146 exerts a force in a direction shown by arrow F on the proximal end portion 122 of the drive rod 120. The exerted force F, however, is insufficient to move the distal end portion 124 of the drive rod 120 into the drug container 130. For example, the second region R2 (e.g., the sclera of the eye) may produce a second back pressure which overcomes the force F, thereby preventing and/or limiting the delivery of the substance.

<img file="MX372859B_D0045.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

M to the second region R2. In other words, the apparatus 100 is specifically configured or calibrated so that the force F is insufficient to transmit the substance M to the second region R2.

In the second configuration shown in Figure

6, the distal tip 142 of the needle is now disposed in the first region R1 (e.g., the SCS of the eye). Due to anatomical differences and/or differences in material properties between the first region R1 and the second region

R2, the force F is sufficient to move the distal end portion 124 of the drive rod 120 an injection distance within the medicament container 130. For example, the force F may be sufficient to overcome a first back pressure produced by the first region R1. In this way, the injection assembly 111 can be configured to ensure that the injection is initiated only when the distal tip 142 of the needle is in the first region R1 so that the substance M (e.g., a drug such as, for example, VEGF, a

VEGF, a combination thereof, or any other medicament described herein) may be delivered only to region R1. In some embodiments, the force F exerted by the energy storage member 146 may be between about 2 N and about 6 N, e.g., about 3, about 4 N, or

<img file="MX372859B_D0046.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY approximately 5, including all intervals therebetween. In some embodiments, the actuating rod 120 and the drug container 130 may be collectively configured such that the force produces an injection pressure within the drug container.

130 between approximately 1.02 kgf/cm² (100 kPa) and approximately 5.1 kgf/cm² (500 kPa). For example, in some embodiments, the injection pressure may be approximately 0.1 kgf/cm² (10 kPa) , 1.12 kgf/cm² (110 kPa), 10 1.22 kgf/cm² (120 kPa), 1.33 kgf/cm² (130 kPa) , 1.43 kgf/cm² (140 kPa), 1.53 kgf/cm² (150 kPa), 1.63 kgf/cm² (160 kPa),

1.73 kgf/cm² (170 kPa), 1.84 kgf/cm² (180 kPa), 1.94 kgf/cm² (190 kPa), 2.04 kgf/cm² (200 kPa) , 2.24 kgf/cm² (220 kPa) ,

2.45 kgf/cm² (240 kPa) , 2.65 kgf/cm² (260 kPa) , 2.86 kgf/cm²15 (280 kPa), 3.06 kgf/cm² (300 kPa), 3.26 kgf/cm² (30 kPa), 3.47 kgf/cm² (340 kPa) , 3.67 kgf/cm² (360 kPa) , 3.87 kgf/cm² (380 kPa) , 4.08 kgf/cm² (400 kPa) , 4.28 kgf/cm² (420 kPa) , 4.49 kgf/cm² (440 kPa), 4.69 kgf/cm² (460 kPa), or approximately 4.89 kgf/cm² (480 kPa), inclusive of all ranges and 20 values in between. The injection pressure may be sufficient to overcome the back pressure produced by region R1, but insufficient to overcome the back pressure produced by region R2. For example, the force F may be varied (e.g., by varying the energy storage member 146) depending on the diameter of the

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY container of the medication 130 and/or the actuating rod, the viscosity of the substance M, and/or the material of the medication container 130 and/or the actuating rod 120. In this manner, with respect to variations in the actuating rod 120, the medicament container 130, and/or the substance M, the injection assembly all produce an injection pressure within the medicament container of between approximately 1.02 kgf/cm² (100 kPa) and approximately 5.1 kgf/cm² (500 kPa) .

In some embodiments, the injection assembly 111 may be configured to be reversibly engaged or disengaged by a user on demand. For example, the injection assembly 111 may include an ON/OFF switch which may be engaged by the user to activate or deactivate the injection assembly and/or the energy storage member 146. By way of example, in such embodiments, the injection assembly 111 may be activated by the user (e.g., by turning the injection assembly ON) to release the energy storage member 146 such that the energy storage member 146 exerts force on the proximal end portion 122 of the actuating rod 120 (e.g., as shown in Figure 6) to move the distal end portion 124 of the energy storage member 146 into the drug container 130. The

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY user may then deactivate the injection assembly 111 (e.g., by turning the injection assembly to OFF). The decoupling may result in the force exerted on the proximal end portion 122 of the drive rod 120 to be removed (e.g., to stop any further movement of the drive rod 120 within the medicament container 130) or reduced. In some embodiments, the injection assembly 111 may be configured so that the direction of the force F may be reversed or the actuating rod

120 and/or the energy storage member 146 may be moved in a direction opposite to arrow F (Figure 5). In this way, the medical injector 100 may be returned to the first configuration so that, for example, the energy storage member 146 and/or the actuating rod 120 may be secured. This may, for example, allow the user more flexibility to perform drills to correct an error, for example, inadvertent activation of the injection assembly 111 (e.g., 20 during transportation to the target tissue), or injection into an incorrect insertion site (e.g., an unintended location in an eye). In such embodiments, the energy storage member 146 may include any suitable coupling member which may be reversibly coupled or decoupled by the user such as, for example,

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY a valve (for example, a flap valve, a butterfly valve, or the like), a diaphragm, a mechanical actuator (for example, a rack and pinion actuator, a lead screw and nut actuator, a cam, etc.), a hydraulic actuator (for example, a hydraulic piston), an electromechanical actuator (for example, a piezoelectric actuator), a magnetic actuator, or any other suitable energy storage member 146 which may be reversibly engaged by the user. Such an energy storage member 146 may, for example, allow the medical injector 100 to be moved between the first configuration and the second configuration on demand.

In some embodiments, the injection assembly

111 It may be configured so that the injection distance a traversed by the actuating rod 120 is sufficient to deliver substantially all of the desired doses of the substance M into the first region Rl. In other embodiments, the injection assembly 111 may be configured such that the injection distance traversed by the actuating rod 120 is sufficient to deliver only a portion of the desired dose of substance M into the first region R1. In such embodiments, the injection assembly 111 may be configured to initiate delivery of substance M into the first region R1.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Rl, for example, to inform the user that the distal tip 142 of the needle 140 is disposed within the first region Rl (for example, the user could see or otherwise detect that the drive rod 120 has moved, thereby indicating the desired positioning of the needle)

140 ). In other words, the injection assembly 111 may assist the user in determining whether the distal tip 142 of the needle 140 is within the region Rl or not by initiating delivery of the substance M. In such embodiments, the injection distance may be a first injection distance. The user may then move the distal end portion 124 of the drive rod 120 a second injection distance, for example, by applying manual force to the drive rod 120 (e.g., by moving the housing 110 relative to the medicament container 130, as described herein). In some embodiments, any suitable delivery mechanism (e.g., a mechanical actuator or a pump) may be used to move the distal end portion 122 of the drive rod 120 the second injection distance such that substantially all of the desired dose of substance M is delivered to the first region R1.

In some embodiments, the proximal end portion 122 of the drive rod 120 moves with

<img file="MX372859B_D0051.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY relation to housing 110 to move the distal end portion 124 of drive rod 120 within drug container 130, for example, when distal tip 142 of needle 140 is disposed within the first region R1 (e.g., the SCS of the eye) of target location T. For example, in some embodiments, the proximal end portion 122 of the drive rod 120 may be configured to move freely within the housing 11 such that the distal end portion 124 may move within the medication container 130 without the housing 110 and the medication container 130 moving relative to each other. This may, for example, ensure that the force F exerted by the energy storage member 146 does not move the housing relative to the medicament container 130. In this way, substantially all of the force F may be transferred to the proximal end portion 122 of the drive rod 120. In such embodiments, the housing 110 and/or the medication container 130 may include features, for example, ridges, notches, grooves, indentations, locks, latches, high friction, or any other suitable mechanism, sufficient to prevent the housing 110 and the medication container 130 from moving relative to each other due to force F.

In some embodiments, the injection assembly

<img file="MX372859B_D0052.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

111 may include a release member (not shown) configured to selectively limit movement of the drive rod 120 relative to the housing 110. In such embodiments, the housing 110 may be configured to move relative to the medicament container 130 to move the distal end portion 124 of the drive rod 120 within the medicament container 130 independently of force F. In this manner, the release member may be configured to close or otherwise secure the drive rod 120, for example, the proximal end portion 122 of the drive rod 120, and/or the energy storage member 146 in the first configuration. This may, for example, bias the energy storage member 146 to exert force F on the distal end portion 122 of the drive rod 120. Of . In this way, movement of the drive rod 320 can be substantially limited within the housing 110 such that any movement of the housing 110 relative to the medicament container 130 also displaces the distal end portion 124 of the drive rod 120 within the medicament container 130. For example, the user may move the housing 110 relative to the medication container 130 to move the distal end portion 324 of the drive rod 320 into the housing 110.

<img file="MX372859B_D0053.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY of the drug container 130. The relative movement may be used to extract the substance M into the drug container 130 and/or move the distal end portion 124 the second injection distance to expel substantially all of the substance M into the first region R1 or any other target region of the target location, as described herein.

In some embodiments, the release member may be configured to move between a first position 10 and a second position such that the release member is configured to release the energy storage member 146 when the release member moves from the first position to the second position. The release member may include any suitable release member 15 such as, for example, a pawl, lock, latch, or any other suitable release member. By way of example, in the first position the release member may secure or otherwise engage the proximal end portion 122 of the drive rod 120, 20 and/or the energy storage member 14 6, such that the energy storage member 14 6 is biased and/or the drive rod 120 is locked within the housing 330, as described herein. Once the distal tip 142 of the needle 140 is disposed within the second region R2, the release member may be

<img file="MX372859B_D0054.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY moved into the second position to release the energy storage member 146 and/or the drive rod 120. In other words, the release member may be configured to maintain a position of the drive rod 20 relative to the housing 110 when the release member is in the first position such that movement of the housing 110 relative to the medicament container 130 moves the distal end portion 124 of the drive rod 120 within the medicament container. Furthermore, the release member may be configured to release the drive rod 120 when it moves from the first position to the second position. This may allow the force p produced by the energy storage member 146 to move the distal end portion 124 of the drive rod 120 relative to the housing 110 and into the drug container 130 and thereby transmit at least a portion of the substance M from the drug container 130 through the needle 140. In some embodiments, an actuating mechanism, for example, a button, a pull tab, or any other actuating mechanism, may be coupled to the release member. The actuating mechanism may, for example, be configured to be engaged by the user to move the release member into the second position thereby

<img file="MX372859B_D0055.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY by releasing the drive rod 120 and/or the energy storage member 146.

In some embodiments, the injection assembly 111 may also include a guide rod (not shown) fixedly coupled to the housing 110. The actuating rod 120 may be configured to slide around the guide rod when the energy storage member 146 is released. For example, in some embodiments, at least a portion of the guide rod 10 may be disposed within a cavity defined in the proximal end portion 122 of the drive rod 120. In some embodiments, the guide rod may be a hollow rod within which the proximal end portion 122 of the drive rod 120 is disposed. The guide rod may be configured to ensure that the drive rod 120 moves within the housing 110 and/or medicament container 130 substantially along a centerline A1 of the apparatus 100. In this manner, the guide rod may prevent any lateral (or sideways) movement of the drive rod 120.

In some embodiments, an ocular injection system may include a drug-containing chamber, at least a portion of which is disposed in a housing. Referring now to Figures 7-8, in

<img file="MX372859B_D0056.tif" />

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In some embodiments, a system 1000 includes at least a housing 1110, a drug containment chamber 1310, and an actuator 1320. The system 1000 may be configured to deliver a drug to a region and/or layer of an eye of a patient, for example, to the SCS of the eye.

The housing 1110 includes a first portion 1110a and a second portion 1110b, which can be coupled to define an internal volume to house at least a portion of the drug containment chamber 1310 and the actuator 1320. The first portion 1110a and the second portion 1110b may be removably or fixedly coupled together using any suitable means, for example, screws, nuts, bolts, rivets, adhesives, a snap-fit mechanism, notches, grooves, grooves, locking, latching, or any other suitable coupling mechanism. The housing 1110 includes a gripping portion 1112. A plurality of grooves 1113 are provided on the gripping portion 1112 to allow a user to easily grasp the housing 1110, for example, between the user's index and/or middle finger and thumb. A plurality of ridges 1114 are provided on an external surface of a distal portion of the housing 1110. The ridges 1114 may provide an additional gripping surface for the user to securely hold the housing 1110. For example, a user can grab the

<img file="MX372859B_D0057.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY gripping portion 1112 with a first hand and gripping ridges 1114 with a second hand to limit any movement of housing 1110 during injection of a medicament disposed in medicament containment chamber 1310. A series of ridges (also referred to as side walls and/or protrusions) 1116 are disposed in the internal volume defined by housing 1110. The splines 1116 are configured to engage a mating portion 1312 and/or a flange 1313 of the drug containment chamber 1310, for example, to define a travel range of the actuator 1320, as described herein. Similarly stated, the splines 1116 are configured to limit movement of the actuator 1320 and/or the flange 1313 relative to the housing 1110 during use.

A plurality of mounts 1118 are disposed at a proximal end, within the interior region, of the housing. The mounts 1118 are configured to mount and/or retain a coupling portion 1322 of the actuator 1320, such that a linear translation of the housing

1110 along a longitudinal axis A_L of the system 1000 drives the actuator 1320 to also move along the longitudinal axis A_L, relative to the drug containment chamber 1310. A securing member 25 1119 may be disposed on a distal end of the

<img file="MX372859B_D0058.tif" />

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Housing. The securing member 1119 may be a ring-shaped member formed of a relatively resilient material, for example, rubber, silicone, plastics, polymers, any other suitable material, or combination thereof. The securing member 1119 may be configured to secure the first portion 1110a and the second portion 1110b of the housing 1110 to each other at a distal end of the housing 1110.

The drug containment chamber 1310 defines an internal volume configured to house a drug (e.g., triamcinolone acetonide, VEGF, VEGF inhibitor, or any other drug described herein).

The drug containment chamber 1310 includes a coupling portion 1312 and a supply portion

1314. The delivery portion 1314 may include any suitable coupling feature, for example, a luer connector, threads, a push fit, a latch, a lock, a push-fit coupling, or any other suitable coupling features. The coupling features may be configured to couple the delivery portion 1314 with a piercing member (not shown), for example, a microneedle (e.g., a 27 gauge, 30 gauge, or even smaller microneedles). The piercing member may be any suitable piercing member (such as

<img file="MX372859B_D0059.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY those described in application '009 PCT) configured to pierce a portion of a patient's body, for example, an eye, and establish fluid communication between the drug containment chamber 1310 and the portion of the user's body (for example, the eye).

The coupling portion 1312 is disposed proximate the user and includes a flange 1313. The coupling portion 1312 is disposed in the housing 1110 such that the grooves 1116 are distal to the flange 1313, and interact with the flange 1313 to define a range of movement of the actuator 1320 and/or the drug containment chamber 1310. In some embodiments, the drug containment chamber 1310 may include a commercially available syringe such as, for example, a BD™ ICC syringe 15, or any other commercially available syringe.

The actuator 1320 includes a coupling portion 1322 and a plunger portion (not shown) movably disposed within the internal volume defined by the drug containment chamber 1310. At least a portion of the actuator 1320 is slidably disposed in the internal volume defined by the drug containment chamber 1310. In this way, the actuator 1320 can be moved within the internal volume defined by the drug containment chamber 1310 for extraction of the drug into or expulsion of the drug from the chamber.

<img file="MX372859B_D0060.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY internal volume defined by the drug containment chamber 1310. The coupling portion 1322 is fixedly mounted on the mounts 1118 of the housing 1110. Oθ in this way &gt; any linear displacement of the housing 1110 along the longitudinal axis A_L of the system 1000 also drives the actuator 1320 to slide within the internal volume of the drug containment chamber 1310.

In use, a user may grasp the housing 1110, for example, at the grip portion 1112 with one hand, and with the other hand grasp a portion of the drug-containing chamber 1310 disposed outwardly of the housing 1110. The user may then move the housing 1110 relative to the drug-containing chamber 1310. The displacement of the housing 1110 also drives the actuator 1320 to slide within the internal volume defined by the drug containment chamber 1310. The serrations 1116 may prevent the user from sliding the housing 1110 beyond a predetermined threshold to prevent the actuator 1320 from being separated from the drug containment chamber 1310. In addition, the range of motion may also define a maximum dose of the medication that can be extracted into the internal volume of the medication containment chamber 1310. In this way, the user can extract an iMPi medication

Mexican Institute W^r OF THE PROPERTY

INDUSTRIAL in the drug containment chamber 1310, or inject the drug into ocular tissue, for example, the SCS of an eye.

In some embodiments, a system for injecting a medicament into ocular tissue may include an injector assembly configured to produce a force to assist in the delivery of a medicament. Referring now to Figures 9 through Figures 16A^—C, a system 2000 includes a housing 2110, an injector assembly 2100, a medicament containment chamber 2310, and an actuator 2320. The system 2000 may be configured to deliver a medicament to a desired layer and/or region of a patient's eye, e.g., to the SCS of the eye,

The housing 2110 includes a first portion 2110a and a second portion 2110b, which can be coupled to define an internal region for housing the components of the injector assembly 2100 and at least a portion of the drug containment chamber 2310 and/or the actuator 2320. The first portion 2110a and the second portion 2110b may be removably or fixedly coupled together using any suitable means, for example, screws, nuts, bolts, rivets, adhesives, a snap-fit mechanism, notches, grooves, grooves, locking, latch, or any other suitable coupling mechanism. The housing 2110 includes a gripping portion.

<img file="MX372859B_D0061.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

2112. A plurality of grooves 2113 are provided on the gripping portion 2112 to allow a user to easily grasp the housing 2110, for example, between the index and/or middle finger, and thumb of the user. A plurality of ridges 2114 are also provided on an external surface of a distal portion of the housing 2110, for example to allow easy gripping of the housing 2110 by the user. For example, a user may grasp the gripping portion 2112 with a first hand and grasp the 10 ridges 2114 with a second hand to limit any movement of the housing 2110 during injection of a medicament disposed in the medicament containment chamber 2310. A plurality of ridges 2116 are disposed in the internal region defined by the housing 2110. The 15 grooves 2116 (also referred to as ribs or protrusions) are configured to engage a flange 2313 included in an engagement portion 2312 of the drug containment chamber 2310, for example, to define a travel range of the actuator 2320 and/or the drug containment chamber 2310, as described herein. A proximal end of housing 2110 includes slots 2117 (see Figure 11) configured to receive at least a portion of a drive member 2120 included in injector assembly 2100, as described herein.

A series of 2118 mounts are arranged at one end

<img file="MX372859B_D0062.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY next, within the interior region, of the housing. Mounts 2118 are configured to mount a coupling portion 2142 of a guide rod 2140 included in the injector assembly 2100. A securing member 2119 may be disposed on a distal end of the housing. The securing member 2119 may be a ring-like member formed of a relatively resilient material, for example, rubber, silicone, plastics, polymers, any other suitable material, or combination thereof. The securing member 2119 may be configured to secure the first portion 2110a and the second portion 2110b together at a distal end of the housing 2110.

The drive member 2120 (Figures 12A-C) is disposed at the proximal end of the housing 2110 and is configured to drive the injector assembly 2100, as described herein. The drive member 2120 includes an engaging projection 2122 and a guide projection 2124. At least a portion of the engaging projection 2122 and the guide projection 2124 are slidably disposed in the slots 2117 (see Figure 11). A user can engage a coupling surface 2121 of the drive member 2120, and move the drive member 2120 between a first configuration, in which the coupling projection 2122 and the guide projection 2124 are arranged.

<img file="MX372859B_D0063.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY partially within the internal volume defined by the housing 211, and a second configuration, in which the coupling projection 2122 and the guide projection 2124 are arranged substantially within the internal volume 5 defined by the housing 2110. In other words, the actuating member 2120 can be moved relative to the housing 2110 between a first position (see Figure 16D) and a second position (Figure 16E).

The coupling projection 2122 is configured to engage a pawl 2130 included in the injector assembly 2100 in the second configuration (or position), as described herein (see Figure 16E). The guide projection 2124 is configured to slide within the slots 2117 together with the coupling projection 2122, to prevent any angular movement of the drive member 2120 about the longitudinal axis A11. A biasing member 2123, for example, a spring (e.g., helical spring, compression, extension, spring washers, Belleville washers, tapered, any other type of spring) is coupled to the coupling projection 2122, for example, disposed around the coupling projection 2122. The biasing member 2123 is configured to bias the drive member 2120 into the first configuration (or position). A washer 2125 is coupled to a proximal end of the guide projection 2124 and is arranged

<img file="MX372859B_D0064.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY within the internal volume defined by housing 2110. Washer 2125 has a diameter, or otherwise cross-section, which is substantially larger than the diameter or otherwise cross-section of slots 2117, such that washer 2125 prevents drive member 2120 from being removed from housing 2100.

The pawl 2130 (Figures 13A-C) is disposed at the proximal end of the internal volume defined by the housing 2110. The pawl 2130 includes an engaging portion 2132, a latch 2134, and a biasing portion 2136. A plurality of projections 2137 are disposed on the pawl 2130. The projections 2137 are configured to pivotally mount the pawl 2130 in the internal volume defined by the housing 2110. This allows the pawl 2130 to rotate about the projections 2137 between a first configuration (or angular position) and a second configuration (or angular position) as described herein. The coupling portion 2132 defines a flat surface, which is configured to be engaged by the coupling projection 2122 of the drive member 2120 (see, for example, Figure 16E). More particularly, when the drive member 2120 moves from its first configuration (or position) to its second configuration (or position), the projection of

<img file="MX372859B_D0065.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY coupling 2122 can drive the pawl 2330 from the first configuration into the second configuration. The latch 2134 defines a profile or bracket configured to engage a coupling portion 2322 of the actuator (or push rod) 2320 in the first configuration, as described herein. The deflection portion 2136 includes a thin, guide-like structure configured to elastically bend in the second configuration. In this manner, the deflection member 2136 can drive the pawl 2130 in the first configuration, as described herein. For example, in the first configuration, the latch 2134 may engage the coupling portion 2322 of the actuator 2320 (see Figures 16B-16D) and the biasing portion 2136 may be in an extended position (i.e., maintaining the position of the pawl 2130). A user may engage the coupling portion 2121 of the drive member 2120 and drive it into its second configuration (or position). In . In the second configuration of the drive member 2120, the coupling projection 2322 may engage the coupling portion 2132 of the pawl 2330. This may drive the pawl 2130 to rotate around the projections 2137 and move in the second configuration. When the latch 2134 is in the second configuration, the latch 2134 may be disengaged from the engaging portion 2322 of the actuator 2320 such that the biasing portion 2136 is bent against the housing 2110 and biased (or compressed). The user may then disengage the actuating member 2120. The biasing member 2123 coupled to the engaging projection 2122 may bias the actuating member 2120 back into the configuration. This disengages the coupling protrusion 2122 from the mating surface 2132 of the pawl 2130 so that the biasing portion 2136 can drive the pawl 2130 in the first configuration,

Guide rod 2140 (Figure 15) includes a mounting portion 2142 that is movably mounted to mounts 2118 included in housing 2110. In a similar manner stated, guide rod 2140 is coupled within housing 2110 such that movement (distal movement and proximal movement) is limited. At least a portion of guide rod 2140 is disposed in a cavity 2326 defined within actuator 2320. The guide rod 2140 is configured to prevent lateral movement of the actuator 2320 when the actuator 2320 slides in a linear direction along the longitudinal axis A._L of the system 2000 within the housing 2110, as described in further detail herein. The guide rod 2140 also engages a biasing member 2146 (or energy storage member which is disposed around

<img file="MX372859B_D0066.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY the guide rod 2140, see, for example, Figure 16A) between the mounts 2118 and the actuator (or push rod) 2320. The biasing member 2146 may include, for example, a spring, (for example, a helical spring, compression, extension, spring washers, Belleville washers, tapered, any other type of spring), any other suitable biasing member or combination thereof. A proximal end of the biasing member 2146 is coupled to and/or coupled with the mounting portion 2142 of the guide rod 2140, and a distal end of the biasing member 2146 is coupled to and/or coupled with the coupling portion 2322 of the actuator 2320. The biasing member 2146 is configured to bias the actuator 2320 when the coupling portion 2322 of the actuator 2320 is arranged relative to the mounting portion 2142 of the guide rod 2140 in the prepared position (see, for example, Figures 16B16D). In this manner, the biasing member 2146 may exert a predetermined biasing force on the actuator 2320 to allow or otherwise assist the actuator 2320 to expel a medicament from the medicament containment chamber 2310, as described in further detail herein.

The drug containment chamber 2310 defines an internal volume 2316 configured to house a drug (e.g., a VEGF, a VEGF inhibitor,

<img file="MX372859B_D0067.tif" />

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Mexican Institute of Industrial Property triamcinolone acetonide, any other drug described herein, or a combination thereof). The drug containment chamber 2310 includes a coupling portion 2312 and a delivery portion 2314. The delivery portion 2314 may include coupling features, for example, luer connectors, threads, push-fit, latch, lock, friction fit, or any other suitable coupling features. The coupling features may be configured to couple the delivery portion 2314 with a piercing member (not shown), for example, a microneedle (e.g., a 27 gauge, or 30 gauge, or even smaller needles). The puncture member may be any suitable piercing member (such as those described in PCT application Ό99) configured to pierce a portion of a patient's body, e.g., an eye, and establish fluid communication between the drug containment chamber 2310 and the portion of the user's body (e.g., the eye). The coupling portion 2312 includes a flange 2313. The coupling portion 2312 is arranged in the housing 2110 such that the grooves 2116 are distal to the flange 2313, and interact with the flange 2313 to define a range of movement of the actuator 2320 and/or the drug containment chamber 2320. In other words, the grooves 2116 and the flange 2313

<img file="MX372859B_D0068.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY may serve in combination as a locking mechanism to prevent the drug containment chamber 2310 from moving beyond a threshold distance within the Anto 2110. In some embodiments, the drug containment chamber 2310 may include a commercially available syringe such as, for example, a BD™ ICC syringe, or any other commercially available syringe.

The actuator (or drive rod) 2320 (Figures 14A-B) includes a coupling portion 2322 and a plunger portion 2324. As described above, the coupling portion 2322 defines a cavity 2326 configured to receive at least a portion of the guide rod 2140. A proximal end of the coupling portion 2322 is coupled to and/or engaged with the biasing member 2146, as described hereinbefore. At least a portion of the actuator 2320, for example, the plunger portion 2324, is slidably disposed within the internal volume 2316 defined by the drug containment chamber 2310. Thus, the actuator 2320 may be moved within the internal volume 2316 to extract and/or expel the drug from the internal volume 2316 defined by the drug containment chamber 2310.

As shown in Figures 14A and 14B, a projection 2325 is disposed at a distal end of the plunger portion 2324. The projection 2325 is configured

<img file="MX372859B_D0069.tif" />

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Mexican Institute of Industrial Property to be inserted into a plunger 2328 with close tolerance (e.g., friction fit). The plunger 2328 may be slidably disposed within the internal volume 2316 of the drug-containing chamber 2310. A distal end of the plunger 2328 may be in fluid communication with the drug disposed within the internal volume 2316 defined by the drug-containing chamber 2310. The side walls of the plunger 2328 may contact the side walls of the internal volume 2316 such that the plunger forms a fluid-tight seal to prevent leakage of the medication. The plunger 2328 may be made of an inert and/or biocompatible material that is rigid yet soft. Exemplary materials include rubber, silicone, plastic, polymers, any other suitable material, or combinations thereof.

The injector assembly 2100 is configured to produce a force to inject or otherwise assist in injecting the medicament from the medicament containment chamber 2310 into ocular tissue, e.g., the SCS. In addition, the injector assembly 2100 may be configured to exert a predetermined force and/or a force within a desired range on the actuator 2320 sufficient to expel the medicament only when an exit of a piercing member (e.g., a needle such as a 27 gauge needle, a 30 gauge needle, or

<img file="MX372859B_D0070.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY⁷³ any needle described herein) is within or otherwise near the target injection site, e.g., the SCS. In a similar manner stated, the injector assembly 2100 may be configured to exert a predetermined force 5 on the actuator (or push rod) 2320 and/or the plunger 2328 such that the actuator 2320 and/or the plunger 2328 move when back pressure against the opening of a delivery member (e.g., a puncture member or needle, not shown) is below a desired level 10. As described below, the amount of back pressure against the delivery member may be a function of the tissue characteristics of the target tissue (e.g., tissue density, presence of voids, tissue type, etc.). Thus, the injector assembly 2100 may produce driving force when the opening of the delivery member is within a desired target location (e.g., the SCS). Figures 16A through 16E show the system 2000 including the injector assembly in various states of operation as described herein.

In a first state shown in Figure 16A, a portion of the drug containment chamber 2310 is disposed in the housing 2110 of the injector assembly 2100. The flange 2313 of the drug containment chamber 231 may be adjacent and/or in contact with the splines 2116 of the housing 2110. The actuator 2320 is

<img file="MX372859B_D0071.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY pushed into the drug containment chamber 2310 such that the plunger portion 2324 of the actuator 2320 occupies substantially all of the internal volume 2316 of the drug containment chamber 2310 and there is no drug in the internal volume 2316. Additionally, the guide rod 2140 is disposed in a first relative position within the actuator (or push rod) 2320. In the first state, the deflection member 2146 is coupled to the coupling portion 2322 of the actuator 2320 and is undeflected (or in an expanded configuration). In other words, the system 2000 is disassembled in the first state. Thus, in the first state (or configuration), the system 2000 may be transported, stored, or the like.

To move the system 2000 to the second state shown in Figure 16B, the user moves the drug containment chamber 2310 proximally relative to the injector assembly 2100. This may be accomplished by applying a force to the housing 2110 and/or the drug containment chamber 2310 such that the force pushes the drug containment chamber 2310 into the housing 2110 in the direction shown by arrow A. The housing 2110 is conveyed and sized to prevent any rotational movement of the drug containment chamber 2310 relative to the housing 2110. . Movement of the drug containment chamber 2130 relative to the housing 2110.

<img file="MX372859B_D0072.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY relative to injector assembly 2100, also drives actuator 2320 to slide over guide rod 2140 and move relative to injector assembly 2100. Thus, when injector assembly 2100 is in the second state, guide rod 2140 is disposed in a second relative position within actuator (or push rod) 2320. Furthermore, the biasing member 2146 is biased (or compressed) when the injector assembly 2100 is in the second state. The force is maintained until the latch 2134 of the pawl 2130 engages and secures the coupling portion 2322 of the actuator 2320. The pawl 2130 includes an angled surface such that the engaging portion 2322 can slide past the latch 2134 in a proximal direction but cannot move past the latch 2134 in a distal direction. Thus, in the second state, the system 2000 is armed and ready to be filled with a medicament.

The user may now couple a transfer needle, puncture member, and/or delivery member 20 (not shown) to the delivery portion 2314 of the drug containment chamber 2310. The puncture member may be inserted into a container of the drug, e.g., inserted through a septum of a vial containing the drug. The system 2000 may then be moved into a third state (or configuration) to fill the

<img file="MX372859B_D0073.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY drug containment chamber 2310 with a substance. To move the injector assembly 2100 to the third state shown in Figure 16C, a force may be applied to the drug containment chamber 2310 and/or the housing 2110 to move the drug containment chamber 2310 distally relative to the injector assembly 2100 in the direction shown by arrow B. In this manner, the drug containment chamber 2310 is removed from (moved distally relative to) the housing 2110. The coupling portion 2322 of the actuator 2320 remains secured by the latch 2134 of the ratchet 2130 in the third state. Therefore, relative movement of the drug containment chamber 2310 to the housing 2110 drives the plunger portion 2324 of the actuator 2320 to slide within the internal volume 2316 of the drug containment chamber 2310 until the plunger portion 2324 is proximate the mating portion 2312 of the drug containment chamber 2310. The movement of the actuator 2320 and the plunger 2328 creates a suction force within the internal volume 2316 of the drug containment chamber 2310, which draws the drug into the internal volume 2316.

To place the injector assembly 2100 in a fourth state (shown in Figure 16D), the user may move the drug containment chamber 2310 so that

<img file="MX372859B_D0074.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY next to the injector assembly 2100 so that the drug containment chamber 2310 moves in the housing 2110 as shown by arrow C. In the fourth state, the drug containment chamber 2310 is partially withdrawn in the housing 2110. Since the actuator 2320 is still secured by the pawl 2130 in the fourth state, moving the pawl 2310 away urges the plunger portion 2324 of the actuator 2320 (and thus the plunger 2328) to also slide in the internal volume 2316 proximally relative to the drug-containing chamber 2310. In this manner, the plunger portion 2324 of the actuator 2320 expels a portion of the drug from the internal volume 2316. In other words, the user can expel air from the internal volume 2316 and/or adjust a dose of the medication in the fourth state.

Before injecting the medicament (i.e., moving the injector assembly 2000 into a fifth state shown in Figure 16E), a piercing member (e.g., a 27 gauge needle, a 30 gauge needle, or any of the other piercing members described herein), or a needle assembly (e.g., the needle assembly 3200 or any other needle assembly described herein) may be coupled to the delivery portion 2314 of the drug containment chamber 2310. Although not shown, a hub may also be coupled to the delivery portion 2314.

<img file="MX372859B_D0075.tif" />

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Mexican Institute of Industrial Property supply 2314, which is configured to contact ocular tissue. The hub may include a hub including a convex distal end, a flat distal end, characteristic for aligning the system 2000 on a surface (e.g., conjunctiva) of the eye, or any other hub described herein. For example, in some embodiments, the hub may include a convex distal end surface configured to form a substantially fluid tight seal with a target surface around the insertion site (see e.g., hub 7270 included in medical injector 7000).

The user may insert the piercing member into an eye, until an outlet of the piercing member is at or otherwise near a target delivery layer, e.g., the SCS. The user may manually adjust the insertion depth of the piercing member or a needle assembly to increase or decrease the insertion depth of the piercing member (e.g., as further described in detail with reference to needle assembly 3200). To initiate injection (i.e., to move the injector assembly 2100 to the fifth configuration), the user may then exert a force on the mating surface 2121 of the drive member 2120 in the direction shown by arrow 25D. This drives the mating projection 2122 to

<img file="MX372859B_D0076.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY slide in the slot 2117 distally to the user in the housing 2110 and engage the mating surface 2132 of the pawl 2130. The mating projection 2122 can urge the pawl 2130 to rotate about the 5 projections 2137, so that the biasing portion 2136 is biased and the latch 2134 is disengaged from the coupling portion 2322 of the actuator 2320. The biasing member 2146 exerts a force on the coupling portion 2322 of the actuator 2320 and urges the actuator 2320 to move proximally relative to the drug-containing chamber 2310. In this way, the plunger portion 2324 of the actuator slides an injection distance within the internal volume 2316 of the drug-containing chamber 2310 and expels the drug into the eye via the piercing member. The housing 2110 and/or the drug containment chamber 2310 may be configured to prevent the housing 2110 from moving distally relative to the drug containment chamber 2310 in the fifth state. For example, in some embodiments, the rim 2313 of the drug containment chamber 2310 and/or an internal surface of the housing 2110 may have high surface friction. The flange 2313 and the inner surface of the housing 2110 may contact each other to provide a high friction interface which may be

<img file="MX372859B_D0077.tif" />

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Mexican Institute of Industrial Property prevent housing 2110 from moving distally relative to drug containment chamber 2310 in the fifth state. In some embodiments, notches, grooves, grooves, or any other features may be defined in the internal volume of housing 2110, and/or flange 2313. In some embodiments, a locking mechanism, for example, a twist lock mechanism, a push pin, a latch, a profile, or any other suitable locking mechanism may be included in the housing 2110. In such embodiments, the user may engage the locking mechanism (e.g., rotate the housing 2110 relative to the drug-containing chamber 2310, depress a bolt, etc.) such that the housing 2110 may be prevented from moving distally relative to the drug-containing chamber 2310 in the fifth state, thereby, The force exerted by the biasing member 2146 is applied to move the actuator (or drive rod) 2320 distally relative to (and/or within) the drug-containing chamber 2310, as opposed to being applied to move the entire drug-containing chamber 2310 relative to the housing 2110.

In some embodiments, the injector assembly 2100 may be used as an injection assist assembly to allow a user to inject the medication.

<img file="MX372859B_D0078.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY within a desired tissue of the eye, for example, the SCS. In such embodiments, the biasing member 2146 may be configured to exert a predetermined force on the actuator 2320, for example a force of less than about 6, less than about 5 N, less than about 4 N, less than about 3 N, or less than about 2 N, inclusive of all ranges therebetween. The force may be sufficient to expel the drug from the drug containment chamber 2310 when the back pressure, existing or applied to an outlet of the piercing member, is below a certain threshold. As described hereinbefore, different layers of the eye may have different densities, for example, the sclera is much denser than the eye.

SCS. Therefore, a piercing member inserted into the sclera will experience much higher back pressure than a piercing member near or within the SCS. The biasing member 2146 may be configured to exert a force which is only sufficient to overcome the back pressure experienced at the target layer, e.g., the SCS, but is not sufficient to overcome the back pressure of any other layer, e.g., the sclera, thus the biasing member 2146 drives the actuator 2320 to eject the medicament only at the target layer, e.g., the SCS. The back pressure experienced by the

<img file="MX372859B_D0079.tif" />

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The actuator may vary based on the drug used, the size of the piercing member, the target ocular tissue layer, and/or the thickness of the target layer. If the force supplied by the biasing member 2146 is too high, the injection may occur in the wrong target layer, e.g., the sclera. Conversely, if the biasing force is too small, injection may not occur even when the exit of the piercing member is within or near the target layer, e.g., the SCS. To overcome this, the biasing member 2146 may be adjusted based on the drug used, the needle size, the size of the drug-containing chamber 2310, the actuator 230, and/or the target layer. In some embodiments, the actuator 2320 and the drug containment chamber 2310 may be collectively configured such that the force exerted by the biasing member 2146 produces an injection pressure within the internal volume 2316 of the drug containment chamber 2310 of between approximately 1.02 kgf/cm² (100 kPa) and approximately 5.1 20 kgf/cm² (500 kPa). For example, the system 2000 may be configured such that the same injection pressure occurs within the drug containment chamber 2310, relative to the size (e.g., diameter or otherwise cross-section) of the drug containment chamber 2310 and/or the actuator 2320, the material of the

<img file="MX372859B_D0080.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY actuator 2320 or the drug containment chamber 2310, the volume of the drug, the viscosity of the drug, and/or the size of the puncture member. In some embodiments, the pressure produced in the drug containment chamber 2310 may be approximately 1.02 kgf/cm²(100 kPa), 1.12 kgf/cm² (110 kPa), 1.22 kgf/cm² (120 kPa) , 1.33 kgf/cm² (130 kPa), 1.43 kgf/cm² (140 kPa) , 1.53 kgf/cm² (150 kPa) , 1.63 kgf/cm² (160 kPa) , 1.73 kgf/cm² (170 kPa) ,

1.84 kgf/cm² (180 kPa), 1.94 kgf/cm² (190 kPa), 2.04 kgf/cm² (200 kPa), 2.24 kgf/cm² (220 kPa) , 2.45 kgf/cm² (240 kPa),

2.65 kgf/cm² (260 kPa) , 2.86 kgf/cm² (280 kPa), 3.06 kgf/cm²(300 kPa), 3.26 kgf/cm² (30 kPa), 3.47 kgf/cm² (340 kPa), 3.67 kgf/cm² (360 kPa), 3.87 kgf/cm² (380 kPa), 4.08 kgf/cm² (400 kPa), 4.28 kgf/cm² (420 kPa) , 4.49 kgf/cm² (440 kPa) , 4.69 15 kgf/cm² (460 kPa), or approximately 4.89 kgf/cm² (480 kPa), inclusive of all intervals and values between these.

Additionally, in some embodiments, the injector assembly 2100 may also be used to inform the user when the piercing member is within or near the target layer. For example, the housing 2110 may be transparent such that the user can see the actuator 2320 and/or the drug containment chamber 2310. The user may insert the piercing member into the eye and engage the actuating member 2120 such that the latch 2134 disengages from the actuating portion.

<img file="MX372859B_D0081.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY coupling 2322 of actuator 2320. If the piercing member is within or near the target layer, for example, the SCS, the diverting member 2146 overcomes the back pressure exerted by the target layer and moves the actuator 2320 to move the injection distance and initiate injection of the medicament into the target layer. The user may visibly observe the actuator 2320 and/or plunger 2328 moving within the housing 2110 and may be informed that the piercing member is within or otherwise near the target layer, e.g., the SCS. If the piercing member is in a. layer other than the target layer, for example, the sclera, θ1 biasing member 2146 will not overcome the back pressure of the other layer and the actuator 2320 will not move proximally relative to the drug containment chamber 2310. This may inform the user that the piercing member is not within or near the target layer. The user may then manipulate the piercing member to reach into or near the target layer and initiate injection of the medicament. In some embodiments, any other communication mechanism, e.g., audible alarm, LED light, a message, a display, a tactile alert, or any other communication mechanism may be used to inform the user about the location of the piercing member. In some embodiments, the piercing member

<img file="MX372859B_D0082.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY diverter 2146 may be configured to exert a force sufficient to expel substantially all of the medicament in the target layer, e.g., the SCS. In some embodiments, diverter member 2146 may be configured to exert a force sufficient to initiate injection but not enough to expel all of the medicament in the target layer. In such embodiments, the injection distance may be a first injection distance. Once the injection is initiated, the user may then move the injection assembly 2100 and thus the actuator 2320 a second injection distance proximally relative to the medicament containment chamber 2310. In this manner, the remaining medicament may be delivered to the target layer of the eye.

Figure 17 shows a schematic flow diagram of a method 200 for delivering a drug to the target layer of a target tissue (or at a predetermined distance within the target tissue) using a medical injector that includes an injection assembly. The method 200 20 includes inserting a distal tip of a needle of a medical injector (e.g., system 100, 1000, 2000, or any other system described herein) a first distance into a target tissue, at 202. The needle may include any suitable needle, e.g., needle 140 or any other needle described herein. The injector

<img file="MX372859B_D0083.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY medical includes a medication container (for example, medication container 130, 1310, 2310, or any other medication container described herein) and an injection assembly (for example, injection assembly 111, 2100, or any other injection assembly described herein). The medication container is in fluid communication with the needle. The injection assembly includes an actuating rod (e.g., actuating rod 120, actuator 2320, or any other actuator described herein) and an energy storage member (e.g., energy storage member 146, 2146, or any other energy storage member described herein). The energy storage member is configured to produce a force at a portion of the proximal end of the drive rod.

Method 200 further includes releasing the drive rod from the injection assembly by allowing a portion of the distal end of the drive rod 20 to move within the medicament container in response to the force, at 204. For example, a portion of the proximal end of the drive rod may be secured or otherwise engaged by a release member, for example, a ratchet (e.g., ratchet 2130) or any other release member described herein.

<img file="MX372859B_D0084.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

The release member may, for example, be moved from a first position in which the drive rod is secured to a second position in which the drive rod is released. As described herein, in certain situations, the force will be insufficient to overcome viscous forces, tissue back pressure, friction losses, or the like within the fluid delivery path defined by the drug container, the needle, and the target tissue when the needle is within the first distance of the tissue. Thus, the actuating rod may not move, or may move less than a threshold injection distance.

Accordingly, the distal tip of the needle included in the medical injector may be inserted, upon release of a second distance greater than the first distance into the target tissue (e.g., ocular tissue of an eye) if the distal end portion of the drive rod moves less than a threshold injection distance within the drug container in response to the force, at 206. The injection distance may be the distance the distal end portion of the actuating rod moves within the drug container after release. In some embodiments, the injection distance is less than about 1 cm.

<img file="MX372859B_D0085.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY in this way, the lack of movement and/or the limited movement of the drive rod in operation 204 provides an indication to the user that further movement and/or repositioning of the needle tip is desirable. Conversely, when the distal end portion of the drive rod moves through the injection distance within the drug container, the user is aware that the needle tip is in a suitable region of the target tissue.

In some embodiments, the distal end portion of the drive rod may move a first injection distance within the drug container in response to force, for example, to deliver a portion of the drug to the target tissue, e.g., the SCS. In such embodiments, the method 200 may further include moving the injection assembly relative to the medicament container to move the distal end portion of the drive rod a second injection distance greater than the first injection distance within the medicament container 208. For example, the force may move the drive rod to the first injection distance once the distal tip of the needle is disposed within or near a desired region of the target tissue. This may indicate to a user that the distal tip of the needle is disposed within or

<img file="MX372859B_D0086.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY near a desired region of the target tissue. The actuator rod can then be moved proximally relative to the drug container such that the actuator rod moves the second injection distance within the drug container. In some embodiments, the distal end portion of the drive rod may be moved the second injection distance manually by a user, for example, by moving the housing proximally to the medication container. In other embodiments, the medical injector may include an automated delivery mechanism (e.g., a mechanical actuator, a pump, or any other suitable automated delivery mechanism) configured to move the drive rod to the second injection distance and deliver substantially all of the medicament to the target tissue.

In some embodiments, the target tissue may be an eye. In such embodiments, inserting the distal tip of the medical injector needle the second distance 20 into the eye includes inserting at least a portion of the distal tip into a suprachoroidal space of the eye. In some embodiments, inserting the distal tip of the medical injector needle the second distance includes contacting a surface of the eye with a hub coupled to the needle. The cube may include the 7270, 8270, 9270 or cube

<img file="MX372859B_D0087.tif" />

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY any other cube described herein in additional detail below.

Figure 18 shows a schematic flow diagram of a method 300 for delivering a medicament 5 to the target layer of a target tissue or a predetermined distance within the target tissue using a medical injector including an injection assembly. The method 300 includes inserting a distal tip of a needle of a medical injector (e.g., the medical injector 100, 1000, 2000, or any other medical injector described herein), into a medicament contained within a medicament vial 302. The medicament vial may be any suitable commercially available medicament vial, bottle, container, or any other container that houses a medicament. The medicament may include any suitable medicament (e.g., VEGF, a VEGF inhibitor, a combination thereof, or any other medicament described herein) formulated to be delivered to a target tissue (e.g., the SOS of the eye). The medical injector includes a medicament container and an injection assembly, and is in fluid communication with the needle. The injection assembly includes an actuating rod, an energy storage member, a release member, and an actuating member. In some embodiments, the injection assembly and the

<img file="MX372859B_D0088.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY components of the injection assembly described herein may be substantially similar to the components of the injection assembly 111, 2100, or any other injection assembly described herein. The energy storage member 5 (e.g., a spring, a compressed gas container, or a container containing a propellant) is configured to produce a force on a proximal end portion of the drive rod 10. The proximal end portion of the drive rod 10 may be engaged and secured by the release member. For example, the lock may block movement of the drive rod relative to a housing within which the drive rod, the injection assembly, and/or at least a portion of the medicament container is disposed. In other words, securing the proximal end portion of the drive rod by the release member prevents a distal end portion of the drive rod from moving relative to the housing. Furthermore, any movement of the housing relative to the medication container also urges the distal end portion of the drive rod to move within the medication container.

The method then includes moving the distal end portion of the drive rod distally with

<img file="MX372859B_D0089.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY relative to the medication container to extract a volume of the medication into the medication container, at 304. The medication container then moves proximally relative to the drive rod to 5 expel a volume of the medication from the distal tip of the needle and leave a dose volume of the medication remaining in the medication container, at 306. In other words, any excess medication drawn into the medication container may be expelled from the medication container 10 by moving the medication container proximally relative to the drive rod.

The distal tip of the needle is then inserted a first distance into a target tissue, e.g., ocular tissue, at 308. The drive member is activated (e.g., by a user) to disengage the release member from the drive rod, thereby releasing the proximal end portion of the drive rod. This allows the distal end portion of the drive rod 20 to move a first injection distance within the drug container in response to the force produced by the energy storage member, at 310. As described herein, the drive rod will move the first injection distance (or a greater amount) 25 when the needle tip is disposed within a

<img file="MX372859B_D0090.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY desired region of the target tissue. Conversely, when the needle tip is not disposed within a desired region of the target tissue, the force produced by the energy storage member is insufficient to move the drive rod through the first injection distance.

The method 300 then includes determining whether the drive rod has moved a threshold injection distance, at 312, for example, the first injection distance. For example, a user may visually observe whether the distal end portion of the drive rod has moved within the medicament container or not (e.g., through a transparent housing of the medical injector). If the drive rod does not move, the distal tip of the medical injector needle is inserted, after release, a second distance greater than the first distance into the target tissue, at 314. In this manner, the user may reposition the needle tip (e.g., by further insertion 20, or removal from the tissue) in response to the indication produced by the drive rod.

For example, the first distance may correspond to a sclera of the eye, which has a back pressure that, together with friction losses, viscosity losses and the like through the path of

<img file="MX372859B_D0091.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY fluid flow cannot be overcome by the force of the energy storage member. Thus, the drive member moves the first injection distance to deliver at least a portion of the drug into the sclera. The distal tip of the needle is then moved the second distance, which may correspond to a target region of the target tissue, for example, the SCS. The method then returns to step 312 to determine whether the drive rod has moved the first injection distance. If the drive rod has moved the first injection distance, this confirms that the distal tip of the needle is disposed in the desired target region. For example, the target region may be the SCS, which has a lower back pressure than that produced by the sclera.

The force exerted by the energy storage member can be configured to overcome this back pressure such that the distal end portion of the drive rod can be moved the first injection distance and deliver at least a portion of the medicament into the target tissue via the distal tip of the needle. In some embodiments, the force can be between about 2 N to about 6 N. Finally, the distal end portion of the drive rod is moved a second injection distance until

<img file="MX372859B_D0092.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY substantially all of the drug is expelled from the drug container into the target tissue (e.g., the SCS) at 316, through the distal tip of the needle. For example, the user may manually move the distal end portion of the drive rod, or use any suitable drive mechanism included in the medical injector to move the distal end portion of the actuator the second injection distance.

In some embodiments, a medical injector may include a needle assembly configured to adjust the length of a needle, e.g., to adjust a distance the needle penetrates into a target tissue, e.g., ocular tissue. Figures 19 and 20 are schematic illustrations of a medical injector 400 in a first configuration and a second configuration, in accordance with one embodiment. The medical injector 400 includes a housing 410, an actuator rod 420, a medication container 430, a needle 440, and an adjustment member 423. Optionally, the medical injector 400 may also include a hub 470 coupled to the housing 410. The housing 410 is configured to receive a portion of the medication container 430. Housing 410 may include any suitable housing, for example, housing 3210, or any other housing described herein with respect to a needle assembly.

<img file="MX372859B_D0093.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Needle 440 may be any suitable puncture member configured to puncture a target tissue. For example, needle 440 may be a microneedle configured to puncture ocular tissue. In some embodiments, needle 440 may be a 32 gauge microneedle or a 34 gauge microneedle. In some embodiments, such microneedle may be substantially similar to or the same as the microneedles described in the PCT '009 application incorporated by reference above. In some embodiments, the shape and/or size of needle 440 may correspond, at least partially, to at least a portion of a target tissue. For example, in some embodiments, the length of the needle 440 may correspond to a thickness of a portion of ocular tissue such that when the needle 440 is inserted into the ocular tissue, at least a portion of the needle 440 is disposed within the sclera or suprachoroidal space of the eye, as described in further detail herein. Needle 440 defines a lumen 441 extending through a proximal end portion 443 and a distal end portion 442 of needle 440. Distal end portion 442 of needle 440 may include a beveled or sharpened tip configured to pierce a target tissue. At least a portion of the proximal end portion of needle 440 may be disposed in a passageway defined by hub 470, as described herein.

<img file="MX372859B_D0094.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

The medicament container 430 of the medical injector 400 has a proximal end portion 432 and a distal end portion 434. The medicament container 430 defines an internal volume 436 that can store, accommodate, and/or otherwise contain a substance (e.g., a medicament, a prophylactic agent, a therapeutic agent, and/or a diagnostic agent). For example, in some embodiments, a cartridge or the like containing a drug formulation may be disposed within the internal volume 436 of the drug container 430. In other embodiments, a drug formulation may be disposed directly within the internal volume 436 (e.g., without a cartridge or other intermediate reservoir). In some embodiments, the internal volume 436 may contain a drug formulation with a volume of approximately

0.5 mL or less. In other embodiments, internal volume 436 may contain a drug formulation with a volume of about 0.1 mL. In still other embodiments, internal volume 436 may contain a drug formulation with a volume greater than about 0.5 mL. In some embodiments, drug container 430 may be substantially similar to drug container 1310, 2310, 3310, or any other drug container described herein.

The proximal end portion 432 of the container

<img file="MX372859B_D0095.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY of medicine 430 is substantially open to receive the actuating rod 420. More specifically, a distal end portion 424 of the drive rod 420 is disposed within the internal volume 436 and is movable between a first position (e.g., a proximal position) and a second position (e.g., a distal position). In other words, the distal end portion 424 of the drive rod 420 is movable an injection distance within the internal volume 426. A sealing member such as, for example, a plunger may be coupled to the distal end portion 424 of the actuating rod 420. The sealing member may be configured to form a friction fit with one or more surfaces of the medicament container 430 defining the internal volume 436. In this manner, the seal member and the drug container 430 may form a fluidic seal that substantially isolates a portion of the internal volume 436 that is distal to the seal member from a portion of the internal volume 436 that is proximal to the seal member. In other words, the drug container 430 and the actuator rod 420 form at least a portion of a syringe.

In some embodiments, the distal end portion 434 of the medication container 430 is physically and fluidly coupled to the hub 470. For example, in

<img file="MX372859B_D0096.tif" />

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In some embodiments, the hub 470 and the distal end portion 434 of the drug container 430 may form a snap fit, a press fit, a threaded coupling, and/or the like. In other embodiments, the hub 470 may be formed monolithically with the drug container 430. The hub 470 may define a passage configured to receive the needle 440 therethrough such that the distal end portion 442 of the needle extends past a distal end surface of the hub 470 by a distance, for example, a first distance d (see e.g., Figure 19) which may change to, for example, a second distance d2 (see e.g., Figure 20) or any other distance, when the needle moves through a plurality of discrete increments along the longitudinal axis of the housing 410, as described herein. In some embodiments, the hub 470 may also be configured to limit movement of the adjustment member 422 within the housing 410.

A proximal end portion of the fitting member 423 is configured to be coupled to the medicament container 430. The coupling may be accomplished using any suitable coupling mechanism, for example, a Luer lock, threads, push fit, friction fit, or any other suitable coupling mechanism. A distal end portion of the fitting member 423 is configured to be coupled to the medicament container 430. The coupling may be accomplished using any suitable coupling mechanism, for example, a Luer lock, threads, push fit, friction fit, or any other suitable coupling mechanism.

<img file="MX372859B_D0097.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY adjustment 423 is coupled to the needle 440, for example, to the proximal end portion 443 of the needle 440. In some embodiments, the adjustment member 423 may define a lumen configured to place the drug container 430 in fluid communication with the needle 440. In some embodiments, the proximal end portion of the adjustment member 423 may also include a flange configured to be removably coupled to the medicament container 430. The adjustment member 420 is configured to transition between a first configuration (Figure 19) and a second configuration (Figure 20) to adjust the distance that the distal end portion 442 of the needle 440 extends past the distal end surface of the hub 470. For example, the adjustment member 423 may be movably disposed within the housing 410 such that when the adjustment member 423 is rotated relative to the housing 410, the needle 440 moves through a plurality of discrete increments along a longitudinal axis of the housing 410. In this manner, the adjustment member 423 may adjust the effective length of the needle.

440 in the plurality of discrete increments. In other words, the adjustment member 423 may allow digital adjustment of the length of the needle 440. Although not shown, in some embodiments, the adjustment member 423 and/or the housing 410 may include a plurality of detents.

<img file="MX372859B_D0098.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY retainers may be configured such that each increment from the plurality of discrete increments is associated with a corresponding retainer from the plurality of retainers defined by at least one of the adjustment member 423 and/or the housing 410. For example, housing 410 may include a projection configured to be removably disposed within each of the plurality of detents when adjustment member 423 is rotated relative to housing 410 to move the needle.

440 through the plurality of discrete increments. As another example, in some embodiments, a bearing may be coupled within housing 410 and configured to be removably disposed within each of the plurality of detents when adjustment member 422 is rotated within housing 410 to move the needle through the plurality of discrete increments. In such embodiments, a biasing member may also be provided in the housing 410 and configured to retain the bearing within one of the plurality of retainers. In some embodiments, the medical injector 400 may also include a locking member, e.g., a lock, a latch, a tab, a rod, or any other suitable locking member removably coupled to the housing 410. The locking member may be configured to engage the adjustment member 423 to

<img file="MX372859B_D0099.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

102 limiting movement of adjustment member 423 relative to housing 410. In some embodiments, at least a portion of adjustment member 423 may include an indicating portion, e.g., a portion including a plurality of indicia. The indicia may be configured to indicate a distance that needle 440 extends beyond housing 410 (e.g., extends beyond a distal end surface of hub 470). In such embodiments, the housing 410 may define a window such that the indication portion is visible through the window. For example, a user may view the indication portion through the window to determine the distance the needle 440 extends beyond the housing 410 and estimate an insertion depth of the distal end 442 of the needle 440 into a target tissue.

As shown in Figure 19, in the first configuration of the adjustment member 423, the distal end portion 442 of the needle 440 may be spaced apart 20 from a distal end surface of the hub 470 by a first distance di. The adjustment member 423 may then be moved in a second configuration by moving (e.g., rotating, translating, or rotating and translating) the adjustment member 423 within the housing 410. This 25 drives the needle 440 to move in a discrete increment

<img file="MX372859B_D0100.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

103 so that the distal end portion 442 of the needle 440 extends a second distance dg, greater than di, beyond the distal end surface of the hub 470, as shown in Figure 20. In this way, a length of the needle 440 extending beyond the distal edge surface of the hub 470 can be adjusted.

In use, an operator (e.g., a doctor, technician, nurse, specialist, ophthalmologist, etc.) may manipulate the delivery device 400 to insert the needle 440 into, for example, ocular tissue. In this manner, the distal end portion 442 of the needle 440 may be advanced into the target tissue to pierce the sclera and place the hub 470 in contact with an external surface of the sclera. However, with the adjustment member 422 in the first configuration, the first distance di between the distal end surface of the hub 470 and the distal end portion 442 of the needle 440 may substantially correspond to the thickness of the sclera. In this manner, a distal tip of the needle 440 may be disposed within the sclera (e.g., the sclera 20 of the eye 10 in FIG. 1 ).

The adjustment member 423 may be transitioned from the first configuration to the second configuration by moving, translating, or rotating the adjustment member 423 within the housing 41. In some embodiments, the adjustment member 423 may be moved from the first configuration to the second configuration.

<img file="MX372859B_D0101.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY Movement of the adjustment member 423 can be performed by moving (e.g., rotating) the medication container 430 relative to the housing 410. This can increase the distance between the distal end surface of the hub

470 and the distal end portion 423 of the needle 440 from the first distance di to the second distance da (as described above). In this manner, when the adjustment member 422 is in the second configuration, the distal tip of the needle 440 may be further moved proximally relative to the ocular tissue to place the lumen 441 of the needle 440 in fluid communication with the suprachoroidal space (e.g., the suprachoroidal space 36 of eye 10 in Figure 1). With the lumen 441 of the needle 440 in fluid communication with the suprachoroidal space, the drive rod 420 can be moved relative to the drug container 430 from its first position to its second position. With the distal end portion 424 of the drive rod 420 forming a substantially fluidic seal (i.e., a substantially airtight seal) with an internal surface of the drug container 430, movement of the drive rod 420 to its second position to expel the drug formulation (contained within the internal volume of the drug container 430) through the lumen 441 of the needle 440.

In this way, the medical injector 400 can deliver the

<img file="MX372859B_D0102.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY drug formulation to the SCS of the eye and the drug formulation can flow within the suprachoroidal space to be delivered to, for example, the posterior region of the eye.

By adjusting the distance between the distal edge surface of the hub 470 and the distal end portion 442 of the needle 440 in discrete increments using the adjustment member 423, the distal end portion 442 of the needle 440 can be positioned within the SCS with more accuracy and precision than could otherwise be achieved with a fixed distance therebetween. For example, in some cases, the adjustment member 423 may be arranged so that the first distance di between the distal end surface of the hub 470 and the distal end portion 442 of the needle 440 is less than the thickness of the sclera. In this way, the adjustment member 423 can be moved to the second configuration to increase the distance between the distal edge surface of the hub 470 and the distal end portion 442 of the needle 440 (e.g., to the second distance d).₂) which is greater than the thickness of the sclera, thereby placing the distal end portion 442 of the needle 440 in contact with the SCS. However, the second distance d₂ may be less than a combined thickness of the sclera and SCS such that when the adjustment member 423 is moved to the second configuration, the distal end portion 442 of the needle 440 does not pierce the choroid.

<img file="MX372859B_D0103.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

106 (for example, choroid 28 of eye 10 in Figure 1).

The arrangement of the adjustment member 423, the needle 440, and the hub 470 allows control of the effective length of the needle 440. Accordingly, the medical injector 400 may be used for procedures involving different portions of a target tissue (e.g., the eye) having different thicknesses. However, control over the effective length of the needle 440, as described herein, allows the medical injector 400 to be used in a variety of patients having a range of anatomical differences (e.g., the device may be used in adult applications and pediatric applications).

The transition of the adjustment member 423 (and any of the needle assemblies described herein) between the first configuration and the second configuration may be performed at any suitable time before and/or during a procedure. For example, in some embodiments, the adjustment member 423 may be transitioned to the second configuration to establish and/or adjust the effective length of the needle 440 prior to insertion of the needle 440 into the target tissue. The desired effective length of the needle 440 in such embodiments may be based on the known thickness of the sclera based on pre-operative measurements or the like. In other embodiments, however, the adjustment member 422 may be

<img file="MX372859B_D0104.tif" />

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107 transitioned to the second configuration after the needle 440 has been inserted into the target tissue. In this manner, the adjustment member 422 may provide the operator with a mechanism for adjusting the effective length of the needle 440 in discrete increments during the procedure (e.g., based on tactile feedback, optical feedback, or the like).

The medical injector 400 is shown in Figures 19-20 by way of example to provide context for the discussion of the method. Thus, for simplicity, only portions of a medical injector are shown in accordance with specific embodiments. It should be understood that any of the embodiments described herein may be arranged in a similar arrangement as described above with reference to Figures 19-20. However, while the . Delivery device 400 is shown and described with reference to Figures 19-20. Because of its particular arrangement, the embodiments described herein may be used with any suitable delivery mechanism or device.

In some embodiments, a system for injecting a medicament into ocular tissue may include a needle assembly configured to perform any of the functions described herein. In other embodiments, a needle assembly may be configured to adjust the

<img file="MX372859B_D0105.tif" />

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108 needle insertion length and/or depth. Referring now to Figures 21-33, a system 3000 may include at least a housing 3110, a drug containment chamber 3310, an actuator 3320, and a needle assembly 3200. The needle assembly 3200 may be configured to accommodate a length of a piercing member 3240 (also referred to as a delivery member and/or a needle) included in the needle assembly 3200, as described herein. The system 3000 may be configured to deliver a medicament to a layer or region of a patient's eye, e.g., to the SCS of the eye.

The housing 3110 may include any of the housings described herein and is configured to receive at least a portion of the drug containment chamber 3310. In some embodiments, the housing 3110 may be substantially similar to the housing 1110 described with respect to the system 1000. In such embodiments, the housing 3110 may be configured for manual manipulation of the actuator 3320 to inject the drug. In some embodiments, an injector assembly may be disposed in housing 3110. The injector assembly may be substantially similar to injector assembly 2100 or any other injector assembly described herein, and is therefore not described in further detail herein.

<img file="MX372859B_D0106.tif" />

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109

The drug containment chamber 3310 defines an internal volume 3316 configured to house a drug (e.g., a VEGF, a VEGF inhibitor, triamcinolone acetonide, any other drug described herein, or a combination thereof). The drug containment chamber 3310 includes a coupling portion disposed within the internal volume defined by the housing 3110. The drug containment chamber 3310 also includes a delivery portion disposed outwardly of the internal volume defined by the housing 3110 and coupled to the needle assembly 3200. The drug containment chamber 3310 may be substantially similar to the drug containment chamber 1310, 2310 or any other drug containment chamber described herein, and therefore is not described in further detail herein.

The actuator 3320 includes a coupling portion and a plunger portion. The plunger portion is slidably disposed within the internal volume 3316 defined by the drug-containing chamber 3310 and is configured to draw the drug into or expel the drug from the internal volume 3316 defined by the drug-containing chamber 3310. Actuator 3320 may be substantially similar to actuator 1320, 2320 or any other actuator described herein, and

<img file="MX372859B_D0107.tif" />

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110 Therefore, it is not described in further detail herein.

As shown in Figure 22, the needle assembly 3200 includes a housing 3210, a bearing (or locking ball 5) 3220, an adjustment member 3230, a piercing member 3240, a lead screw 3242, a bushing 3250, a locking pin 3260, and a hub 3270. The needle assembly 3200 is configured to allow linear translation of the piercing member 3240 in fixed and/or discrete increments to allow a user to insert the piercing member to a desired depth within the eye, e.g., insertion to the depth of the SCS.

The housing 3210 (Figures 23A-C, Figures 32 and 33) includes a proximal portion 3211 and a distal portion 3212. The housing 3210 may be substantially cylindrical in shape and tapered toward the distal portion 3212. The housing 3210 defines an internal volume 3213 within which the bearing 3220, the adjusting bore 3230, at least a portion of the drilling member 3240, the lead screw 3242, the bushing 3250, and at least a portion of the locking pin 3260 may be disposed. The internal volume 3213 defines a substantially circular cross-section to allow one or more components, for example, the adjustment member 3230 and/or the lead screw 3242 to rotate approximately a longitudinal axis A._L of the 3000 system

<img file="MX372859B_D0108.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY within internal volume 3213. A supply portion of drug containment chamber 3310 may also be disposed in internal volume 3213. Distal portion 3212 of housing 3210 is configured to receive a proximal end 3272 of hub 3270 (see Figures 31A-31C) or any other hub described herein. Coupling features may be included on the distal portion 3212 to removably or fixedly engage the proximal end 3272 of the hub 3270. Suitable coupling features may include, for example, a friction fit mechanism, threads, a Luer assembly, adhesive, locking, latch, gaps, grooves, detents, a snap fit mechanism, or any other suitable coupling mechanism. A multiplicity of ridges 3214 are disposed on an outer surface of housing 3210. Ridges 3214 may be configured to allow a user to evenly grip housing 3210, for example, when injecting a medication into the eye. A window 3216 is defined in housing 3210. The window

3216 is configured to align with an intermediate portion 3233 of the adjustment member 3230, such that the user can see a series of marks 3236 defined on an external surface of the intermediate portion 3233. The marks 3236 may indicate a length of the piercing member.

3240 protruding from a distal end! 3274 of the

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY hub 3270, which may correspond to an insertion depth of piercing member 3240 (e.g., a distance that a distal tip of piercing member 3240 pierces into ocular tissue). A cavity 3218 is defined in housing 3210. Cavity 3218 is configured to receive bearing 3220, a biasing member 3221, and a plunger 3222, as described in further detail herein. A plurality of through holes 3219 are defined in the side wall of the housing 3210. The locking pin 3260 is inserted through the through holes 3219 such that the locking pin passes through the internal volume 3213 defined by the housing 3210, and at least a portion of the locking pin 3260 is disposed within the internal volume 3213.

The bearing (or locking ball) 3220 is disposed in the cavity 3218 of the housing 3210. The bearing may be any suitable bearing, for example, a metal, plastic or wooden bearing, a contoured cylindrical member, or any other suitable bearing. A first end of the biasing member 3221 is coupled and/or engaged with the bearing 3220, and a second end of the biasing member 3221 is coupled to the plunger 3222. The biasing member 3221 may include a spring, e.g., helical, compression, extension, spring washers,

Belleville washers, tapered, any other type of

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY spring, or any other suitable biasing member. At least a portion of plunger 3222 (Figures 24A-B) is disposed within the cavity such that plunger 3222 secures biasing member 3221 and bearing 3220 within cavity 3218. Plunger 3222 may include a domed surface with rounded edges. In some embodiments, plunger 3222 may be fixedly coupled to cavity 3218, for example, by adhesives. In some embodiments, plunger 3222 may be removably coupled to cavity 3218 using a suitable coupling mechanism such as, for example, friction fit, threads, splines, grooves, detents, any other suitable coupling mechanism, or combination thereof. The plunger 3222 may be configured to exert a force on and/or maintain a position of the biasing member 3221 such that the biasing member 3221 exerts a force against the bearing 3220. The bearing (or locking ball) 3220 is configured to engage at least one of a plurality of detents 3235 disposed on a distal portion 3234 of the adjustment member 3230. The biasing member 3221 biases the bearing 3220 inward relative to the retainers 3235 such that the bearing 3220 prevents the adjusting member 3230 from rotating freely relative to the housing 3210 about the longitudinal axis A._L of the 3000 system. In this way, the bearing

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114

3220 allows for digital length adjustment of a length of the piercing member 3240, as described in further detail herein. In a similar manner, the engagement of the bearing 3220 in the retainers 3235 allows the rotational position of the adjustment member 3230 (and thus the effective length of the piercing member 3240) to be adjusted in discrete increments.

The adjustment member 3230 (Figures 25, Figures 26ΆB, Figure 33) includes a proximal portion 3232, an intermediate portion 3233, and a distal portion 3234. The proximal portion 3232 is configured to engage a delivery portion of the drug containment chamber 3310. The proximal portion 3232 may include coupling features, for example, Luer lock connectors, threads, grooves, notches, grooves, push-fit, friction-fit, locking, latching, any other suitable coupling features, or combinations thereof. In this manner, the distal end portion of the drug-containing chamber 3310 may be coupled to the adjustment member 3230. In some embodiments, the delivery portion of the drug containment chamber 3310 may be fixedly coupled to the proximal portion 3232, for example, by an adhesive. In other embodiments, the delivery portion of the drug containment chamber 3310 may be fixedly coupled to the proximal portion 3232, for example, by an adhesive.

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115 removable to the proximal portion 3232, for example, to allow the user to reposition the drug containment chamber 3310 to reuse the needle assembly 3200. In some embodiments, a locking feature 5 (not shown), for example, a lock, a latch, or a friction fit, may be included in the proximal portion 3232. The locking feature may be configured to prevent disengagement of the delivery portion of the medicament containment chamber 3310 from the proximal portion 3232 of the adjustment member 3230 due to a rotation of the medicament containment chamber 3310 (e.g., due to a rotation of the housing 3310 by the user). For example, a user may rotate the housing 3310 about the longitudinal axis A._L of the system 3000 15 driving the drug containment chamber 3310 and thus the adjustment member 3230 to also rotate around the longitudinal axis A_L. In this manner, the adjustment member 3230 may be configured to vary the length of the piercing member 3240 protruding through the distal end 3274 of the hub 3270. As described in further detail herein.

The intermediate portion 3233 of the adjustment member 3230 includes marks 3236 corresponding to the length of the piercing member 3240 protruding through the distal end 3274 of the hub 3270. The intermediate portion 3233 is

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY aligned with the window 3216 included in the housing 3210 so that the user can see the marks 3236 through the window 3216 and determine the protruding length of the piercing member 3240. This may, for example, indicate the insertion depth of the piercing member 3240 into the eye. In some embodiments, the indicia 3236 may indicate a length in the range of about 850 microns, 950 microns, 1050 microns, 1150 microns, or about 1250 microns. In such embodiments, the length range may be about 100 microns.

The intermediate portion 3233 also includes a fluidic channel 3238 defined therethrough. The fluidic channel 3238 may be in fluidic communication with the internal volume 3316 of the drug containment chamber 3310.

The distal portion 3234 is fixedly coupled to a proximal portion 3244 of the lead screw 3242. For example, the proximal portion 3244 of the lead screw 3242 may be welded, bonded, adhered, screwed, riveted, or fixedly mounted using any other coupling mechanism to the distal portion 3234 of the adjustment member 3230. In this manner, a rotation of the adjustment member 3230 may also rotate the lead screw 3242, about the longitudinal axis A1 of the system 3000. The series of detents 3235 are defined on the outer surface of the distal portion 3234 and are configured to be engaged by the

117 bearing 3220, as described herein. Although the lead screw 3242 and the adjustment member 3230 are shown and described as being separate components, they are joined together. In other embodiments, the lead screw 3242 and the adjustment member 3230 may be formed monolithically.

The lead screw 3242. (Figures 22

25, 27A-B

33) includes proximal portion 3244 and a distal portion 3246. Proximal portion 3244 is fixedly coupled to distal portion 3234 of adjustment member 3230, as described herein. Distal portion 3246 is coupled to a proximal end of piercing member 3240 coupled thereto. The piercing member 3240 may be a needle (e.g., a 27 gauge, 30 gauge, or even smaller needles), or any other piercing member described herein. The piercing member 3240 defines a lumen 3241 (Figure 33) configured to fluidly communicate the medicament to a target tissue of the eye, e.g., the SCS. The piercing member 3240 is fixedly coupled to the lead screw 3242 by any suitable mechanism. In this way, a rotation of the adjustment member 3230 and lead screw 3242, around the longitudinal axis A_L, which causes a linear translation of the lead screw 3242 along the longitudinal axis A_L, also drives the member of

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY drilling 3240 to rotate around or translate along the longitudinal axis A1, respectively. The lead screw 3242 defines a lumen 3247 therethrough. The lumen 3247 is in fluid communication with the fluidic channel 3238 of the adjustment member 3230 and the lumen 3241 of the drilling member 3240. Thus, the fluidic channel 3238 of the adjustment member 3230, and the lumen 3247 of the lead screw 3242 provide a fluidic path for the medicament to be communicated between the internal volume 3316 of the medicament containment chamber 3310 and the lumen 3241 of the piercing member 3240, e.g., delivered to the target layer (e.g., the SCS) of the eye.

At least a portion of the outer surface of the lead screw 3242, e.g., the distal portion 3246, includes threads 3248. The threads 3248 are configured to mate with mating threads 3254 included in the bushing 3250. The bushing 3250 (Figures 22, 28A-C, Figure 33) is fixedly disposed within the internal volume 3213 defined by the housing 3210. The bushing 3250 defines a lumen 3252 configured to receive the distal portion 3246 of the lead screw 3242 such that the threads 3248 of the lead screw 3242 are mated with the mating threads 3254 disposed along the surface of the lumen 3252 of the bushing 3250. Because the

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119 bushing 3250 is fixedly arranged in housing 3210, a rotation of adjusting member 3230 and lead screw 3242 relative to housing 3210 around longitudinal axis A_L drives the lead screw 3242 to move linearly relative to the housing 3210 along the longitudinal axis A_L of the system 3000. Each rotation of the lead screw blade 3242 may correspond to a predetermined translation distance of the lead screw 3242 and thus, the drilling member 3240, along the longitudinal axis A_l of the system 3000. In this manner, the adjustment member 3230 may be rotated (e.g., by rotating the housing 3110) by rotating the lead screw 3230 and thereby advancing or retracting a predetermined length of the piercing member 3240 from the distal end 3274 of the hub 3270.

Locking pin 3260 (Figure 29) is coupled to a tab 3262. As shown in Figures 30A-C, tab 3262 includes a cavity 3264 configured to receive at least a portion of locking pin 3260. In some embodiments, tab 3262 may be removably coupled to locking pin 3260, for example, by threads, grooves, notches, grooves, detents, friction fit, or coupled using any other suitable coupling mechanism. In some

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In some embodiments, the tab 3262 may be fixedly attached to the locking pin 3260, for example, by adhesives. At least a portion of the tab 3262 may be substantially planar. However, the locking pin 3260 is shown to be substantially cylindrical. In other embodiments, the locking pin may define a circular, oval, square, rectangular, polygonal, or any other suitable cross-section. The locking pin 3260 is configured to be inserted through and/or into the through holes 3219 of the housing 3210, such that at least a portion of the locking pin 3260 is disposed in the internal volume 3213 defined by the housing 3210.

The locking pin 3260 is configured to be moved from a first configuration (or position) and a second configuration (or position), in the first configuration, the locking pin 3260 is inserted through the through holes 3219 and at least a portion of the locking pin 3260 is disposed in proximity to the intermediate portion 3233 of the adjustment member 3230. In the first configuration, the locking pin 3260 is configured to prevent rotation of the adjustment member 3230 relative to the housing 3210, and thus, the lead screw 3242. Thus, when the locking pin 3260 is in the first configuration, movement

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY of the piercing member 3240 along the longitudinal axis Al of the system 3000 distally relative to the drug containment chamber 3310, for example, due to rotation of the adjustment member 3260, is limited.

In a second configuration, the user can pull the tab 3262 and thus the locking pin 3260 out of the through holes 3219 and the internal volume 3213. Thus, in the second configuration the adjustment member 3230 can rotate freely relative to the housing 3210, and thus move linearly along the longitudinal axis.

TO_l, for example, to advance a length of piercing member 3240 from a distal end 3274 of hub 3270. In other words, locking pin 3260 may serve as a safety mechanism to prevent accidental activation of needle assembly 3200 and prevent advancement of piercing member 3260 out of distal end 3274 of hub 3270.

Hub 3270 includes a proximal portion 3272 and a distal portion 3274. Proximal portion 3272 is configured to be coupled to distal portion 3214 of the housing.

3210 (or any other housing defined herein) using any suitable coupling mechanism, for example, friction fit, threads, press fit, notches, grooves, grooves, detents, any other suitable coupling mechanism or combination thereof.

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122 τη i amos. The cube 3270 defines a lumen 327 6 through it.

At least a portion of the piercing member 3240 (or any other piercing member described herein) may be disposed in the lumen 3276, and may be configured to advance through the lumen 3276 out of the distal end 3274. The distal end 3274 of the hub 3270 is substantially planar, and is configured to contact an external surface of the conjunctiva of the eye. Although the cube 3270 is shown and described as having a flat distal end (or contact) surface, in some embodiments, a distal portion of a cube may define a substantially convex or curved surface, as described in further detail herein.

In operation, the needle assembly 3200 is configured to allow a user to adjust a length of the piercing member 3240 emerging from the distal end of the hub 3270. Figure 32 shows a perspective view of the needle assembly 3200 and Figure 33 shows a cross-section of the needle assembly 3200 taken along line 33-33. Although shown as including hub 3270, any other hub may be coupled to distal end 3212 of housing 3210, e.g., hub 7270, 8270, 9270, or any other hub described herein. Proximal portion 3232 of adjustment member 3230 may be coupled to delivery portion 3314 of the

<img file="MX372859B_D0119.tif" />

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Mexican Institute of Industrial Property drug containment chamber 3310. In a first configuration, a first length of piercing member 3240 may protrude from distal end 5274 of hub 5270, for example, approximately 850 microns. This information may be communicated to the user by indicia 3236 visible to the user through window 3216. At least a portion of the bearing 3220 is disposed in a first notch 3235 defined in the outer surface of the distal portion 3234 of the adjustment member 3230. The bearing 3220 is biased against the first notch 3235 by the biasing member 3221, and prevents any inadvertent rotation of the adjustment member 3270, thereby maintaining the position of the adjustment member 3230. In the first configuration, the piercing member 3240 15 may protrude a known distance from the distal end 3274 of the hub, for example a length of approximately 850 microns.

To allow actuation of needle assembly 3200, the user may remove locking pin 3260 by pulling on tab 3262 to remove locking pin 3260 from housing 3210. The user then positions distal end 3274 of hub 3270 against the outer surface of the conjunctiva of the eye, which results in the initial length of piercing member 3240 being inserted into the eye. In a similar manner stated, the user

<img file="MX372859B_D0120.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY may apply a distal force to the system 3000 such that a distal end of the piercing member 3240 pierces the conjunctiva and is disposed in a layer of ocular tissue beneath the conjunctiva, e.g., the sclera. The user may then determine, using any suitable technique, whether a distal end of the piercing member 3240 is within or otherwise near the target layer, e.g., the SCS of the eye. In some embodiments, the user may determine that the distal end of the piercing member 3240 is not in the target layer of the eye, e.g., the SCS. For example, in some embodiments, a relative thickness of the ocular tissue layers may be known to the user through prior visualization techniques. In other embodiments, the system 3000 may include an injection assembly, for example, injection assembly 111, 2100, or any other injection assembly described herein, which may be activated and thereby inform the user that the distal end of the piercing member 3240 is not in the target layer, as described hereinbefore. More particularly, because the injection assembly provides a force to assist in injection within a predetermined range, when the end of the piercing member 3240 has not reached the SCS, actuation of the injection assembly will not result in movement of the plunger within the SCS.

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125 drug containment chamber. In this way, the user will receive feedback that the piercing member 3240 is not in the target region (i.e., not seeing any plunger movement).

To move the needle assembly 3200 to a second configuration, the user may apply a first torque to rotate or otherwise turn the drug containment chamber 3310 such that the adjustment member 3230 rotates relative to the housing 3210 about the longitudinal axis A._L. The first torque may drive the bearing 3220 to slide out of the first notch 3235 such that the adjusting member 3230 is free to rotate by applying a second torque substantially smaller than the first torque. Rotation of the adjusting member 3230 drives the lead screw 3242 to also rotate in the bushing 3250. Since the bushing 3250 is fixedly disposed in the internal volume 3213 of the housing 3210, the lead screw 3242 translates linearly along the longitudinal axis Al. This drives the piercing member 3240 to also translate and advance deeper into the layers of the ocular tissue.

The adjustment member 3230 may be rotated until the bearing 3220 reaches a second notch 3235 of the series of grooves 3235. At least a portion of the bearing 3220 moves into the second notch 3235 and thereby prevents the

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Mexican Institute of Industrial Property further rotation of the adjustment member 3230 by the second torque. Each notch 3235 may correspond to a predetermined length of the piercing member 3240 protruding through the distal end 3274 of the hub 3270. For example, the second notch 3235 may correspond to a protruding length of the piercing member 3240 of approximately 950 microns. A third notch 3235 may correspond to a protruding length of the piercing member 3240 of approximately 1050 microns, and so on. Thus, in some embodiments, each notch 3235 may correspond to a difference in the protruding length of the piercing member 3240 of approximately 100 microns. Since, in the second configuration, the bearing 3220 is disposed in the second notch 3235, the adjusting member 3230 may no longer be rotated by applying the second torque. The user may now apply a third torque, greater than the second torque (e.g., substantially equal to the first torque) to further rotate the adjusting member 3230, thereby increasing the protrusion length or otherwise insertion depth of the piercing member 3240. In this manner, the needle assembly 3200 may serve as a digital length adjustment mechanism to allow the user to adjust a protrusion length or otherwise insertion depth of the piercing member 3240 in discrete increments.

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127 reliably and repeatedly. In addition, the different touches required for rotation of the adjustment member 3240 at different positions of the bearing 3220 relative to the grooves 3235 also provide tactile feedback to the user in adjusting the protruding length or otherwise insertion depth of the piercing member 3240.

In some embodiments, a device includes an adjustment member configured to move relative to a hub and/or a puncture member. However, although described above as being transitionable between a first configuration and a second configuration, in some embodiments, an adjustment member may be transitionable between any number of configurations and/or positions. For example, Figures 34^—36 are schematic illustrations of a portion of a delivery device in accordance with one embodiment. As shown in Figure 34, a hub 4270 is coupled to a puncture member 4240 and an adjustment member 4230. The hub 4270 has a proximal end portion 4271 and a distal end portion 4272. The proximal end portion 4271 may be physically and fluidically coupled to a fluid reservoir such as, for example, the housing 4230 of the delivery device 400, 100, 1000, 2000, 3000, or any other medical injector or delivery device described in the present invention.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY present). Although not shown in Figures 34-36, the proximal end portion 4271 of the hub 4270 may be coupled to a housing of a delivery device using any suitable coupling method such as, for example, a snap fit, a press fit, a threaded coupling, a Luer connection, a mechanical fastener, an adhesive, and/or the like. In other embodiments, the hub 4270 may be monolithically formed with a housing of a delivery device. For example, the hub 4270 may be included in and/or form the distal end portion of a housing (e.g., the drug containment chamber 1310, 2310, 331, or any other drug containment chamber described herein). In this way, an internal volume of the hub 4270 may be placed in fluid communication with a drug formulation contained within a fluid reservoir (e.g., a drug container or the like not shown in Figures 34-36).

As shown in Figure 34, the distal end portion 4272 of the hub 4270 includes a substantially elongated portion that includes a series of annular walls 4274. As described in further detail herein, the annular walls 4274 have an outer surface 4275 that includes and/or forms a series of threads 4277 that are configured to engage a portion of the member.

<img file="MX372859B_D0125.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY adjustment 4230. Annular walls 4274 define a lumen 4276 that extends through the distal end portion 4272 of the hub 4270. The lumen 4276 is configured to receive a portion of the puncture member 4240 to physically and fluidically couple the puncture member 4240 to the hub 4270.

The puncture member 4240 (also referred to herein as a microneedle) may be configured to pierce and/or penetrate a portion of the eye to deliver a drug formulation to, for example, the suprachoroidal space. In some embodiments, the puncture member 4240 may be a 32 gauge microneedle or a 34 gauge microneedle. The microneedle 4240 has a proximal end portion 4242 and a distal end portion 4244, and defines a lumen 4241. As shown in Figure 34, the proximal end portion 4242 is disposed within the lumen 4276 of the hub 4270. For example, in some embodiments, the hub 4270 may be over molded around the proximal end portion 4242 of the puncture member 4240. In other embodiments, the hub 4270 and the puncture member 4240 may be formed monolithically (e.g., the puncture member 4240 may be a microcatheter or the like that is unitarily formed with the hub 4270). Thus, with the hub 4270 physically and fluidically coupled to a fluid housing or reservoir (such as

<img file="MX372859B_D0126.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY described above), the lumen 4241 of the puncture member 4240 may be placed in fluid communication with a drug formulation contained herein.

As described above, the lumen 4241 of the puncture member 4240 extends through the proximal end portion 4242 and the distal end portion 4244. In this manner, the lumen 4241 may be placed in fluid communication with a substantially outward volume of the microneedle 4240. The distal end portion 4244 may be of any suitable shape, size, or configuration. For example, in some embodiments, the distal end portion 4244 may form a bevel or the like. In some embodiments, the distal end portion 4244 may be substantially similar to or the same as those described in the PCT '099 application incorporated by reference above. In this manner, the distal end portion 4244 of the puncture member 4240 may be configured to pierce ocular tissue while minimizing tissue deformation at the insertion site.

As shown, the microneedle 4240 extends from the distal end portion 4272 of the hub 4270 in the distal direction. In this manner, the microneedle 4240 may have an axis length H between a distal edge 4245 of the puncture member 4240 and a distal surface of the hub 4270. The axis length H may be any length.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY suitable. For example, in some embodiments, the length of the H axis may substantially correspond to at least a portion of the eye. In some embodiments, the length of the H axis may be such that when the microneedle 4240 is inserted into the eye, the distal end portion 4244 of the microneedle 4240 is disposed within the suprachoroidal space without piercing the choroid. By way of example, the H-axis length of the microneedle 4240 may be about 1000 pm or less, about 900 pm or less, about 850 pm or less, about 800 pm or less, about 750 pm or less, about 700 pm or less, about 650 pm or less, or about 600 pm or less. In some embodiments, the H-axis length of the microneedle 4240 may be about 750 pm. In other embodiments, the length of the microneedle shaft 4240 may be about 800 pm, or about 850 pm, or about 900 pm, or about 950 pm, or about 1 mm.

The adjustment member 4230 may be of any suitable shape, size or configuration and may be movably disposed about a portion of the hub 4270 and the puncture member 4240. The adjustment member 4230 has a proximal end portion 4231 and a distal end portion 4232 and defines an opening 4236 therethrough. However, the adjustment member 4230 includes a surface

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132 internal 4235 which includes and/or forms a series of threads 4237 that can mately engage the threads 4277 of the hub 4270 (described above). In this manner, the distal end portion 4272 of the hub 4270 may be movably disposed within a portion of the opening 4236. For example, with the distal end portion 4272 of the hub 4270 disposed within the portion of the opening 4236, the adjustment member 4230 may be rotated relative to the hub 4270 to advance the threads 4237 of the adjustment member 4230 along a length of the threads 4277 of the hub 4270.

D_and In this way, the adjustment member 4230 can be moved between a first position relative to the hub 4270 (e.g., a distal position, see e.g., Figures 34 and 35) and a second position relative to the hub 4270 (e.g., a proximal position, see e.g., Figure

36) . However, the adjustment member 4230 may be moved through any number of different positions relative to the hub 4270.

The arrangement of the hub 4270, the adjustment member 4230 and the puncture member 4240 is such that a portion of the puncture member 4240 is disposed within the opening 4236 defined by the adjustment member 4230 while the distal end portion 4244 of the puncture member 4240 extends beyond a distal surface 4234 of the adjustment member 4230. For example, as shown in FIG.

<img file="MX372859B_D0129.tif" />

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Figure 34, the distal end portion 4244 of the puncture member 4240 may extend a distance Di (also referred to as an effective length of the puncture member 310) from the distal surface 4234 of the adjustment member 4230. In a similar manner stated, the distal edge 4245 of the puncture member 4240 is spaced apart from the distal surface of the adjustment member 42.30 by the distance Di. Thus, when the adjustment member 4230 moves a given distance relative to the hub 4270, the effective length of the puncture member 4240 (i.e., the distance Di) is changed by a corresponding distance. By way of example, while the adjustment member 4230 is in the first position relative to the hub 4270 (e.g., the distal position), the distance Di may be, for example, 350 pm and when the adjustment member 4230 moves to the second position relative to the hub 4270 (e.g., the proximal position), the distance Di may be increased to, for example, 650 pm. In other embodiments, the distance Di may be increased to, for example, 500 pm.

550 pm, 6:00 pm, 7:00 pm, 7:50 pm, 8:00 pm, 8:50 pm, 9:00 pm, 9:50 pm, or any suitable fraction thereof.

As shown in Figures 35 and 36, in use, a user (e.g., a doctor, technician, nurse, specialist, ophthalmologist, etc.) may manipulate a delivery device (not shown) to insert the

<img file="MX372859B_D0130.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY puncture member 4240 into, for example, a portion of the eye 10. In this manner, the distal end portion 4244 of the puncture member 4240 may be advanced through a portion of the sclera 20 until the distal surface 4234 of the adjustment member 4230 is placed in contact with an external surface of the sclera 20. With the adjustment member 4230 in the first configuration, the distance Di (e.g., the first distance) between the distal surface 4234 of the adjustment member 4230 and the distal edge 4245 of the puncture member 4240 may substantially depend on and/or be associated with the thickness of the sclera 20. For example, in some embodiments, when the adjustment member 4230 is in the first configuration, the distance Di (Figure 34) between the adjustment member 4230 and the distal edge 4245 may be about 450 μη. In other embodiments, the distance Di when the adjustment member 4230 is in the first configuration may be about 350 μη, 400 μη, 500 μη, 550 μη, 600 μη, 650 μη, 700 μη, 750 μη, or any fraction therebetween. In still other embodiments, the distance Di when the adjustment member 4230 is in the first configuration may be less than 350 μη. In this manner, the distal edge 4245 of the puncture member 4240 may be disposed within the sclera 20, as shown in Figure 35, although it is shown in Figure 35 to be disposed completely within the sclera 20. In ...

<img file="MX372859B_D0131.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY modalities, at least a portion of the distal edge 4245 may be disposed within the suprachoroidal space 36.

The adjustment member 4230 may be moved from its first position relative to the hub 4270 to its second position relative to the hub 4270 to increase the distance Di (Figure 34) between the adjustment member 4230 and the distal edge 4245 of the puncture member 4240 from the first distance (Figure 35) to a second distance, as shown in Figure 36. For example, in some embodiments, a user may manipulate a gripping portion (e.g., a textured finish and/or a series of handles, grooves, detents, splines, etc.) of the adjustment member 4230 to rotate the adjustment member 4230 relative to the hub 4270, as indicated by arrow AA in Figure 36.

In this manner, the threads 4237 of the adjustment member 4230 are advanced along a length of the threads 4277 of the hub 4270. In this manner, the hub 4270 moves in a distal direction relative to the adjustment member 4230 such that the adjustment member 4230 is positioned at its second position relative to the hub 4270, as indicated by arrow BB in Figure 36. Movement of the adjustment member 4230 may be performed at any suitable time, i.e., either before or while the puncture member 4240 is disposed within the sclera 20.

In addition, expanding by rotating the adjustment member

<img file="MX372859B_D0132.tif" />

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4230 relative to the hub 4270 (as indicated by arrow ΑΆ), the adjustment member 4230 is placed in its second position relative to the hub 4270. Thus, with the adjustment member 4230 in the second position, the distance

Di (Figure 34) is increased between the distal surface 4234 of the adjustment member 4230 and the distal edge 4245 of the puncture member 4240 (e.g., at the second distance). In some embodiments, the distance Di may be increased to about 600 pm. In other embodiments, the distance Di may be increased to about 650 pm, 700 pm, 750 pm, 800 pm, 850 pm, 900 pm, 950 pm, 1000 pm, or any fraction therebetween; in still other embodiments, the distance Di may be increased to less than 600 pm (e.g., such as, for example, in use in pediatric eyes).

As shown in Figure 36, distal movement of hub 4270 may allow distal end portion 4244 of puncture member 4240 (e.g., in a distal direction) to be moved distally relative to sclera 20 to place lumen 4241 of puncture member 4240 in fluid communication with suprachoroidal space 36. With the lumen 4241 of the puncture member 4240 in fluid communication with the suprachoroidal space 36, a drug formulation (contained within a fluid reservoir that is in fluid communication with the lumen 4241, for example, as

<img file="MX372859B_D0133.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY described above with reference to the medical injector 400 of Figures 19-20) may be expelled through the lumen 4241 of the puncture member 4240 and into the suprachoroidal space 36 of the eye 10. In this manner, the drug formulation 5 may flow within the suprachoroidal space 36 to be delivered to, for example, the posterior region of the eye (e.g., the posterior region 14 of the eye 10 in Figure 1). However, with the adjustment member 4230 in the second configuration, the distance between the distal surface 4234 of the adjustment member 4230 and the distal edge 4245 of the puncture member 4240 (e.g., distance Di in Figure 34) may be less than a combined thickness of the sclera 20 and the suprachoroidal space 36 such that the distal end portion 4244 of the puncture member 4240 does not puncture the choroid 28.

In some embodiments, the relative position of the distal edge 4245 of the lancing member 4240 within the eye may be located (e.g., determined, performed, etc.) by any suitable method. For example, in some instances, the amount of force exerted to advance the distal edge 4245 of the lancing member 4240 through the sclera 20 may be greater than an amount of force exerted to advance the distal edge 4245 through the suprachoroidal space 36. Thus, the reduction in the amount of force that is exerted to advance the portion

<img file="MX372859B_D0134.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY of the distal end 4244 of the lancing member 4240 may indicate to a user the relative position of the distal edge 4245 of the lancing member 4240 in the eye. In some cases, imaging techniques (e.g., fluoroscopy, X-ray Computed Tomography (CT) scans, or the like) may be used to provide an indication of the relative position of the distal edge 4245 with respect to the anatomy of the target tissue.

Although not shown in Figures 34-36, in some embodiments, the hub 4270 and/or the adjustment member 4230 may provide an indicator associated with the distance Di between the adjustment member 4230 and the distal edge 4245 of the puncture member 4240. In some embodiments, the indicator may be a visual indicator such as a measuring scale or the like. For example, in some embodiments, the puncture member 4240 may include indicia (e.g., lines, marks, tick marks, etc.) representing a gradation of a length of the puncture member 4240 associated with the .0 distance Di between the distal surface 4234 of the adjustment member 4230 and the distal edge 4245 of the puncture member 4240. In some embodiments, the indicia may represent distances of 100 microns or less. In this way, a user can see the indications to determine, for example, a 2 5 change in distance D_x that could otherwise be

<img file="MX372859B_D0135.tif" />

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Mexican Institute of Industrial Property undetermined. In other embodiments, the adjustment member 4230 and/or the hub 4270 may produce an audible or haptic indicator such as, for example, a clicking sound or the like.

Although the adjustment member 4230 is described above with reference to Figures 34-36 as rotating approximately cube 4270 to change the distance (e.g., distance Di in Figure 34) between the distal surface 4234 of the adjustment member 4230 and the distal edge 4245 of the puncture member 4240. In other embodiments, an adjustment member may be transitioned relative to a cube in any suitable manner. For example, in some embodiments, an external surface of a hub may include a plurality of projections that can engage a plurality of detents defined by an internal surface of an adjustment member (or vice versa). In such embodiments, the adjustment member may be linearly movable relative to the hub such that the detents of the adjustment member sequentially engage the projections of the hub.

Figure 37 is a schematic illustration of a portion of a delivery device in accordance with one embodiment. As shown, a hub 5270 is coupled to a puncture member 5240 and an adjustment member 5230. The hub 5270 has a proximal end portion 5271 and a distal end portion 5272. The proximal end portion 5273 is coupled to a puncture member 5240 and an adjustment member 5230. The hub 5270 has a proximal end portion 5271 and a distal end portion 5272. The proximal end portion 5273 is coupled to a puncture member 5240 and an adjustment member 5230.

<img file="MX372859B_D0136.tif" />

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140 next 5271 may be physically and fluidically coupled to a fluid reservoir such as, for example, the medication container 430 of the medical injector 400 described above with reference to Figures 19-20, or any other medication container described herein.

Although not shown in Figure 37, the proximal end portion 5271 of the hub 5270 may be coupled to a housing (e.g., a drug container) of a delivery device using any suitable coupling method such as, for example, a snap fit, a press fit, a threaded coupling, a Luer connection, a mechanical fastener, an adhesive, and/or the like. In other embodiments, the hub 5270 may be formed monolithically with a housing of a delivery device. For example, the hub 5270 may be included in and/or form a distal end portion of a housing (e.g., the distal end portion 434 of the medicament container 430). In this way, an internal volume of the hub 5270 can be placed in fluid communication with a drug formulation contained within a fluid reservoir (e.g., a drug container), as described above with reference to the hub 4270 of Figures 34-36. As shown in Figure 37, the distal end portion 5272 of the hub 5270 can be a substantially elongated portion including

<img file="MX372859B_D0137.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY and/or is formed from a series of annular walls 5274. As described in further detail herein, the annular walls 5274 define a lumen 5276 that extends through the distal end portion 5272 of the hub 5270. The lumen 5276 is configured to receive a portion of the puncture member 5240 to physically and fluidically couple the puncture member 5240 to the hub 5270.

The puncture member 5240 (also referred to herein as a microneedle) may be configured to pierce or penetrate a portion of the eye to deliver a drug formulation to, for example, the suprachoroidal space. The microneedle 5240 has a proximal end portion 5242 and a distal end portion 5244, and defines a lumen 5241. As shown in Figure 37, the proximal end portion 5242 is disposed within the lumen 5276 of the hub 5270. For example, in some embodiments, the hub 5270 may be over-molded approximately to the proximal end portion 5242 of the puncture member 5240. In other embodiments, the hub 5270 and the puncture member 5240 may be formed monolithically (e.g., the puncture member 5240 may be a microcatheter or the like that is unitarily formed with the hub 5270). Thus, with the hub 5270 physically and fluidically coupled to a fluid housing or reservoir (as described above), the

<img file="MX372859B_D0138.tif" />

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142 lumen 5241 of the puncture member.5240 may be placed in fluid communication with a drug formulation contained herein.

As shown, the microneedle 5240 extends from the distal end portion 5272 of the hub 5270 in the distal direction. Thus, the microneedle 5240 may have an axis length H between a distal edge 5245 of the lancing member 5240 and a distal surface of the hub 5270. In this manner, the lancing member 5240 may be substantially similar to or the same as the lancing member 5240 described above with reference to Figures 34-46. Thus, portions of the puncture member 5240 are not described in further detail herein.

The adjustment member 5230 may be of any suitable shape, size or configuration and is transitional between a first configuration and a second configuration.

The adjustment member 5230 is coupled to the distal end portion 5272 of the hub 5270. For example, in some embodiments, the adjustment member 5230 may be coupled to the hub 5270 by a snap fit, a press fit, a threaded coupling, a mechanical fastener, an adhesive, and/or the like. In other embodiments, the adjustment member 5230 may be disposed around a portion of the puncture member 5240 such that a portion of the adjustment member 5230_andis not in contact with the portion of the

<img file="MX372859B_D0139.tif" />

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143 distal end 5272 of hub 5270 (e.g., adjacent not yet coupled to hub 5270). In this manner, hub 5270 and lancing member 5240 may be reusable (following sterilization) and may be temporarily coupled to a disposable adjustment member 5230. In some embodiments, adjustment member 5230 and hub 5270 may be formed monolithically. In some embodiments, the adjustment member 5230 may be over-molded around the distal end portion 5272 of the hub 5270. For example, in some embodiments, the hub 5270 may be formed from a relatively rigid material such as a metal or hard plastic and may act as a substrate around which the adjustment member 5230 is molded (e.g., from a relatively soft material such as an elastomeric, thermoplastic, rubber, silicone, or the like). As shown in Figure 37, when the adjustment member 5230 is in the first configuration, the adjustment member 5230 has a thickness of Ti. In some embodiments, the thickness Ti of the adjustment member 5230 may be, for example, about 25 pm, 50 pm, 100 pm, 400 pm, or any suitable fraction therebetween. In other embodiments, the adjustment member 523 may have a thickness Ti that is greater than 400 pm. In other embodiments, the total thickness Ti of the adjustment member 5230 may be less than about 25 25 pm.

<img file="MX372859B_D0140.tif" />

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The adjustment member 5230 is removably disposed around a portion of the puncture member 5240. More specifically, the puncture member 5240 may extend in the distal direction from the hub 5270 such that a portion of the puncture member 5240 extends through the adjustment member 5230. For example, as shown in Figure 37, the distal end portion 5244 of the puncture member 5240 may extend a distance (i.e., D) between the adjustment member 5230 and ...₂ or D3) from a distal surface 5234 of the adjustment member 5230. Similarly stated, the distal edge 5245 of the puncture member 5240 is spaced apart from the distal surface 5234 of the adjustment member 5230 by the distance D₂ (also referred to as an effective length of the puncture member 5240). As described above, the adjustment member 5240 may be transitioned between a first configuration and a second configuration. More specifically, the first configuration may be associated with the first thickness Ti of the adjustment member 5230 and the second configuration may be associated with a second thickness T₂. Thus, when the adjustment member 5230 moves from the first configuration to the second configuration (for example, from the first thickness Ti to the second thickness T₂), the effective length of the puncture member 5240 between the distal edge 5245 of the puncture member 5240 and the surface

<img file="MX372859B_D0141.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY distal 5234 of adjustment member 5230 is increased by a corresponding distance (for example, increased from the first distance Di, to a second distance D₂). Similarly stated, the nominal change in thickness from the first thickness Ti to the thickness T₂ substantially corresponds to (or is the same as) the nominal change in distance from the first distance D₂ at the second distance D₃. By way of example, while the adjustment member 5230 is in the first configuration, the first thickness Ti may be, for example, 250 pm and the first distance D₂ may be, for example, approximately 450 pm. When the adjustment member 5230 moves to the second setting, the second thickness T₂ of the adjustment member 5230 may be, for example, 100 pm and the second distance D₃ It may be, for example, approximately 600 pm.

In use, a user (e.g., a doctor, technician, nurse, specialist, ophthalmologist, etc.) may manipulate a delivery device (not shown) to insert the lancing member 5240 into, e.g., a portion of the eye (e.g., the eye 10 shown in Figure

1) . In this manner, the distal end portion 5244 of the puncture member 5240 may be advanced through a portion of the sclera until the distal surface 5234 of the adjustment member 5230 is placed in contact with an external surface of the sclera. With the adjustment member

<img file="MX372859B_D0142.tif" />

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5230 In the first configuration, the distance D₂ (e.g., the first distance) between the distal surface 5234 of the adjustment member 5230 and the distal edge 5245 of the puncture member 5240 may substantially depend on and/or may be associated with the thickness of the sclera. For example, in some embodiments, when the adjustment member 5230 is in the first configuration, the distance D₂ between the distal surface 5234 of the adjustment member 5230 and the distal edge 5245 may be approximately 550 pm. In other embodiments, the distance D₂ when the adjustment member 5230 is in the first configuration may be approximately 350 pm, 400 pm, 450 pm, 500 pm, 600 pm, 650 pm, 700 pm, 750 pm, 800 pm, 850 pm, 900 pm, 950 pm, 1000 pm, or any fraction thereof. In still other embodiments, the distance D₂ when the adjustment member 5230 is in the first configuration may be less than about 350 pm, in this way, a distal edge 5245 of the puncture member 5240 may be disposed within the sclera (for example, the sclera 20 of the eye 10 in Figure 1).

The adjustment member 5230 can be moved from its first configuration to its second configuration to increase the distance between the distal surface 5234 of the adjustment member 5230 and the distal edge 5245 of the puncture member 5240 from the first distance D₂ at the second distance D₃. For example, in some cases, a user may

<img file="MX372859B_D0143.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY exert a force (either directly or indirectly) on the hub 5270 to advance the lancing member 5240 relative to the eye. With the distal surface 5234 of the adjustment member 5230 in contact with an external surface of the sclera, the force exerted on the hub 5270 may be operable to compress the adjustment member 5230 from the first thickness Ti to the second thickness T₂. In this way, the adjustment member 5230 is placed in the second configuration and the distance between the distal surface 5234 of the adjustment member 5230 is increased from the first distance D₂ at the second distance D₃. For example, in some cases, the second distance D₃ It can be approximately 600 pm. In other modalities, the second distance D₃ may be approximately 650 pm, 700 pm, 750 pm, 800 pm, 850 pm, 900 pm, 950 pm, 1000 pm, or any fraction between these. In still other embodiments, the second distance D₃ may be increased to less than about 600 pm (e.g., such as in use in pediatric eyes).

As described above with reference to the

Figure 36, movement of the adjustment member 5230 to the second configuration may be such that further movement of the puncture member 5240 (e.g., in a distal direction) relative to the sclera positions the lumen

5241 of the puncture member 5240 in fluid communication with

<img file="MX372859B_D0144.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY the suprachoroidal space (e.g., the suprachoroidal space 36 of eye 10 in Figure 1). In a similarly stated manner, the increase in distance from the first distance D2 to the second distance D3 may be large enough to extend the distal edge 5245 of the puncture member 5240 through the sclera, such that the lumen 5241 is placed in fluid communication with the suprachoroidal space. With the lumen 5241 of the puncture member 5240 in fluid communication with the suprachoroidal space, a drug formulation (contained within a fluid reservoir as described above with reference to Figure 36) may be expelled through the lumen 5241 of the puncture member 5240 and into the suprachoroidal space of the eye. In this manner, the drug formulation 15 may flow within the suprachoroidal space to be delivered to, for example, the posterior region of the eye (e.g., the posterior region 14 of the eye 10 in Figure 1). However, with the adjustment member 5230 in the second configuration, the distance between the distal surface 5234 of the adjustment member 5230 and the distal edge 5245 of the puncture member 5230 (e.g., the second distance D)₃) may be less than a combined thickness of the sclera and suprachoroidal space such that the distal end portion 5244 of the puncture member 5240 does not puncture the choroid.

Also to adjust and/or control the length

<img file="MX372859B_D0145.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY effective puncture member 5240 to improve the likelihood that lumen 5241 is placed in fluid communication with the desired region of target tissue (e.g., the suprachoroidal space of the eye), in some 5 modalities, The adjustment member 5230 (and any of the adjustment members shown and described herein) can form a substantially fluid-tight seal and/or a substantially liquid-tight seal with the outer surface of the target tissue (e.g., the conjunctiva of the eye). In this way, leakage of the injected medicament along the needle path during the injection event can be reduced and/or eliminated. Expanding further, in some embodiments, the anatomy of the target tissue and/or the arrangement of the delivery device may be such that, in use, a portion of the lumen opening 5241 may be positioned in fluid communication with the suprachoroidal space 36 of the eye, while another portion of the lumen opening 5241 may be positioned within the sclera 20. Thus, when the drug formulation is delivered into the eye by the puncture member 5240, a portion of the drug formulation may be prone to migrate away from the desired region (e.g., the suprachoroidal space 36) and out of the eye via the needle path. Forming a substantially fluid-tight seal 25 and/or a substantially airtight seal

<img file="MX372859B_D0146.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY to the liquid, the adjustment member 5230 can produce an area of high flow resistance, thereby minimizing and/or eliminating flow migration and/or leakage.

Although the adjustment member 5230 is described above as being constructed from a relatively soft material, which may be well suited to forming a fluid-tight seal, in some embodiments, the adjustment member 5230 may be constructed from multiple materials. For example, in some embodiments, the distal end surface 5234 of the adjustment member 5230 may be constructed from and/or may include a layer or portion constructed from a material formulated to form a substantially fluid tight seal with the outer surface of the target tissue (e.g., the conjunctiva).

Although not shown in Figure 37, in some embodiments, the adjustment member 5230 and/or the puncture member 5240 may include a locking feature that can be configured to at least temporarily retain the adjustment member 5230 in the second configuration. For example, in some embodiments, the puncture member 5240 and/or hub 5270 may include one or more detents, grooves, protrusions, etc. which can coincidentally engage a portion of the adjustment member 5230 to retain the adjustment member 5230 in the second configuration. More specifically,

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In some embodiments, the adjustment member 5230 may include a series of projections (not shown) extending from the adjustment member toward the puncture member 5240. In such embodiments, the adjustment member 5230 may be moved to the second configuration to decrease the thickness of the adjustment member (as described above). In this manner, the projections may move along a surface of the puncture member 5240 while the adjustment member 5230 is being moved to the second configuration. Once the adjustment member 5230 is in the second configuration, the projections may coincidentally engage a plurality of detents that may at least temporarily retain the projections therein. In this manner, the adjustment member 5230 may be at least temporarily locked in the second configuration. In other embodiments, the adjustment member 5230 and the puncture member 5240 do not include a locking feature and a user can exert a substantially constant force to retain the adjustment member 5230 in the second configuration.

In some embodiments, the puncture member 5240 and/or the adjustment member 5230 may include a visual indicator that is associated with the distance between the distal surface 5234 of the adjustment member 5230 and the distal edge 5245 of the puncture member 5240. For example, in ...

<img file="MX372859B_D0148.tif" />

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In some embodiments, the puncture member 5240 may include a measuring indicator. In such embodiments, a user determines the distance between the distal surface 5234 of the adjustment member 5230 and the distal edge 5245 of the puncture member 5240 by visually inspecting the measuring indicator.

Figure 38 is a schematic illustration of a portion of a delivery device in accordance with one embodiment. As shown, a hub 6270 is coupled to a puncture member 6240 and an adjustment member 6230. The hub 6270 has a proximal end portion 6271 and a distal end portion 6272. The proximal end portion 6271 may be physically and fluidically coupled to a fluid reservoir such as, for example, the medication container 430 of the medical injector 400 described above with reference to Figures 19-20. Although not shown in Figure 38, the proximal end portion 6271 of the hub 6270 may be coupled to a housing (e.g., a drug container) of a delivery device using any suitable coupling method such as, for example, a snap fit, a press fit, a threaded coupling, a Luer connection, a mechanical fastener, an adhesive, and/or the like. In other embodiments, the hub 6270 may be formed monolithically 25 with a housing for a delivery device. For

<img file="MX372859B_D0149.tif" />

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153 For example, the hub 6270 may be included in and/or form a distal end portion of a housing (e.g., the distal end portion 343 of the housing 430). In this way, an internal volume of the hub 6270 may be placed in fluid communication with a drug formulation contained within a fluid reservoir (e.g., a housing), as described above with reference to the hub 6270 of Figures 34-36. As shown in Figure 38, the distal end portion 6272 of the hub 6270 10 may be a substantially elongated portion that includes and/or is formed from a series of annular walls 6274. The annular walls 6274 define a lumen 6276 that extends through the distal end portion 6272 of the hub 6270. The lumen 6276 is configured to receive a portion of the puncture member 6270 to physically and fluidically couple the puncture member 6270 to the hub 6270.

The puncture member 6240 (also referred to herein as a microneedle) may be configured to pierce and/or penetrate a portion of the eye to deliver a drug formulation to, for example, the suprachoroidal space. The microneedle 6240 has a proximal end portion 6242 and a distal end portion 6244, and defines a lumen 6241. As described above, the proximal end portion 6242 is disposed within the lumen 6276 of the hub 6270. For example, in some

<img file="MX372859B_D0150.tif" />

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In some embodiments, the hub 6270 may be over-molded around the proximal end portion 6242 of the puncture member 6240. In other embodiments, the hub 6270 and the puncture member 6240 may be formed monolithically (e.g., the puncture member 6240 may be a microcatheter or the like that is unitarily formed with the hub 6270). Thus, when the hub 6270 is physically and fluidically coupled to a fluid housing or reservoir (as described above), the lumen 6241 of the puncture member 6240 may be placed in fluid communication with a drug formulation contained therein.

As shown, the microneedle 6240 extends from the distal end portion 6272 of the hub 6270 in the distal direction. The microneedle 6240 has a length 15 of the axis H between a distal edge 6245 of the puncture member 6240 and a distal surface of the hub 6270. In this way, the puncture member 6240 may be substantially similar to or the same as the puncture member 6240 described above with reference to Figures 34-36. Thus, portions of the puncture member 6240 are not described in further detail herein.

The adjustment member 6230 may be of any suitable shape, size or configuration and may be disposed around a portion of the hub 6270 and/or the puncture member 6240. For example, although some of the

<img file="MX372859B_D0151.tif" />

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Mexican Institute of Industrial Property adjustment members are described herein as being monolithic. In other embodiments, such as herein, an adjustment member may be constructed from multiple different components that are joined together. In particular, adjustment member 6230 includes a base 6238 and a plurality of removable layers 6239. Base 6238 is coupled to distal end portion 6272 of hub 6270. For example, in some embodiments, the base 6238 may be removably coupled to the hub 6270 (e.g., by a snap fit, a press fit, a threaded coupling, a mechanical fastener, and/or the like). In this manner, the hub 6270 may be reusable (after sterilization) and may be temporarily coupled to a disposable adjustment member 6230. In other embodiments, the base 6238 may be fixedly attached to the hub 6270 (e.g., by adhesive, ultrasonic welding, and/or the like).

The series of layers 6239 is comprised of relatively thin strips that are sequentially stacked together. More specifically, a first layer 6239 is removably coupled to the base 6238 and each subsequent layer 6239 is stacked on top of the preceding layer. In some embodiments, the layers 6239 may be relatively thin strips of a self-adhering flexible material such as sheets of polyethylene, polyvinylidene chloride,

156 polypropylene, polyacrylate, or the like. In other embodiments, the layers 6239 may be at least temporarily retained together and/or to the hub by an adhesive. In such embodiments, the layers 6239 may be retained by one or more adhesive materials having varying adhesive strengths. For example, in some embodiments, the adhesive strength between adjacent layers 6239 may be increased from a first adhesive strength between the most distal layer and its adjacent layer and a second adhesive strength between the most proximal layer and its adjacent layer. In some embodiments, each layer may be adhered to an adjacent layer by a single adhesive. In other embodiments, each layer may be adhered to an adjacent layer by the same adhesive with, for example, varying adhesive strengths. In still other embodiments, the layers may be retained by a combination of an adhesive and one or more self-adhesive materials. In this manner, one or more layers 6239 may be removed from the series of layers 6239 to transition the adjustment member 6230 from the first configuration to the second configuration. However, by varying the properties of the adhesive, the user can more easily remove the desired layer(s) without inadvertently removing additional layers.

As shown in Figure 38, each layer 6239

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY has a thickness of Tl. In some embodiments, the thickness T_L of each layer 6239 may be, for example, about 5 pm, 10 pm, 20 pm, 30 pm, 40 pm, 50 pm, 100 pm, or any suitable fraction therebetween. In other embodiments, a layer 6239 may have a thickness T_L which is greater than 100 pm.

Although each layer 6239 is shown and described as having substantially the same thickness T_L. In other embodiments, the layers 6239 may have varying thicknesses. As shown in Figure 38, the series of layers 6239 may have a total thickness T_TO which is the sum of the thicknesses T_L of each stacked layer 6239. For example, in some embodiments, the total thickness T_TO of the series of layers 6239 may be approximately 50 pm, 100 pm, 150 pm, 200 pm, 250 pm, 300 pm, 400 pm, 500 pm, 1000 pm, or any suitable fraction 15 between these. In other embodiments, the total thickness T_TO of the 6239 layer series may be less than about 50 pm. In still other embodiments, the total thickness T_TO of the array of layers 6239 may be greater than about 1000 pm. Although three removable layers 6239 are shown in Figure •20 38. In other embodiments, an adjustment member may include any suitable number of removable layers (e.g., two layers, four layers, five layers, six layers, seven layers, eight layers, nine layers, ten layers, or more).

As described above, the adjustment member 6230 is disposed around a portion of the hub.

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6270 and the puncture member 6270. More specifically, the puncture member 6240 may extend in the distal direction from the hub 6240 such that a portion of the puncture member 6240 extends through the trim member 6230 (e.g., through the base 6238 and the array of layers 6239). For example, as shown in FIG. 38 , the distal end portion 6244 of the puncture member 6240 may extend a distance D₄ from the outermost layer 6239 of the adjustment member 6230 (also referred to as an effective length of the puncture member)

6240). Similarly stated, the distal edge 6245 of the puncture member 6240 is spaced apart from a distal surface of the adjustment member 6230 (e.g., the outermost layer 6239) by the distance D₄. Thus, when a layer 6239 is removed from the series of layers 6239 of the adjustment member 6230, the effective length of the puncture member 6240 (e.g., distance D₄) is increased by a distance that substantially corresponds to the thickness T_L of the layer 6239 that was removed. For example, while the adjustment member 6230 is in the first configuration (e.g., where all the layers included in the series of layers 6239 are stacked), the distance D₄ may be, for example, approximately 550 pm and when the adjustment member 6230 moves to the second setting (for example, when one or more layers are

<img file="MX372859B_D0154.tif" />

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159 removed from the series of layers 6239), the distance D4 may be increased to, for example, about 650 pm. In other embodiments, the effective length of the puncture member 6240 may be increased to 600 pm, 700 pm, 750 pm, 800 pm, 850 pm, 900 pm, 950 pm, 1000 pm, or any suitable fraction therebetween.

In use, a user (e.g., a doctor, technician, nurse, specialist, ophthalmologist, etc.) may manipulate a delivery device (not shown) to insert the puncture member 6240 into, e.g., a portion of the eye (e.g., the eye 10 shown in Figure 1). In this manner, the distal end portion 6244 of the puncture member 6240 may be advanced through a portion of the sclera until an outermost layer of the series of layers 6239 included in the adjustment member 6230 is placed in contact with an outer surface of the sclera. With the adjustment member 6230 in the first configuration, the distance D4 (e.g., a first distance) between the outermost layer 6239 of the adjustment member 6230 and the distal edge 6245 of the puncture member 6240 may substantially depend on and/or may be associated with the thickness of the sclera. For example, in some embodiments, when the adjustment member 6230 is in the first configuration, the distance D4 between the outermost layer 6239 of the adjustment member 6230 and the distal edge

<img file="MX372859B_D0155.tif" />

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6245 may be approximately 450 pm. In other modalities, the distance D₄ when the adjustment member 6230 is in the first configuration may be approximately 350 pm, 400 pm, 500 pm, 550 pm, 600 pm, 650 pm, 700 pm, 750 pm, or any fraction therebetween. In still other embodiments, the distance D₄ When the adjustment member 6230 is in the first configuration, it may be less than about 350 pm. In still other embodiments, the distance D₄ When the adjustment member 6230 is in the first configuration, it may be greater than 750 pm. In this way, a distal edge 6245 of the puncture member 6240 may be disposed within the sclera (e.g., the sclera 20 of eye 10 in Figure 1).

The adjustment member 6230 may be moved from its first configuration to its second configuration to increase the distance D.₄ between the outermost layer 6239 of the adjustment member 6230 and the distal edge 6245 of the puncture member 6240 from the first distance to a second distance. For example, in some embodiments, a user can manipulate an engaging portion 6280 of one or more layers to remove (e.g., peel, tear, cut, separate, etc.) one or more layers from the stack of layers 6239 (i.e., the series of layers). In this way, the total thickness T_TO of the 6239 layer series is 25 reduced by the combined thicknesses T_L of each layer that is

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY removed. In addition, by expanding, removing one or more layers, the total thickness T_TO of the series of layers 6239 is reduced, thereby placing the adjustment member in the second configuration. Thus, with the adjustment member 6230 in the second configuration, the distance D4 is increased between the current outermost layer (e.g., the outermost layer after one or more layers have been removed) and the distal edge 6245 of the puncture member 6240 (e.g., at a second distance). In some embodiments, the distance D₄ can be increased up to approximately 600 pm. In other embodiments, the distance D₄ may be increased to approximately 650 pm, 700 pm, 750 pm, 800 pm, 850 pm, 900 pm, 950 pm, 1000 pm, or any fraction therebetween. In still other embodiments, the distance D₄ may be increased to less than about 600 µm (e.g., such as, for example, in use in pediatric eyes). By way of example, in some embodiments, the adjustment member 6230 may include a plurality of 10 layers 6239 with each layer having a thickness of about 50 µm. In such embodiments, the distance D₄ between the outermost layer 6239 and the distal edge 6245 may be, for example, approximately 450 pm. In some cases, three layers may be removed from the series of 10 layers 6239 to increase the distance D₄ until approximately 6:00 pm.

Also to adjust and/or control the length

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY effective puncture member 6240 (e.g., by manipulating a layer from layer stack 6239) to enhance the likelihood that lumen 6241 is placed in fluid communication with the desired region of target tissue (e.g., the suprachoroidal space of the eye), in some embodiments, The adjustment member 6230 (and any of the adjustment members shown and described herein) can form a substantially fluid-tight seal and/or a substantially liquid-tight seal with the external surface of the target tissue (e.g., the conjunctiva of the eye). In this way, leakage of the injected medicament along the needle path during the injection event can be reduced and/or eliminated. Expanding further, in some embodiments, the anatomy of the target tissue and/or the arrangement of the delivery device may be such that, in use, a portion of the lumen opening 6241 may be positioned in fluid communication with the suprachoroidal space 36 of the eye, while another portion of the lumen opening 6241 may be positioned within the suprachoroidal space 36 of the eye.

20. sclera 20. Thus, when the drug formulation is transported into the eye by the puncture member 6240, a portion of the drug formulation may be prone to migrate away from the desired region (e.g., the suprachoroidal space 36) and out of the eye via the needle track. Forming a tight seal

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY substantially fluid and/or a substantially liquid-tight seal, the adjustment member 6230 can produce an area of high flow resistance, thereby minimizing and/or eliminating flow migration and/or leakage.

Although the adjustment member 6230 is described above as being constructed from a relatively soft material, which may be well suited to forming a fluid-tight seal, in some embodiments, the adjustment member 6230 may be constructed from multiple materials. For example, in some embodiments, the adjustment member 6230 may include a plurality of layers 6239 with a first layer constructed from and/or including a portion constructed from a first material, and a second layer constructed from and/or including a portion constructed from a second material different from the first material. In addition to this example, at least a portion of the first material and/or at least a portion of the second material may be constructed from and/or may include a layer or portion constructed from 2Ó a material formulated to form a substantially fluid-tight seal with the outer surface of the target tissue (e.g., the conjunctiva).

Although not shown in Figure 38, in some embodiments, layers 6239 may provide and/or include an indicator associated with the distance D4 between the closest layer.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY external 6269 and the distal edge 6245 of the puncture member 6230. In some embodiments, the indicator may be an indication such as, for example, a value associated with the distance D4 (e.g., 500 pm). In other embodiments, the layers 6239 may be color coded with each layer having a different color and each color being associated with an effective length of the puncture member 6240.

Although not shown in Figure 38, in some embodiments, at least a portion of the layers 6239 may be disposed, at least temporarily, within a housing or the like. For example, in some embodiments, the layers 6239 may be coupled to the base 6238, as described above, and a housing may be disposed around at least a portion of the layers 6239 and the base 6238. Further expanding, in some embodiments, the housing may be movably disposed about the base and may define a window through which the engaging portion 6280 of the layers 6239 may extend. In this manner, a user may manipulate the engaging portion 6280 of a layer 6239 to remove the layer 6239 from the engagement member 6230. In some embodiments, the layer 6239 may be removed through the window defined by the housing. In this way, the housing can be moved in the proximal direction to be placed in contact with the outermost layer 6239, in this way

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY mode allowing a length of the axis of the puncture member 6240 between the distal edge 6245 and a distal surface of the housing to be increased. In some embodiments, the window may provide viewing of the axis length indicator (described above).

As described above with reference to Figure 36, the increase in distance D₄ It may be such that further movement of the lancing member 6240 (e.g., in a distal direction) relative to the sclera 10 places the lumen 6241 of the lancing member 6240 in fluid communication with the suprachoroidal space (e.g., the suprachoroidal space 36 of eye 10 in Figure 1). Similarly stated, the increase in distance D₄ may be large enough to extend the distal edge 6245 of the puncture member 6240 through the sclera such that the lumen 6241 is placed in fluid communication with the suprachoroidal space. In further expanding, by removing one or more layers from the series of layers 6239 of the adjustment member 6230, the distance 20 between the outermost layer 6239 of the adjustment member 6230 and the distal edge 6245 of the puncture member 6240 (e.g., distance D₄) is increased and the user may move the cube 6270 (e.g., either directly or indirectly) to place the current outermost layer in contact with the outer surface of the sclera.

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With the lumen 6241 of the puncture member 6240 in fluid communication with the suprachoroidal space, a drug formulation, (contained within a fluid reservoir as described above with reference to Figure 36) may be expelled through the lumen 6241 of the puncture member 6240 and into the suprachoroidal space of the eye. In this manner, the drug formulation may flow within the suprachoroidal space to be delivered to, for example, the posterior region of the eye (e.g., the posterior region 14 of the eye 10 in Figure 1). However, with the adjustment member 6230 in the second configuration, the distance D₄ may be less than a thickness of the sclera and suprachoroidal space such that the distal end portion 6244 of the puncture member 6240 does not pierce the choroid.

As described herein, a system, for example, system 1000, 2000, 3000, or any other system described herein, may include a hub, for example, hub 3270, 4270, 5270, or any other hub described herein. The hub may be configured to form a substantially fluid-tight zone around the insertion site of a piercing member (e.g., piercing member 3240 or any other piercing member described herein) into the eye.

For example, in some embodiments, a system may include

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167 a hub or contact surface configured to contact a surface of a target tissue to produce desired effects during drug delivery (e.g., maintaining a position of the conjunctiva, forming a seal, or the like).

Figure 39 shows an apparatus 7000 that includes a medical injector 7310, a drive rod 7320, a needle 7240, and a hub 7270, and optionally a needle adjustment mechanism 7230. The system 7000 may be configured to deliver a medicament to the target layer of a patient's eye, for example, to the SCS of the eye.

The medical injector 7310 defines an internal volume 7316 configured to accommodate a medicament L (e.g., a VEGF, a VEGF inhibitor, triamcinolone acetonide, any other medicament described herein, or a combination thereof). The medical injector 7310 includes a coupling portion 7312 and a delivery portion 7314 coupled to the needle adjustment mechanism 7230. The medical injector 7310 may be substantially similar to the drug containment chamber 1310, 2310, 3310, or any other drug containment chamber described herein, and is therefore not described in further detail herein.

The drive rod 7320 includes a coupling portion 7322 and a plunger portion 7324.

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168

The plunger portion 7324 is slidably disposed within the internal volume 7316 defined by the medical injector 7310. The coupling portion 7322 is configured to be engaged by the user and urge the plunger portion 7324 to slide within the internal volume 7316 defined by the medical injector 7310. For example, the user may apply a force in the direction shown by arrow Fi on the coupling portion 7322 to move the plunger portion 7324 proximally relative to the medical injector 7310 thereby expelling at least a portion of the medicament L through a lumen 7241 of the needle 7240. As shown, at least a portion of the drive rod 7320 may be disposed approximately concentric with the medical injector 7310. The plunger portion 7324 is configured to draw the medicament L into or expel the medicament L from the internal volume 7316 defined by the medical injector 7310. In some embodiments, any other actuating rod may be included in the apparatus 7000, for example the actuator 1320, 2320, 3320 or any other actuator described herein.

Needle 7240 defines lumen 7241 and is configured to pierce the eye and deliver medicament L into a target tissue of the eye. Needle 7240 may be substantially similar to any of the members of

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY piercing described herein, and therefore not described in further detail herein, in some embodiments, needle 7240 may be a microneedle movably disposed within a passageway 7276 of hub 7270, as described herein. Needle adjustment mechanism 7230 may be coupled to delivery portion 7314 of medical injector 7310 and a proximal end of needle 7240. In some embodiments, the needle adjustment mechanism 7230 is configured to move the needle 7240 within the passage 7276 such that a portion of the distal end of the needle 7240 extends from the distal end surface 7275 of the hub 7270 by a predetermined amount. For example, the needle adjustment mechanism 7230 may urge the needle 7240 to translate linearly along the longitudinal axis A1 and thereby adjust a length of the needle 7240 protruding through a distal end 7274 of the hub 6270. The needle adjustment mechanism 7230 may be substantially similar to the adjustment member 422, 3200, 4230, 5230, 6230, or any other adjustment mechanism or adjustment member described herein.

The hub 7270 is configured to be coupled to the medical injector 7230. The hub 7270 includes a proximal end 7272 and a distal end 7274. The proximal end 7272 is coupled to a portion of the distal end of the delivery mechanism.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY needle adjustment 7230. In some embodiments, the proximal end 7272 may be coupled to a housing (not shown) which may be included in the system 7000. The hub 7270 defines the passageway 7276 configured to receive at least a portion of the needle 7240 therethrough, in this way, the needle 7240 is configured to pass through the lumen 7276 and into the eye. The distal end surface 7275 of the hub 7270 is configured to contact a target tissue (e.g., the conjunctiva of the eye) when the medicament L (or any other substance disposed within the medical injector 7230) is transported through the needle 7240 into the target tissue. In some embodiments, the distal end surface 7275 of the hub 7270 is configured to deform the target surface (e.g., the conjunctiva of the eye) when the distal end surface 7275 is brought into contact with the target surface. At least a portion of the distal end surface 7275 may have a substantially convex shape, for example, a hemispherical shape such that at least a portion of the distal end surface 7275 defines a sealing portion 7277. The sealing portion 7277 may be configured to define a substantially fluid tight seal with the target surface when the distal end surface 7275 is not in contact with the target surface. For example, the distal end surface 7275

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY may deform the target surface such that the sealing portion 7277 is contiguous with the target surface and forms the substantially fluid-tight seal. In some embodiments, the sealing portion 7277 may be approximately symmetrical to the center A._L of the apparatus 7000 and therefore to the passageway. This may, for example, facilitate perpendicular approach of the needle 7240 to the target tissue (e.g., ocular tissue). In this way, the size of the insertion zone can be minimized, reducing damage. In addition, the needle 7240 may use the shortest path to reach a target region of the target tissue (e.g., the SCS of the eye). While shown to be a cross-section, the hub 7270 may be substantially cylindrical, e.g., having a circular cross-section, such that the convex shape of the distal end surface 7275 resembles, e.g., a hemisphere. In such embodiments, the sealing portion 7277 may circumferentially surround the needle 7240 to form a substantially fluid-tight, hemispherical seal with the target surface. In some embodiments, only a small portion of the sealing portion 7277 surrounding the needle 7240 need contact and form the substantially fluid-tight seal with the target surface. For example, in some embodiments, only a small band of the sealing portion 7277 surrounding the needle 7240

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7240 can contact and form the 'substantially fluid-tight seal' with the target surface,

In some embodiments, the target tissue is an eye and the target surface is a conjunctiva of the eye. For example, Figures 40A-C show a portion of an eye which includes a conjunctiva C, the sclera S, the suprachoroidal space SCS (which may be the target layer), and a retina R. As shown in Figure 40Ά, in a first configuration, the distal end 7274 of the hub 7270 is not in contact with a conjunctiva C of an eye and a distal end of the needle 7240 is disposed in a sclera S of the eye. In addition to this example, the curved shape of the distal end surface 7275 of the hub 7270 may allow a desired distribution of force(s) to be applied to a portion of the eye, for example, the conjunctiva C. In some embodiments, the curved distal end surface 7275 of the hub 7270 may create a taut spherical injection site. For example, the hub 7274 may deform the conjunctiva C in a radial direction from the center point (i.e., away from where the needle 7240 penetrates) as the system 7000 moves from the first configuration to a second configuration (e.g., the second configuration shown in Figure 40B). In this way, the C 25 conjunctiva can be moved into and/or retained in a preferable position.

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173 during injection. In some cases, this may reduce puncture forces needed to penetrate the surface of the eye. In some embodiments, stretching the conjunctiva C may minimize and/or eliminate any bunching of the conjunctiva C that may otherwise occur, and preferably may produce a surface layer (e.g., conjunctiva) having a substantially constant thickness. In some instances, the cube 7270 may, at least temporarily, adhere to a portion of the conjunctiva C. In this way, the cube 7270 can cause movement of and/or stabilize at least a portion of the conjunctiva C such that at least the portion of the conjunctiva C is in a preferable position during the injection.

In some embodiments, insertion of the needle 15 7240 into the target tissue (i.e., the conjunctiva and sclera) may be performed such that a centerline of the delivery passage and a surface line tangent to the target surface define an entry angle of between about 75 degrees and about 20-105 degrees. For example, as shown in Figure 40D, a centerline C_L of the lumen 7241 of the needle 7240 may define an insertion angle Θ with a tangent of the surface line ST formed relative to the conjunctival surface C. The insertion angle Θ may be in the range of between about 75 degrees and about 25 degrees.

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105 degrees, inclusive of all intervals therebetween. For example, in some embodiments, the insertion angle Θ may be approximately 90 degrees. In other words, the needle 7240 may be inserted into the target tissue (i.e., the conjunctiva C, and the sclera S) such that the centerline C_L defined by lumen 7241 of needle 7240 is substantially perpendicular or otherwise normal to the surface of the target tissue. In this way, the size of the insertion zone can be reduced thereby minimizing injury and inflammation, which may be caused by any lateral travel of needle 7240 within the target tissue. Furthermore, normal insertion may also provide the shortest path for the distal tip of the needle 7240 to reach the target tissue (e.g., the SCS) thereby reducing the time required to reach the target tissue (e.g., the SCS).

Referring again to Figures 40A-C, to initiate delivery of medicament L the user may apply a force F2 to the system 7000, for example, to the coupling portion 7322 of the actuating rod 7320. The force F₂ may urge the plunger portion 7324 to slide within the internal volume 7316 of the medical injector 7310 proximally relative to the medical injector 7310 and urge the system into a second configuration.

Although not shown, in some embodiments, the 7000 system

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY may include an injection assembly, for example, injection assembly 100, 2100 or any other injection assembly described herein is configured to exert force on drive rod 7320. In the second configuration, hub 7270 is pressed against conjunctiva C such that conjunctiva C is compressed and approximately conforms to the convex shape of distal end surface 7275 of hub 7270. This also pushes the needle 7240 further into the sclera S. In addition, at least a portion of the sealing portion 7277 defined by the distal end surface 7275 is contiguous with the deformed surface of the conjunctiva C such that the sealing portion 7277 defines a substantially fluid tight seal with the conjunctiva C around the insertion site. In some embodiments, the sealing portion 7277 may be substantially approximately symmetrical to the centerline C1 of the needle 7240 (e.g., as shown in Figure 40D). In some embodiments, only a circular band of the sealing portion 7277 may contact and form a substantially fluid-tight seal with the conjunctiva C surrounding the needle 7240. However, in the second configuration, the distal end of needle 7240 may still be proximal to but not within the suprachoroidal space SCS, which may be the target layer for

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY supply of the medicine L.

In some embodiments, the hub 7270 may be a rigid member having a stiffness substantially greater than the stiffness of the conjunctiva C (e.g., a stiffness substantially similar to a stiffness of stainless steel).

In such modalities, the application of force F₂ only deforms the conjunctiva C, without causing any substantial deformation of the cube 7270. In some embodiments, the cube 7270 may have a stiffness that is intermediate to the stiffness of the conjunctiva C and the sclera S. In such embodiments, the application of the force F₂ can drive the cube 7270 to deform the conjunctiva C (Figure 40B and 40C) until the distal end surface 7275 of the cube 7270 is proximate the sclera S. Since the stiffness of the cube 7270 is less than the stiffness of the sclera S, further application of force F₂ will urge the distal end surface 7275 of the cube 7270 to deform without any substantial deformation of the sclera S. In this way, the cube 7270 can prevent the application of excessive force from causing damage to or otherwise deformation and/or perforation of the inner layers of the eye.

In a third configuration shown in Figure 40C, the user can then maintain force F₂ and increase the length of the needle 7240 protruding into the eye, for example, by using the needle adjustment mechanism

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7230. The length of the needle 7240 may be increased until a distal tip or exit of the needle 7240 is within or otherwise near the suprachoroidal space SCS.

Force F2 may further press distal end surface 7275 of hub 7270 into conjunctiva C. This may urge substantially all of sealing portion 7277 of distal end surface 7275 to be contiguous with conjunctiva C further strengthening the substantially fluid-tight seal. In this manner, leakage of injected medicament L along needle path 7240 during the injection event may be reduced and/or eliminated. Further expanding, in some embodiments, the anatomy of the target tissue and/or the arrangement of the system 7000 may be such that, in use, a portion of the lumen opening 7241 of the needle 7240 may be positioned in fluid communication with the suprachoroidal space SCS of the eye, while another portion of the lumen opening 7241 may be positioned within the sclera S. Thus, when the drug L is transported into the eye via the needle 7240, a portion of the drug L may be prone to migrate away from the desired region, i.e., the suprachoroidal space SCS, and out of the eye via the path of the needle 7240. By forming a substantially fluid-tight seal and/or a substantially liquid-tight seal, the hub 7270 may produce an area of high flow resistance, thus

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY mode minimizing and/or eliminating flow migration and/or leaks.

Although not shown, in some embodiments, the system 7000 may include an injection assembly, for example, injection assembly 100, 2100, or any other injection assembly described herein. As described hereinabove, the injection assembly may be configured to exert a force on the medicament L disposed in the internal volume 7316 of the medicament containment chamber 7310. The force may be sufficient to overcome a back pressure of the suprachoroidal space SCS exerted on the needle opening, but not the back pressure of the sclera S. In such embodiments, the user may insert the needle 7240 into the sclera S as shown in Figure 40A and activate the injection assembly. The injection assembly may pressurize the medicament L but the back pressure of the sclera S may prevent the medicament L from being delivered into the sclera S. As shown in Figure 40B, the user may continue inserting the needle 7240, for example, by maintaining or increasing a magnitude of the force F.₂. This may drive the hub 7240 to deform the conjunctiva C and initiate the formation of the fluid-tight seal around the insertion site, as described herein. The force F₂ can be maintained until a

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY distal end of needle 7240 is within or near the suprachoroidal space SCS. The force exerted by the injection assembly on the drug L can now overcome the back pressure of the suprachoroidal space SCS thereby initiating communication of the drug L into or near the suprachoroidal space SCS as shown in Figure 40C. In this manner, the injection assembly can assist the user in determining the location of the distal end of the needle 7240 such that the medicament L is delivered substantially only to the target layer (i.e., the suprachoroidal space SCS). Furthermore, over-excursion of the piercing member 7240 beyond the suprachoroidal space SCS (i.e., into the retina R) can be prevented.

In some embodiments, the needle adjustment mechanism 7230 may be used to ensure delivery to the target layer. In such embodiments, the user may insert the needle 7240 into the sclera S as shown in Figure 40A and activate the injection assembly to pressurize the medicament L as described herein. While maintaining the force F₂, the user may use the needle adjustment mechanism 7230 to advance the needle 7240 in predetermined increments (e.g., approximately 100 µm increments) into the sclera S, e.g., as described herein with reference to the assembly of the

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY needle 422, 3200, or any other needle assembly described herein. In this manner, the needle adjustment mechanism 7230 may be used to advance the needle 7240 through the sclera S until a distal end of the needle 7240 is within or near the suprachoroidal space.

SCS. The force exerted by the injection assembly on the drug L can now overcome the back pressure of the suprachoroidal space SCS thereby initiating communication of the drug L into or near the suprachoroidal space SCS as shown in Figure 40C. Thus, by allowing the user to advance the needle 7240 in known discrete increments, the needle adjustment mechanism 72.30 may assist the user in preventing over-excursion of the needle 7240 beyond the suprachoroidal space.

SCS (i.e., in the retina R). In this way, the injection assembly can assist the user in determining the location of the distal end of the needle 7240 so that communication of the drug into a layer of the eye other than the target layer (i.e., the suprachoroidal space SCS) can be prevented. In addition, the needle adjustment mechanism 7230 may assist the user in precisely controlling the excursion length of the needle 7240, thereby eliminating the use of excessive force and/or preventing over-excursion of the needle 7240 beyond the target layer (i.e., the suprachoroidal SCS space).

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In some embodiments, the hub 7270 or any of the hubs described herein may be constructed from a relatively soft material, which may be well suited to forming a fluid-tight seal. For example, in some embodiments, the system 7000, or any other system described herein, may be used to deliver a medicament through a user's skin (e.g., for intravenous or intramuscular delivery of the medicament). In such embodiments, the cube 7270 or any other cube described herein may have a stiffness lower than the stratum corneum that forms the top layer of the skin. The distal end surface 7275 of the cube 7270 or any other cube described herein may deform around the stratum corneum as a force is applied to the system 7000. In this manner, the sealing portion 7277 defined by the distal end surface 7275 of the hub 7270 may form a fluid-tight seal around the stratum corneum thereby preventing leakage of medicament, interstitial fluid, and/or blood from the injection site. In still other embodiments, the hub 7270 may be constructed from multiple materials. For example, in some embodiments, the distal end surface 7275 of the hub 7270 may be constructed from and may include a layer or portion constructed from a material formulated to form a substantially non-porous seal.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY fluid-tight with the external surface of the target tissue (e.g., the conjunctiva C).

Figures 41A and 41B show a finite element analysis (FEA) model of the distal portion 7274 of the cube 7270 compressing against the conjunctiva C of the eye. In this model, a force of 1 N is exerted on the cube 7270. At this force, the conjunctiva C is compressed by approximately 2 mm, which is substantially equal to the total thickness of the conjunctiva C. In addition, the conjunctiva forms approximately the distal end surface 7275 of the distal end portion 7274 of the hub 7270. As shown, the sealing portion 7277 of the distal end surface forms a substantially fluid tight seal around the injection site of the needle 7240. The hub

7270 is modeled as a rigid and flexible member. However, the 7270 cube or any other cube described herein may have any suitable stiffness based on the material used to form the cube. In some embodiments, the cube 7270 or any other cube described herein may have a stiffness substantially similar to the stiffness of rubber, silicone, polymers, plastics (e.g., polyethylene, polypropylene, polycarbonate, polytetrafluoroethylene, high-density polyethylene, etc.), metals (e.g., aluminum, stainless steel, metal alloys, etc.), or any other material described in the

<img file="MX372859B_D0178.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY present,

Figures 42A-C show a hub 8270, in accordance with one embodiment. The hub 8270 includes a proximal end portion 8272 and a distal end portion 8274. The proximal end portion 8272 may be configured to be coupled to a distal end of a housing (e.g., a distal end 3212 of housing 3210 of needle assembly 3200, or any other housing described herein) using any suitable coupling mechanism, e.g., friction fit, threads, press fit, notches, grooves, grooves, detents, any other suitable coupling mechanism, or combination thereof. Hub 8270 defines a passageway 8276 therethrough. At least a portion of a needle (e.g., piercing member 3240, needle 7240, or any other piercing member described herein) may be disposed within passageway 8276, and may be configured to advance through passageway 8276 out of distal end 8274. The distal end 8274 of the hub 8270 includes a contact surface that is curved, and for example, defines a convex or hemispherical shape. The contact surface of the distal portion 8274 is configured to (i.e., has a size and/or shape configured to) contact an external surface of a conjunctiva of the eye and define a sealing portion that forms

<img file="MX372859B_D0179.tif" />

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Mexican Institute of Industrial Property a substantially fluid-tight seal around the insertion area of the piercing member 8240 into a target tissue, for example, the eye. In this way, the hub 8270 can prevent leakage of the drug, and/or body fluid 5 from the insertion site, as described with respect to the hub 7270 included in the apparatus 7000.

In some embodiments, a hub may be substantially hollow and/or may define an elongated lumen therethrough. Referring now to Figures 43A-C, a hub 9270 includes a proximal end portion 9272, a distal end portion 9274, and defines an internal volume 9275. The proximal end portion 9272 may be configured to be coupled to a distal end of a housing (e.g., the distal end 3214 of the housing 3210 included in the needle assembly 3200, or any other housing included in a needle assembly described herein). For example, a distal end portion of a housing (e.g., the housing 321) may be configured to slide in the internal volume 9275. At least a portion of a needle (e.g., piercing member 3240, needle 7240, or any other piercing member described herein) may be disposed in internal volume 9275. In some embodiments, at least a portion of a needle assembly, e.g., lead screw 3242, is included in the internal volume 9275.

<img file="MX372859B_D0180.tif" />

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185 needle assembly 3200 or any other component or any other needle assembly, may also be arranged in the internal volume 9275. The distal end 9274 has a contact surface that is curved, for example, defines a convex or hemispherical shape, such that the contact surface defines a sealing portion which can form a substantially fluid tight seal around the insertion zone of the piercing member (for example, piercing member 3240, or needle 7240), as described with respect to hub 8270. The distal end 9274 defines an opening 9276 configured to allow at least a portion of the piercing member (e.g., piercing member 3240) to pass therethrough and into the ocular tissue of the eye.

In some embodiments, a hub may include one or more engaging structures that operate cooperatively to surround the puncture member and/or contact a surface of the target tissue. However, in some embodiments, a hub may also be configured to induce deformation and/or movement of a portion of the target tissue when placed in contact with the target tissue. In such embodiments, the adjustment member may minimize bunching of surface tissue (e.g., the conjunctiva). For example, Figures 44A and 44B are schematic illustrations of a portion of a

<img file="MX372859B_D0181.tif" />

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Mexican Institute of Industrial Property delivery device 10000 in a first configuration and a second configuration, respectively, according to one embodiment. The delivery device 10000 includes a hub 10270, a puncture member 10240 (also referred to herein as a delivery member or a needle), and a coupling assembly 10280. The coupling assembly 10280 includes a first elongated member 10281 and a second elongated member 10285. The elongated members 10281, 10285 may be any suitable structure configured to engage and deform the target tissue (as described herein). For example, in some embodiments, the first elongated member 10281 and/or the second elongated member 10285 may be a thin structure (e.g., feeler gauge, wire, etc.). In some embodiments, the first elongated member 10281 and/or the second elongated member 10285 may be any suitable structure configured to grasp, retain, and/or deform a portion of the target tissue (e.g., the conjunctiva). Although not shown, additional elongated members (or sliders) may be coupled to the hub 10270. For example, in some embodiments, the hub 1270 may include three elongated members attached thereto. In other embodiments, for example, the hub 1270 may include more than three elongated members (e.g., four, five, or more elongated members) attached thereto.

<img file="MX372859B_D0182.tif" />

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As shown, a proximal end portion 10286 of the first elongated member 10281 is coupled to the hub 10270. The first elongated member 10281 has a contact portion 10284 (e.g., the portion where the first elongated member 10281 may contact a portion of the eye 10 shown in Figure 1, during use). The first elongated member 10281 has a distal end portion 10283. At least a portion of the first elongated member 10281 may have a curved shape. The curved shape, for example, may be such that the contact portion 10284 is configured to contact a portion of the eye (e.g., the conjunctiva) along a line tangent to a portion of the first elongated member 10281. In addition to this example, the curved shape of the portion of the first elongated member 10281 may allow a desired distribution of force(s) to be applied to a portion of the eye during use. For example, in this way the contact portion 10284 does not contact the surface of the eye at one point of the angle, but preferably along a surface that is less likely to pierce the eye.

A proximal end portion 10286 of a second elongated member 10285 is coupled to the hub 10270. The second elongated member 10285 has a contact portion 10288 (e.g., where the second elongated member 10285 contacts a portion of the eye 10 shown in Figure 1).

<img file="MX372859B_D0183.tif" />

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Mexican Institute of Industrial Property second elongated member 10285 has a distal end portion 1287. At least a portion of the second elongated member 10285 may have a curved shape. The curved shape, for example, may be such that the contact portion 10288 is configured to contact a portion of the eye (e.g., the conjunctiva) along a line tangent to a portion of the second elongated member 10285. In addition to this example, the curved shape of the portion of the second elongated member 10285 may allow a desired distribution of force(s) to be applied to a portion of the eye, as discussed above with respect to the first elongated member 10281.

When the delivery device 10000 is in a first configuration, as shown in Figure 44A, the distal end portion 10283 of the first elongated member 10281 and the distal end portion 10287 of the second elongated member 10285 are separated by a distance Ai. Similarly, in the first configuration, the contact portion 10284 of the first elongated member 10281 and the contact portion 10288 of the second elongated member 10285 are separated by a distance Bi. However, when the delivery device 10000 is in the first configuration, the distal tip of the puncture member 10240 is spaced apart from the contact portion 10284 and/or the contact portion 10288 by a distance C._x

<img file="MX372859B_D0184.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY taken along a centerline of the puncture member 10240, as shown in Figure 44A. In some embodiments, the distal tip of the puncture member 10240 is spaced apart from a line defined by the contact portion 10284 and the contact portion 10288 by a distance C1 taken along a centerline of the puncture member 10240.

In use, a user (e.g., a doctor, technician, nurse, specialist, ophthalmologist, etc.) may manipulate a delivery device 10000 to insert the lancing member 10240 into, e.g., a portion of the eye (e.g., the eye 10 shown in Figure 1). In this manner, the user may apply a distal force to move the delivery device 10000 from the first configuration to a second configuration. Similarly stated, when the puncture member 10240 is inserted into the eye, the first elongated member 10281 and the second elongated member 10285 may both move from the first configuration to the second configuration. When the delivery device 10000 is in the second configuration, as shown in Figure 44B, the distal end portion 10283 of the first elongated member 10281 and the distal end portion 10287 of the second elongated member 10285 may be separated by a distance A2, A2 being greater than Ai. In ...

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY shows in Figure 44B, the contact portion 10284 of the first elongated member 10281 and the contact portion 10288 of the second elongated member 10285 can be separated by a distance B₂, B₂ being greater than Βχ. However, when the delivery device 10000 is in the second configuration, the distal tip of the puncture member 10240 is spaced apart from the contact portion 10284 and/or the contact portion 10288 by a distance C₂ taken along a center line of the puncture member 1240, 10 as shown in Figure 44B, C₂ being greater than Cx. In some embodiments, the distal tip of the puncture member 10240 is spaced apart from a line defined by the contact portion 10284 and the contact portion 10288 by a distance C₂ taken along a center line 15 of the puncture member 10240, C₂ being greater than Ci when the supply device 10000 is in the second configuration.

In some embodiments, when the delivery device 10000 moves from the first configuration to the second configuration, the contact portion 10284 of the first elongated member 10281 and the contact portion 10288 of the second elongated member 10285 may cause a portion of the eye to move, or preferably, prevent a portion of the eye from moving. Similarly stated, in some embodiments, deformation of the first

<img file="MX372859B_D0186.tif" />

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Mexican Institute of Industrial Property elongated member 10281 and/or second elongated member 10285 may move (or alternatively maintain a position of) a portion of the target tissue. For example, in some uses, at least one contact portion 10284 or the contact portion 10288 may contact the conjunctiva of the eye. In this manner, at least one of the contact portions 10284, 10288 may stabilize, hold ready, grasp, stretch, or mechanically fix a portion of the eye (e.g., the conjunctiva) when the device is moved from the first configuration to the second configuration.

In some embodiments, the contact portions 10284, 10288 may create a spherical injection site shown. For example, the first elongated member 1281 and/or the second elongated member 10285 may deform in a radial direction from the center point (i.e., away from where the puncture member 10280 penetrates) when the delivery device 10000 moves from the first configuration to the second configuration, in this way, the conjunctiva may be retained in a preferable position during injection. In some cases, this may reduce the puncture force to penetrate the ocular surface. In some embodiments, stretching the conjunctiva may minimize and/or eliminate any bunching of the conjunctiva that may otherwise occur, and may preferably produce a surface layer.

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Mexican Institute of Industrial Property (e.g., conjunctiva) having a substantially constant thickness. In some cases, the contact portions 10284, 10288 may, at least temporarily, adhere to a portion of the surface layer (e.g., conjunctiva). In this manner, the contact portions 10284, 10288 may cause movement of and/or stabilize at least a portion of the surface layer such that at least the portion of the surface layer is in a preferable position during injection.

In some embodiments, the elongated member 10281 and/or the elongated member 10285 may be attached to the hub 10270 in any suitable manner, as shown in Figures 44A and 44B. In still other ...

10281 and/or the elongated member 10285 may be coupled to an elongated member retainer or interface (not shown). The elongated member retainer may be coupled to the hub 10270. In some embodiments, the elongated member retainer (not shown) may be a ring.

The elongated members 1281, 10285 may be any suitable material (e.g., metallic or plastic). In some embodiments, the sliders may contain a plurality of different materials. For example, the contact portion 10284 of the first elongated member 10281 may contain a material not contained in a different portion of the first elongated member 10281.

<img file="MX372859B_D0188.tif" />

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193 In some embodiments, for example, additional materials (e.g., a coating) may be applied to any portion of the elongated members 10281, 10285.

In addition to this example, the additional material may be configured to increase or decrease friction between the elongated members 10281, 10285 and a surface layer (e.g., conjunctiva). In some embodiments, a plurality of the additional materials may be applied to the elongated members 10281, 10285. Each additional material 10 (e.g., coating) of the plurality of additional materials, for example, may include relatively unique material properties (e.g., viscosity, density, surface tension, etc.).

In some embodiments, the elongated members 10281, 10285 may provide an indicator associated with at least one of the distance A1, A2, B1, B2, C1, and/or C2. In some embodiments, the indicator may be a visual indicator such as a measuring scale, graduated markings, or the like. For example, in some embodiments, the first elongated member 10281 may include indicia (e.g., lines, tick marks, tick marks, etc.). In some embodiments, the indicia may represent a change in the location of the distal tip of the puncture member 10240 from the first configuration to the second configuration. In yet another embodiment, the indicia may

<img file="MX372859B_D0189.tif" />

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194 represent a portion of the eye where the distal tip of the lancing member 10240 is located. For example, the markings may indicate whether the distal tip of the lancing member 10240 is located in the sclera, choroid, suprachoroidal space, or retina of the eye. For another example, the markings may indicate the named location of the distal tip of the puncture member 10240 (e.g., sclera, choroid, suprachoroidal space, retina, etc.), and may further indicate a location within the named location 10 (e.g., a location within the choroid).

In this way, the markings may indicate, for example, the location of the distal tip of the puncture member 10240 relative to the sclera and/or the choroid when the distal tip is located within the suprachoroidal space.

Although shown to include multiple, deformable elongated members. In other embodiments, a coupling assembly and/or an adjustment assembly, for example, included or coupled to a hub, may include a single deformable member. For example, Figures 45A and 45B are schematic illustrations of a portion of a delivery device 11000, in accordance with one embodiment. Specifically, Figure 45A illustrates a portion of a delivery device 11000 in a first configuration and a second configuration (e.g., illustrated with dotted lines), and Figure 45B illustrates a bottom view of the portion of the

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY delivery device 11000. Delivery device 11000 includes a hub 11270, a puncture member 11240 (also referred to herein as a delivery member or a needle), and a coupling member 11280.

The coupling member 11280 may be any suitable structure configured to couple the target tissue.

As shown, a proximal portion 11282 of coupling member 11280 is coupled to delivery device 11000. Coupling member 11280 is coupled to delivery device 11000 by hub 11270. In still other embodiments, coupling member 11280 may be coupled to a coupling member retainer (not shown). The coupling member retainer may then be coupled to hub 11270. The coupling member 11280 has a contact portion 11284.

When the delivery device 11000 is in a first configuration, as shown in Figure 45A, a portion of the contact portion 11284 of the coupling member 11280 is spaced apart from the distal tip of the puncture member 11240 by a distance Aχ taken along a centerline of the puncture member 11240. In some embodiments, the distal tip of the puncture member 11240 is spaced apart from a line defined by

<img file="MX372859B_D0191.tif" />

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196 the contact portion 11282 of the coupling member 11280 by a distance A_x taken along a center line of the lancing member 11240. In use, a user (e.g., a doctor, technician, nurse, specialist, ophthalmologist, etc.) may manipulate a delivery device (not shown) to insert the lancing member 11240 into, e.g., a portion of the eye (e.g., the eye 10 shown in Figure 1). In this manner, the user may apply a distal force to move the delivery device 11000 from the first configuration to a second configuration. In a similar manner stated, when the lancing member 11240 is inserted into the eye, the coupling member 11280 may move from the first configuration to the second configuration, as illustrated by the dotted line in Figure 45A. When the delivery device 11000 is in the second configuration, as shown in Figure 44A, a portion of the contact portion 11284 of the coupling member 11280 and the distal tip of the puncture member 11240 are separated by a distance A2 (see the distance indicated from the dotted lines), A2 being greater than Ai. In some embodiments, when the delivery device 11000 is in the second configuration, the distal tip of the puncture member 11240 is spaced apart from a line 25 defined by the contact portion 11284 of the puncture member.

<img file="MX372859B_D0192.tif" />

IMPI Mexican Industrial Property Institute

197 coupling 11280 by a distance A₂ taken along a center line of puncture member 11240, A₂ being greater than Ai.

In some embodiments, when the delivery device 11000 moves from the first configuration to the second configuration, the contact portion 11284 may cause a portion of the eye to move, or preferably, prevent a portion of the eye from moving. Similarly stated, in some embodiments, the deformation of the coupling member 11280 may move (or alternatively maintain a position of) a portion of the target tissue. For example, in some uses, the contact portion 11282 of the coupling member 11280 may stabilize, hold ready, grip, stretch, or mechanically fix a portion of the eye (e.g., the conjunctiva) when the delivery device 11000 is moved from the first configuration to the second configuration.

Although the coupling member 11280 is shown and described above as including a contact portion 11284 that is curved in a convex manner (i.e., curved outwardly, or in a manner resembling an outer surface of a sphere). In other embodiments, a hub and/or coupling member may include a contact portion that is curved in a concave manner (i.e.,

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY curved inwardly, or in a manner resembling an internal surface of a sphere).

In some embodiments, the coupling member 11280 may deform at a variable rate. For example, the coupling member 11280 may provide variable resistance as a user manipulates the delivery device 11000. In some embodiments, the coupling member 11280 may provide a hard stop (i.e., a user could be substantially prevented from further inserting the lancing member 11240 into a portion of the eye). In still other embodiments, the coupling member 11280 may be configured to provide variable resistance based on its level of deformity. In this manner, the coupling member 11280 may be configured to provide a first level of resistance when the lancing member 11240 is in a first portion of the eye and a second level of resistance when the lancing member 11240 is in a second portion of the eye, the first level of resistance being different than the second level of resistance. In some modalities, for example, the first portion of the eye may be the sclera and the second portion of the eye may be the suprachoroidal space.

In some embodiments, the coupling member 11000 may provide an indicator associated with at least one of the distance A1 or A2 (i.e., the depth of

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Mexican Institute of Industrial Property penetration of the puncture member 11240). In some embodiments, the indicator may be a visual indicator such as a measuring scale, graduated markings, or the like. For example, in some embodiments, the coupling member 11280 may include indicia (e.g., lines, scores, tick marks, etc.). In some embodiments, the indicia may represent a change in the location of the distal tip of the lancing member 11240 from the first configuration to the second configuration. In still other embodiments, the indicia may represent a portion of the eye where the distal tip of the lancing member 11240 is located. For example, the markings may indicate whether the distal tip of the lancing member 11240 is located in the sclera, choroid, suprachoroidal space, or retina of the eye. For another example, the markings may indicate by anatomical term the location of the distal tip of the lancing member 11240 (e.g., sclera, choroid, suprachoroidal space, retina, etc.) and may further indicate a location within the named location (e.g., a location within the choroid). In this way, the markings may indicate, for example, the location of the distal tip of the puncture member 11240 relative to the sclera and/or the choroid when the distal tip is located within the suprachoroidal space 25.

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200

Although the coupling assembly 10000 is shown and described above as including two or more elongated members having contact portions that are curved in a convex manner (i.e., curved outwardly, or in a manner resembling an external surface of a sphere). In other embodiments, a hub, coupling assembly and/or fitting member may include a contact portion or surface that is curved in a concave manner (i.e., curved inwardly, or in a manner resembling an inner surface of a sphere). Similarly stated, in some embodiments, a delivery device may include a hub, a coupling assembly, and/or an engagement member having a surface configured to engage, affix, and/or conform to the surface of the target tissue (e.g., the eye). As an example, Figures 46-47 are perspective views of a portion of a delivery device in accordance with one embodiment. In particular, Figures 46-47 are perspective views of a coupling member 12280 configured for use in conjunction with any of the delivery devices shown and described herein. The coupling member 12280 includes a proximal end portion 12281 and a distal end portion 12282 and defines a lumen or passageway therebetween.

The proximal end portion 12281 of the member of

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY coupling 12280 may be coupled to a delivery device (not shown in Figure 46). In some embodiments, the proximal end portion 12281 of the coupling member 12280 may be coupled to the hub 10270 (not shown in Figures 45-46), or any other hub described herein. For example, in some embodiments, the coupling member 12280 may be threadably coupled to a hub to control an effective length of a puncture member (also referred to as a delivery member or needle) as described above. In this manner, the coupling member 12280 may perform the function of a needle adjustment mechanism.

As shown in Figures 46 and 47, the distal end portion 12282 of the coupling member 12280 15 includes three contact members 12283. Each of the contact members 12283 has a surface that includes a reverse indented beaded pull pattern 12284. The contact members 12283 are configured to contact a surface of the target tissue (e.g., the conjunctiva of the eye) during use to facilitate insertion of a lancing member (not shown) and/or injection of a drug formulation into the target tissue. The distal end portion 12282 of the coupling member 12280 and/or the contact members 12283 may be any suitable structure configured to couple the

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY target tissue (as described herein). For example, in some embodiments, the distal end portion 12282 of the coupling member 12280 and/or the contact members 12283 may be any suitable structure configured to grip, retain, and/or deform a portion of the target tissue (e.g., the conjunctiva of the eye). As shown, at least a portion of the distal end portion 12282 and/or the contact members 12283 have a curved shape. The curved shape, for example, may be such that the contact members 12283 are configured to contact a portion of the eye (e.g., the conjunctiva) along a line tangent to a portion of the contact members 12283. In addition to this example, the curved shape of the portion of the contact members 12283 15 may allow a desired distribution of force(s) to be applied to a portion of the eye.

In some embodiments, the contact members 12283 may create a spherical injection site shown. For example, the contact members 12283 may deform in a radial direction from the center point (i.e., spaced from where the puncture member penetrates) as the delivery device (not shown) moves from a first configuration to a second configuration. In this way, the conjunctiva can be moved 25 in and/or retained in a preferable position during the

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Mexican Institute of Industrial Property injection, in some cases, this can reduce puncture forces to penetrate the surface of the eye. In some embodiments, stretching the conjunctiva can minimize and/or eliminate any bunching of the conjunctiva that might otherwise occur, and preferably can produce a surface layer (e.g., conjunctiva) that has a substantially constant thickness. In some cases, the contact members 12283 may, at least temporarily, adhere to a portion of the surface layer (e.g., the conjunctiva). In this manner, the contact members 12283 may cause movement of and/or stabilize at least a portion of the surface layer such that at least the portion of the surface layer is in a preferable position during injection.

In some embodiments, the coupling member

12280 (and any of the coupling and/or adjustment members shown and described herein) can form a substantially fluid-tight seal and/or a substantially liquid-tight seal with the external surface of the target tissue (e.g., the conjunctiva of the eye). In this way, leakage of the injected medicament along the needle path during the injection event can be reduced and/or eliminated. Expanding further, in some modalities, the anatomy of the target tissue and/or the arrangement of the delivery device may be such that

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY that, in use, a portion of the needle opening (not shown) may be placed in fluid communication with the suprachoroidal space (e.g., suprachoroidal space 36 in Figure 1) of the eye, while another portion of the needle opening 5 may be positioned within the sclera 20 (e.g., sclera 20 in Figure 1). Thus, when the drug formulation is delivered into the eye via the needle (not shown), a portion of the drug formulation may be prone to migrate away from the desired region (e.g., the suprachoroidal space 36 in Figure 1) and out of the eye via the needle track. By forming a substantially fluid-tight seal and/or a substantially liquid-tight seal, the coupling member 12280 (e.g., the surface of the contact members 12283) can produce an area of high flow resistance, thereby minimizing and/or eliminating flow migration and/or leakage.

In some embodiments, the coupling member 12280 may be constructed from a relatively soft material, which may be well suited for forming a fluid-tight seal. In still other embodiments, the coupling member 12280 may be constructed from multiple materials. For example, in some embodiments, the contact members 12283 of the coupling member 12280 may be constructed from

<img file="MX372859B_D0200.tif" />

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205 and/or may include a layer or portion constructed from a material formulated to form a substantially fluid-tight seal with the outer surface of the target tissue (e.g., the conjunctiva). Although contact members 12283 are shown and described above as including a ridged surface. In other embodiments, contact members 883 may include any suitable surface features. For example, as shown in Figure 48, in some embodiments, a coupling member 13280 may include a plurality of contact members 13283 having a smooth surface. As another example, as shown in Figure 49, in some embodiments, a coupling member 14280 may include a plurality of contact members 14283 having a ridged and/or stepped surface. In other embodiments, for example, a coupling member may include a contact member having a ridged surface (e.g., similar to that shown in Figure 52).

In other embodiments, a coupling member 20 and/or contact members may include any combination of suitable surface features. Thus, for example, a coupling member may include a first contact member with a smooth surface and a second contact member with a ridged surface. As another example, a contact member may include a

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206 first portion having a ridged surface and a second portion having a flanged surface.

Although shown as including three contact members, in other embodiments, a coupling member, hub, and/or adjustment member may include any number of contact members. For example, Figures 50-55 are illustrations of delivery devices in accordance with various embodiments. In particular, Figure 50 is a perspective view of a coupling member 15280 in accordance with some embodiments. Figure 51 is a perspective view of a coupling member 16280 in accordance with some embodiments. As shown, for example, in Figures 50 and 51, in some embodiments, the coupling member 15280, 16280 may include contact members 15283, 16283 that are curved in a spherical manner. In addition to this example, in some embodiments, the contact member 15283 may include an indented surface (e.g., Figure 50). In still other embodiments, for example, the contact member 16283 may include a smooth surface (e.g., Figure 51). Figure 52 is a perspective view of a coupling member 17280 in accordance with some embodiments. Figure 53 is a perspective view of a coupling member 18280 in accordance with some embodiments. As shown, for example, in Figures 52 and 53, in some embodiments, the

<img file="MX372859B_D0202.tif" />

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OF THE PROPERTY

INDUSTRIAL

207 Coupling member 17280, 18280 may include contact members 17283, 18283 that are curved in a planar manner. In addition to this example, in some embodiments, contact member 172823 may include a ridged surface (e.g., Figure 52). In still other embodiments, for example, contact member 18283 may include a smooth surface (e.g., Figure 53). Figure 54 shows a perspective view of the coupling member 18280 in use with the delivery device 18000 for coupling to an eye and/or delivering a medicament thereto, in accordance with one embodiment. The delivery device may be similar to the delivery device 100, 400,

1000, 2000, 3000, 7000, or any other medical delivery device or injector described herein. The

Figure 55 shows a cross-sectional view of the perspective view shown in Figure 54. The delivery device 18000 includes a hub 18270, a puncture member 18240 (also referred to herein as a delivery member or a needle), and a coupling member 18280.

In use, a user (e.g., a doctor, technician, nurse, specialist, ophthalmologist, etc.) may manipulate the delivery device 18000 to insert the lancing member 18240 into, e.g., a portion of the eye (e.g., eye 10 shown in Figure 1). In this way,

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY manner, the user may apply a distal force such that puncture member 18240 is advanced distally relative to and/or through coupling member 18280 (e.g., as shown by arrow Fi along the longitudinal axis ΆA in Figure 55). In this manner, a portion of puncture member 11080 may be advanced through a portion of the eye.

In some embodiments, an ocular injection system may include any of the hubs described herein and/or a drug extraction device configured to mate matingly with a housing and/or a drug delivery container. For example, referring now to Figures 56-71, in some embodiments, a system 19000 may include a housing 19110, an actuator 19320, a drive member 19320, and actuating member 19340.

19140, a drug containment chamber 19310, a hub 19270, a needle 19240, and a cap 19280. The system 19000 may be configured to deliver a substance, e.g., a drug, to a target tissue, e.g., the SCS of an eye.

The housing 19110 (Figure 57) includes a first portion 19110a, and a second portion 19110b (collectively 19110) that can be coupled together to define an internal region for housing at least a portion of the drug containment chamber 19310 and the

<img file="MX372859B_D0204.tif" />

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209 actuator 19320. Housing 19110 includes a grip portion 19112 to allow a user to grasp housing 19110 between his or her index and middle fingers. Housing 1911 also includes ridges 19114 to allow easy gripping of housing 19110 by the user. For example, the user may grasp the gripping portion 19112 with one hand and grasp the ridges 19114 with the fingers of a second hand during injection, e.g., delivering a medicament into a target tissue (e.g., ocular tissue). In this manner, the user may reduce any lateral movement of the system 19000 during medicament delivery. A plurality of windows 19116 are defined in a side wall of the housing 19110. The series of windows 19116 may be configured to allow the user to view the interior volume of the medication containment chamber 19310, for example, to view a level of a medication remaining in the medication containment chamber 19310. The housing 19110 also includes a series of slots 19118, each slot configured to slidably receive a spline 19323 included in an engaging portion 19322 of the actuator 19320, the series of slots being configured to maintain the actuator 19320 aligned as the actuator 19320 is moved within the housing 19110 and the drug containment chamber 19310.

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MEXICAN INSTITUTE^r OF THE PROPERTY

INDUSTRIAL 210.

As shown in Figures 57 and 58, the actuator 19320 includes a coupling portion 19322 and a plunger portion 19324. The coupling portion 19322 includes a series of slidably arranged splines 19323 in the series of slots 19118 of the housing 19110, as described above. A portion of the coupling portion 19322 is disposed in a cavity 19146 defined by the drive member 19140 (see, e.g., Figure 62). The plunger portion 19324 includes a projection 19327 disposed at a distal end of the actuator 19320. The projection 19327 may be configured to be disposed in a cavity 19335 defined by a close tolerance (e.g., friction fit) plunger 19328, as described herein. The plunger 19328 (Figures 5915-60) is disposed in the internal volume 19316 defined by the drug containment chamber 19310. The plunger 19328 includes a proximal end 19332 coupled to the plunger portion 19324 of the actuator 19320 and a distal end 19334 in fluid communication with a medicament or other liquid disposed in the internal volume 19316 defined by the medicament containment chamber 19310. The plunger 19328 may be made of a rigid but soft material, e.g., rubber, and includes the cavity 19335 configured to receive the projection 19327 of the actuator 19320 with close tolerance (e.g., friction fit). The plunger 19328

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211 includes a first side wall 19336a and a second side wall 19336b (collectively referred to as side walls 19336) in contact with a side wall of the internal volume 19316 of the drug containment chamber 19310. The side walls 19336 form a substantially fluid-tight seal with the side walls of the internal volume 19316 defined by the drug containment chamber 19310. In this way, the plunger 19328 can prevent leakage of the liquid medicine from the internal volume 19316, for example, leakage of the medicine in a portion of the internal volume 19316 within which the plunger portion 19324 of the actuator 19320 is disposed.

The actuating member 19140 (Figures 61-62) includes a depression 19142, configured to conform to a user's thumb, for example, to allow easy movement of the actuating member 19140 by the user. The actuating member 19140 also includes ridges 19144 configured to allow easy gripping of the actuating member 19140, for example, when loading a medicament into the medicament holding chamber.

19310. The drive member 19140 also includes a cavity 19146, configured to slidably receive a portion of the coupling portion 19322 of the actuator 19320 with close tolerance (e.g., friction fit). In some embodiments, the coupling member 19322 is configured to be coupled to the coupling portion 19322 of the actuator 19320.

212 19140 may be configured to be engaged by a user to manually move the plunger portion 19324 of the actuator 19320 within the internal volume 19316 of the drug containment chamber 19310. In some embodiments, the actuation member 19140 may be included in an injection assembly, for example, the injection assembly 100, 2100, or any other injection assembly described herein, which may be included in the system 19000. The drive member 19140 may be configured to activate the injection assembly, for example, to release and/or move the actuator 19320 such that the plunger portion 19324 moves within the internal volume 19316 and expels at least a portion of the medicament through the needle 19240 (for example, into the SCS of the eye).

As shown in Figures 63-65, the drug containment chamber 19310 defines an internal volume 19316, configured to house a drug. The drug containment chamber 19310 includes a delivery portion 19324. A first series of threads 19318a and a second series of threads 19318b (Figure 63) are formed on an outer wall of the delivery portion 19314. In other words, the outer wall of the delivery portion 19314 includes double star threads. Threads 19318 are configured to allow coupling of drug containment chamber 19310 to a coupling portion

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19272 of the hub 19270. In some embodiments, any other hub, an injection site marker, for example, the injection site marker 20280 described below, and/or an extraction device, for example, the extraction device 21280, can be coupled to the delivery portion 19324 via the threads 19318. The supply portion 19314 includes a first cavity 19315 configured to receive a coupling portion 19273 (for example, a nozzle) of the hub 19270, such that a fluidic channel 19317 included in the supply portion

19314 is in fluid communication with a first fluidic channel 19277 included in the coupling portion 19273 of the hub 19270. The drug containment chamber 19310 also includes a second cavity 19313. The coupling portion 19322 of the actuator 19320 is disposed within the second cavity 19313 and is configured to be slidably displaced within the second cavity 19313.

As shown in Figures 66-67, the hub 19270 20 includes a coupling portion 19273, a coupling portion 19272, and a supply portion 19274. An inner side wall of the coupling portion 19273 and an outer side wall of the coupling portion 19272 define a cavity 19275 configured to receive the supply portion 19314 of the drug containment chamber.

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19310. The inner side wall of the coupling portion 19272 includes threads 19278, configured to engage the threads 19318a and/or 19318b of the drug containment chamber 19310, thereby coupling the hub 19270 to the drug containment chamber 19310. An outer side wall of the coupling portion 19272 includes a series of ridges 19276. Ridges 19276 may facilitate a user in grasping hub 19270, for example, by engaging or disengaging hub 19270 from drug containment chamber 19230. Engaging portion 19273 defines a fluidic channel 19277 configured to engage fluidic channel 19317 of drug containment chamber 19130 and establish fluidic communication between drug containment chamber 19130 and hub 19270. The delivery portion 19274 defines a second fluidic channel 19279 configured to removably receive the needle 19240, for example, a microneedle (for example, any suitable microneedle described herein). The needle 19240 is configured to be disposed within a target tissue 20, e.g., ocular tissue, and defines a lumen 19241 such that the needle 19240 is configured to establish fluid communication between the drug-containing chamber 19310 and the user's body portion (e.g., the eye). In some embodiments, the needle 19240 may be fixedly disposed in the second channel 19240.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY fluidic 19279. In some embodiments, needle 19240 may be formed monolithically with hub 19270 such that second fluidic channel 19279 and needle lumen 19241 are continuously and/or seamlessly formed.

As shown in Figures 68 and 69, the cover

19280 includes a mating portion 19282 including a first cavity 19283 configured to slidably receive the mating portion 19272 of the hub 19270. A series of grooves 19285 is formed in an inner side wall 10 of the mating portion 19282 configured to mate with the series of ridges 19276 of the hub 19270 with close tolerance (e.g., friction fit). The lid 19280 also includes a mating portion 19284 defining a second cavity 19284 configured to receive the delivery portion 19274 of the hub 19270. At least a portion of an outer side wall of the mating portion 19284 is substantially planar, for example, to allow a user to easily grasp the lid 19280 (e.g., to engage or disengage the hub 19270 from the drug containment chamber).

1150). The cap 19280 may thus allow for secure coupling/decoupling of the hub 19270 to the medication containment chamber 19310 and/or prevent accidental piercing of a portion of a user's body by the needle 19240 during manipulation of the

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY system 19000.

Referring now to Figures 70-71, Figure 70 shows the system 19000 in a first configuration, such that the actuator 19320 and the drive member 19140 are in a first position and the internal volume

19316 of the medication containment chamber 19310 is at least partially filled with the medication. A user may now engage the actuating member 19140 by applying a force in the direction shown by arrow F 10 to the actuating member 19140, for example, using a user's thumb. This drives the actuator 19320, which is coupled to the drive member 19140, to move along a longitudinal axis ΆA of the system 19000 and drive the system 19000 in the second configuration 15 as shown in Figure 71. In the second configuration, the actuator 19320 is moved from the first position to a second position within the internal volume 19316 of the drug containment chamber 19310. This movement causes the plunger 19328, which is in fluid communication with the medicament, to slide from the first position to the second position within the internal volume 19316. The movement expels the medicament from the internal volume 19316 into the fluidic channel 19277 of the hub 19270, and further through the lumen 19241 of the needle 19240 into the target tissue (e.g., the eye).

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217

In some embodiments, an ocular injection system may include an injection marker for marking an injection site in a target tissue, e.g., ocular tissue. Figures 72-73 show a perspective view 5 of an injection site marker 20280 in accordance with one embodiment. As shown, a proximal end 20282 of injection site marker 20280 may be coupled to a delivery device, for example, coupled to coupling portion 19272 of hub 19270 included in system 19000. Injection site marker 20280 has a distal end 20284, which includes a plurality of protrusions 20286 disposed on a distal end surface of distal end 20284. In some embodiments, the proximal end 20282 of the injection site marker

20280 may be used in conjunction with and/or coupled to any of the hubs, coupling members, and/or adjustment members described herein. For example, in some embodiments, injection site marker 20280 may be threadably coupled to a hub of a delivery device (e.g., hub 19270 of delivery device 19000). In other embodiments, for example, the injection site marker 20280 may be friction fit (e.g., interference fit, snap fit, friction fit, etc.).

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In some embodiments, the protrusions 20286 of the distal end 20284 of the injection site marker 20280 may be configured to contact a portion of the eye (e.g., the eye 10 shown in Figure 1), in some embodiments, for example, the protrusions 20286 of the injection site marker 20280 may be configured to leave a mark on a portion of the eye. The mark may, for example, indicate an injection site. For example, the marks may appear as parallel indentations in the conjunctiva of the eye, indicating to the user that the injection is to be performed in the region between the parallel marks. In addition to this example, in some embodiments, the injection site marker 20280 may be removably coupled to a delivery device (e.g., delivery device 19000). In such embodiments, the injection site marker 20280 may be removed from the delivery device after marking the injection site in the target tissue. A needle and/or hub assembly including a needle, e.g., needle 19240 coupled thereto may then be coupled to the delivery device which may be used to deliver the medicament to the injection site marked by the injection site marker 20280. In some embodiments, an injection site marker may define a passageway to allow a needle to pass through.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY this. In such embodiments, the injection site marker may remain attached to the delivery device during delivery of the drug to the target tissue,

In some embodiments, a system for delivering medications may include a withdrawal device for withdrawing medications or other fluid from a container, e.g., a vial. Referring now to Figure 74-80, a system 21000 includes a housing 21110, an actuator (not shown), a drive member

21140, a medicament containment chamber 21310, and an extraction member 21280. The system 21000, which includes the extraction member 21280, can be used to extract a liquid medicament from a medicament container 21294. The housing 21110, the actuator, the medicament containment chamber 21310, and actuating member

21140 of system 21000 may be substantially similar in structure and function to the components of system 19000 described above, and are therefore not described in further detail herein.

Figure 74 shows the extraction member 21280 not coupled from the drug containment chamber 21310 while Figure 75 shows the extraction member 21280 coupled to the drug containment chamber 21310. As shown in Figure 76, the extraction member 21280 includes a portion of

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY coupling 21281, a coupling portion 21284 and an extraction portion 21288. Threads 21282 are formed on an inner side wall of the coupling portion that are configured to mate with the threads 21318a and 21318b of the drug containment chamber 21310 and couple the extraction member 21280 to the drug containment chamber 21310. A plurality of ridges 21283 are formed on an outer side wall of the coupling portion 21281. The ridges 21283 may, for example, serve as 10 grips to facilitate a user to couple/decouple the extraction member 21280 to the drug containing chamber 21250. The inner side wall of the coupling portion 21281 and an outer side wall of the coupling portion 21284 define a cavity 21285, configured to receive a portion of the drug containment chamber 21310, when the extraction member 21280 is coupled to the drug containment chamber 21310. The coupling portion 21284 includes a fluidic channel 21286 configured to establish fluid communication between the extraction member 21280 and the drug containment chamber 21250, for example, to allow fluid communication from the extraction member 21280 (e.g., liquid drug extracted from a drug vial) to the drug containment chamber 21250.

The extraction portion 21288 is configured

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY to be releasably coupled to a container 21294 containing a medication, and establish fluid communication between the container 21294 and the medication containment chamber 21310 by means of the extraction member 21280. The extraction portion 21288 includes a series of arms

21289. Each of the series of arms 21289 has an angled portion configured to flex open to receive a lid of the container, for example, container 21294. Each of the series of arms 21289 also includes a profile 10 21290 configured to secure the lid of the container, for example, container 21294 when the container is coupled to the extraction member 21280, as shown in Figure 75. The extraction portion 21288 also includes a piercing member 21291 defining a fluidic channel 21292. The piercing member 21291 is configured to pierce a seal of a container, for example, container 21294, and establish fluid communication between the container and the drug containment chamber 21310, via the extraction member 21280, as described herein.

Figure 77 shows a perspective view of the sj αΤατπα 21000 in a first configuration, such that the container 21294 is not coupled from the extraction member 21280. The container 21294 includes a lid 21296 25 having a seal 21297, for example, a septum (e.g.,

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY a rubber septum), and defines an internal volume to accommodate a liquid medicament. Figure 78 shows a sectional view of the perspective view shown in Figure 77, but only the extraction member 21280 and the container 21294 are shown for clarity. A user can apply a force shown by arrow F₂ (Figure 78) along a longitudinal axis BB of the system 2100 to urge the extraction member 21280 towards the container 21294. Optionally, a force may also be applied to the container 21294 to urge the container 21294 towards the extraction member 21280. This urges the system 21000 in the second configuration (Figures 79-80) such that the extraction member 21280 is releasably coupled to the lid 1296 of the container 21294. As shown in sectional view 15 of Figure 80, in the second configuration a surface of the profile 21290 included in each of the series of arms 21289 of the extraction member 21280, is brought into contact with a small portion of a lower surface of the lid 21296 of the container 21294. In this way, the container 21294 is releasably secured to the extraction member 21280. In addition, the piercing member 21291 pierces the seal 21297 of the lid 21296 included in the container 21294 to establish fluid communication between the container 21294 and the medicine containment chamber 21310 via the extraction member 21280. The medicine

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY may now be removed from container 21294 by a user by engaging drive member 21240, as described herein with reference to system 19000 (Figures 70-71). To disengage container 21294 from extraction member 21280, the user may simply pull container 21294 away from the extraction member in a direction opposite to the direction indicated by arrow F.₂ (Figure 78).

In some embodiments, a system for injecting a medicament into ocular tissue, for example, the SCS, may include a mechanism for inserting the piercing member as well as delivering the medicament. Referring now to Figures 81-83, a system 22000 includes a housing 22110, a needle assembly 22200 including a piercing member 22240 and a hub 22270, and a medicament-containing chamber 22310. At least a portion of an actuator (not shown) may be disposed in the drug containment chamber 22310. The actuator is configured to communicate a drug disposed in an internal volume of the drug containment chamber 22310 into an ocular tissue, for example, the SCS of an eye.

The housing 22110 is ergonomically shaped and includes ridges 22114 to allow a user to easily grip the housing 22110. The housing 22110 may

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224 define an internal volume within which at least a portion of the drug containment chamber 22310 and the actuator may be disposed. In some embodiments, an injector assembly, for example, injector assembly 2100 or any other injector assembly described herein may be disposed in housing 22110. Housing 22110 is configured to move laterally along a longitudinal axis A_L of the system 22000, between a first configuration shown in Figure 81 and a second configuration shown in Figure 83. In this way, the housing 22110 can move the actuator and extract into or expel out a medicament from the medicament containment chamber 22310. In some embodiments, the housing 22110 can also be configured to insert the piercing member 22240 into ocular tissue.

The medication containment chamber 22310 defines an internal volume within which a medication may be disposed. A series of indicia 22315 may be defined on an external surface of the medication containment chamber 22310. The medication containment chamber 22310 may be substantially transparent such that the user may visually observe a volume of the medication disposed in the internal volume and use the markings 22315 to determine the amount of medication remaining. In some

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY embodiments, the drug containment chamber 22310 may be substantially similar to the drug containment chamber 1310, 2310, 3310, or any other drug containment chamber described herein.

The needle assembly 22200 includes a housing 22210 that may define an internal volume configured to house components of the needle assembly 22200. A plurality of ridges 22216 are disposed on an external surface of the housing 22210. The ridges 22216 are configured to allow a user to easily grasp the housing 22210 (e.g., to rotate the housing 22210). The needle assembly 22200 may be configured to adjust a length of the piercing member 22240 protruding from a distal end 22274 of the hub 22270. For example, a user may rotate the needle assembly 22200 about the longitudinal axis A._Lto adjust a length of the piercing member 22240 protruding from a distal end 22272 of the hub 22270. In some embodiments, the needle assembly 22200 may include an adjustment member, a lead screw, bushing, bearing, locking pin, marks, or any other components as described with respect to the needle assembly 3200 described herein,

The piercing member 22240 is configured to be inserted into the eye and to deliver a

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY medication in the eye. The piercing member 22240 may be substantially similar to the piercing member 3240 or any other piercing member described herein. At least a portion of the piercing member

22240 is disposed in hub 22270. For example, a portion of the proximal end of piercing member 22240 may be disposed in a passageway defined by hub 22270. Hub 22270 includes a proximal end 22272 and a distal end 22274. Distal end 22274 may be curved, for example, defining a convex or hemispherical shape. A distal end surface of the distal end 22274 may define a sealing portion configured to contact an external surface of the eye, e.g., the conjunctiva, and form a substantially fluid-tight seal around an insertion site of the piercing member 22240, as described with respect to the hub 7270. The proximal end 22272 of the hub 22270 may be removably or fixedly coupled to a distal portion of the housing 22210. For example, the proximal end

22272 may include a friction fit, press fit, threads, splines, notches, grooves, detents, or any other suitable coupling mechanism for coupling the hub 22270 to the housing 22210. In some embodiments, the hub 3270, 7270, 8270, 9270, or any other hub described herein may be coupled to the housing 22210.

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In a first configuration shown in Figure 81, the housing 22210 may be disposed distally relative to the needle assembly 22200 and the drug containment chamber 22310. The drug may be disposed in the internal volume of the drug containment chamber 22310. In the second configuration, shown in Figure 83, a user may dispose the hub 22270 of the system 22000 on an outer layer of the eye (e.g., the conjunctiva C). The user may then exert a force 10 on the housing 22110 in the direction shown by arrow F3 to move the housing 22110 proximally relative to the needle assembly 22200. This may cause the piercing member 22240 to be inserted into ocular tissue, for example, a sclera of the eye, and the drug to be expelled from the internal volume of the drug-containing chamber 22310. The user may use the needle assembly 22200 to adjust an insertion depth of the piercing member 22240 to ensure that the medicament is delivered to the target ocular tissue 20 (e.g., the SCS).

In some embodiments, a needle adjustment mechanism may include adjusting the insertion depth of a needle into a target tissue, e.g., ocular tissue, by varying the force on a drive rod 25 included in a medical injector. For example, Figures 84A

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY and 84B show a portion of a medical injector 23000, including a drive rod 23320 and a needle disposed in a target tissue in a first configuration and a second configuration, respectively, in accordance with one embodiment. A distal end portion of the drive rod 23320 is disposed in a drug container included in the medical injector. The medical injector may be substantially similar to the drug container 130, 1310, 2310, 3310, or any other drug container described herein. The needle 23240 may be any suitable puncture member, for example, a microneedle (e.g., a 27 gauge needle, a 30 gauge needle, or even smaller). The medical injector 23000 also includes a needle adjustment mechanism that can be used to adjust the distance that the distal tip of the needle 23240 travels in the target tissue, for example, ocular tissue based on the magnitude of the force applied at a proximal portion, for example, an engagement portion of the drive rod 23320. By way of example, in some embodiments, the needle adjustment assembly may include any suitable mechanism configured to increase the distance that the distal tip of the needle 23240 travels in the target tissue based on the force applied to the drive rod 23320. The forces applied to the rod

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY drive 23320 may continue to increase the distance traveled by the distal tip of the needle 23240 without delivering the drug from the distal tip of the needle 23240, until the distal tip of the needle 23240 is disposed within a target region (e.g., the SCS) of the target tissue. The force may then, for example, overcome the back pressure of the target region of the target tissue so that the distal tip of the needle 23240 does not travel any further into the target tissue and the drug is delivered to the target region. The needle adjustment mechanism may include any suitable components such as, for example, a biasing member (e.g., a spring or a hydraulic biasing member), one or more valves, and/or a force-sensing mechanism. In some embodiments, the forces applied to the actuating rod 23320 may be manually adjusted, for example, by haptic feedback to a user engaging the actuating rod 23320. In some embodiments, an automated force adjustment mechanism, for example, included in the needle adjustment mechanism or an injection assembly (e.g., injection assembly 100, 2100, or any other injection assembly described herein) may be used to adjust the force and thereby control the insertion depth of the distal tip of the needle.

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230

23240.

For example, the distal tip of the needle 23240 may be inserted into ocular tissue and configured to deliver a medicament to the SCS of the ocular tissue. In the first configuration shown in Figure 84Ά, a first force Fi is applied to the drive rod 23320. The first force Fi (e.g., less than about 2 N) may be sufficient to overcome the back pressure of the conjunctiva (not shown) and achieve insertion into the sclera.

S, but insufficient to drive the distal tip of needle 23240 to travel through the thickness of the sclera S and be disposed in the SCS. The user can then apply a second force F₂ greater than the first force F and sufficient to overcome a back pressure and/or density of the sclera S such that the distal tip of the needle 23240 travels through the sclera S and is disposed within or near the SCS. In some embodiments, the second force F2 may be between about 2N and about 6N, e.g., about 3N, about 4N, about 5N, or any other range or value therebetween. The user may maintain the force F₂ so that once the distal tip of needle 23240 reaches the SCS, the force F₂ can overcome the back pressure of the SCS and thus deliver the drug to the SCS. In some embodiments, the transition from the first force Fi to

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY the second force F₂ It may be gradual. For example, the force applied to the actuator may be slowly increased from force Fi until the force has a sufficient magnitude (e.g., substantially equal to the second force F).₂) to drive the distal tip of needle 23240 to travel through the sclera S and be disposed in the SCS.

In some embodiments, a medical injector may include an injection assembly including a drive member configured to drive an actuating rod included in the medical injector. For example, Figures 85A and 85B show a medical injector 24000 including a drug container, a needle, and an injection assembly, in a first and second configuration respectively, in accordance with one embodiment. The injection assembly includes an actuating member 24120 and an actuating rod 24320. The injection assembly may include other components such as, for example, an energy storage member (e.g., a spring, a compressed gas cylinder, or a propellant container), a release member (e.g., a lock, latch, a pawl), a guide rod, or any of the other components described with respect to the injection assembly 100, 2100, or any other injection assembly described herein. In some embodiments, the

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY drive member 24120 may be configured to engage and/or secure a portion of the proximal end of the drive rod 24120. In some embodiments, the drive member 24120 may be configured to engage or otherwise secure a portion of the proximal end of the drive rod 24120. The drive member 24120 may be engaged by a user such that the drive member 24120 releases the drive rod 24320 or drives the release member to release the drive rod 24320. This may allow a portion of the distal end of the drive rod 24320 to move within the medicament container, as shown in Figure 85B.

For example, as shown in Figure 84A-B, the drive member 24120 includes a lever-like member that may be disposed on a side wall of a housing coupled to the medicament container. In the first configuration shown in Figure 84A, the drive member may be in a first position in which a distal end of the drive member 24120 is distally disposed in the medicament container. In the first configuration, a portion of the proximal end 25 of the drive member 24120 may be engaged by the

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY drive member 24120 or the release member and prevent a deflection of the end portion of the drive rod 24320 from moving within the medication container. In addition, an energy storage member 5 or a deflection member may be coupled to the proximal end portion of the drive rod 24320. In the second configuration shown in Figure 84B, a user may engage the drive member 24120, for example, to move a distal end 10 of the drive member 24120 proximally relative to the drug-containing chamber in a direction shown by arrow A. This may urge the drive member to release the proximal end portion of the drive rod 24320. In some embodiments, the coupling of the drive member

24120 may engage a release member by engaging or otherwise securing the proximal end portion of the drive rod 2320 such that the release member releases the proximal end portion of the drive rod 24320. The energy storage member or biasing member coupled to the proximal end portion of the drive rod 24320 may then urge the distal end portion of the drive rod 24320 to move within the drug container and thereby deliver drug to a

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY target tissue using the needle.

In some embodiments, a medical injector may include a needle adjustment mechanism that includes a wheel. For example, Figure 86 shows a medical injector 25000 that may include a drug container, a needle assembly 25200, and a needle 25240. The needle adjustment mechanism 25200 includes a wheel 25230. The wheel 25230 is pivotally mounted in a housing of the medical injector 25000. The wheel 25230 may include a plurality of 10 projections defined thereon, which can be engaged by a user to move or otherwise rotate the wheel 25230. The wheel 25230 can be configured to be rotated in discrete angular displacements, such that each discrete angular displacement corresponds to a discrete adjustment of the length of a portion of the needle 25240 emerging from a distal end of a housing, or a hub coupled to the housing. In some embodiments, each discrete angular displacement may correspond to a length adjustment of approximately 100 microns of the needle.

25240. In this manner, wheel 25230 may allow for digital adjustment of the length of needle 25240. For example, a user may insert a distal tip of the needle a first distance (e.g., corresponding to the depth of the sclera) into a target tissue (e.g., ocular tissue). The user may then couple the

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY wheel 25230 by rotating wheel 25230 around its pivot mount in discrete increments as described herein. This may adjust the length of the needle 25240 such that a distal tip of the needle 25240 travels a second distance into the target tissue (e.g., corresponding to the depth of the SCS) such that the distal tip of the needle 25240 is disposed within or near a target region (e.g., the SCS) of the target tissue. The medical injector 25000 may deliver at least a portion of the medicament disposed within the medicament container into the target tissue (e.g., the SCS). For example, an injection assembly (e.g., injection assembly 100, 2100, or any other injection assembly described herein) included in medical injector 25000 may be configured to initiate delivery of the medicament to the target region (e.g., the SCS), thereby informing the user that the distal tip of needle 25240 is disposed in the target region. In some embodiments, wheel 25230 may also be configured to move a distal end of a drive rod disposed within the drug container, for example, to deliver the drug to the target tissue via needle 25240.

In some embodiments, a medical injector may include a pressure-assist assembly configured to

<img file="MX372859B_D0229.tif" />

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Mexican Institute of Industrial Property exert a pressure on a portion of the proximal end of an actuating rod and assist, facilitate, and/or affect the delivery of a medicament from a medicament container. For example, Figure 87 shows a portion of a medical injector 26000 that includes a housing 26110, a pressure-assist assembly that includes an actuating member 26120, and a medicament container 26310 coupled to the housing 26110. A needle is also coupled to the medication container 26310 and in fluid communication with a medication disposed within the medication container 26310. As shown, in some embodiments, the actuating member 26120 may be a button disposed within a side wall of the housing 26110. The pressure-assist assembly may also include other components such as, for example, one or more energy storage members (e.g., a spring, a compressed gas container, or a propellant container). The energy storage member may be coupled to a proximal end portion of an actuating rod 20 included in the medical injector 26000. A distal end portion of the drive rod may be disposed within the drug container 26310 and configured to move within the drug container 26310. In some embodiments, the pressure assist assembly 25 may also include a release member configured to move within the drug container 26310.

<img file="MX372859B_D0230.tif" />

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Mexican Institute of Industrial Property to engage or otherwise secure the proximal end portion of the drive rod in a first configuration in which the medicament container is filled with a volume of the medicament. In such embodiments, the drive member 26120 may be configured to engage the release member and urge the release member to release the proximal end portion of the drive rod. For example, in a second configuration, the drive member 26120 may be engaged (e.g., pressed) by a user thereby urging the release member to release the proximal end portion of the drive rod. The energy storage member may now exert a force on the proximal end portion of the drive rod 15 configured to move a distal end portion of the drive rod within the medicament container 26310. This applies a pressure to the medicament disposed within the medicament container 26310 and dissipates the medicament through a distal end 20 of the needle.

In some embodiments, a medical injector may include a needle adjustment mechanism that includes a leaf spring. For example, Figure 88 shows a portion of a medical injector 27000 that includes a medication container 25 27310, a leaf spring 27230, and a needle.

<img file="MX372859B_D0231.tif" />

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27240 in a first position (solid lines) and a second configuration (dotted lines). Leaf spring 27230 may be coupled to medication container 27310 or a hub coupled to medication container 27310, and configured to move from a first position to a second position in response to a force applied in a direction shown by arrow F. Movement of leaf spring 27230 is configured to allow a distal tip of needle 27240 to be disposed within a target region. More force may be required to move leaf spring 27230 further and move the distal tip of the needle deeper into the target tissue (e.g., ocular tissue). For example, as shown in Figure 88, in the first configuration a distal end surface of leaf spring 27230 may be in contact with the outer surface of the conjunctiva C of an eye. In addition, a limbus 27242 defined at a distal end of needle 27240 may be disposed a first distance Li into the eye as measured by forming a distal end of leaf spring 27230.

27230 so that the limbus 27242 is disposed in the sclera S of the eye. A force F may be applied to move or otherwise compress the leaf spring 27230 and move the limbus 27242 deeper into the eye. For example, a magnitude of the force F may be increased until the leaf spring 27230 moves into the second configuration.

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This also drives the distal end of the needle 27240 to move deeper into the eye, until in the second configuration, the limbus 27242 is disposed a second distance L₂ in the eye as measured from the distal end 5 of leaf spring 27230. The second distance

L₂ may correspond to a depth of the suprachoroidal space within the eye, such that the limbus 27242 is disposed within or near the suprachoroidal space SCS (e.g., the target region) in the second configuration. In this manner, the leaf spring 27230 may be used to adjust a length of the needle 27240 thereby facilitating delivery of a medicament to the target region of a target tissue. In some embodiments, movement of the leaf spring 27230 from the first position to the second position may be configured to move the needle a predetermined distance corresponding to the depth of a target region of a target tissue (e.g., the SCS).

In some embodiments, a needle adjustment mechanism may include an adjustment member movable between a first position and a second position to adjust a distance that the distal tip of a needle travels within a target tissue. For example, Figures 89A and 89B show a portion of a medical injector 28000 that includes a drug container 28310, a hub 28270, a member

<img file="MX372859B_D0233.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY adjustment 28230 and a needle 28240 in a first configuration and a second configuration, respectively.

The medication container 28310 may be substantially similar to the medication container 130, 1310, 2310, 3310, or any other medication container described herein. The proximal end portion of the hub 28270 may be coupled to the medication container 28310 and a distal end portion of the hub 28270 may be coupled to a proximal end of the needle 28240 such that a medication contained within the medication container

28310 is in fluid communication with needle 28240. Hub 28270 may be substantially similar to hub 7270, 8270, 9270, or any other hub described herein. Adjustment member 28230 may be slidably disposed about needle 28240 and configured to be movable between a first position A and a second position B. As shown, the adjustment member 28230 defines a curved surface, which may be configured to conform to the curved surface of a target tissue, e.g., an eye. Movement of the adjustment member 28230 may be used to adjust a distance that a distal tip of the needle 28240 may be inserted into the target tissue, e.g., ocular tissue.

For example, in the first configuration shown 25 in Figure 89A, the adjustment member 28230 may be

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Mexican Institute of Industrial Property disposed in the first position A and a distal tip of the needle 28240 can be inserted a first distance into a target tissue (e.g., into the sclera of an eye). In addition, the curved surface of the adjustment member 5 28230 can contact and conform to an external surface of the target tissue (e.g., the conjunctiva of the eye). A force may be applied to the medical injector 28000, for example, to a proximal end portion of the drug container 28310, or a proximal end portion of a drive rod included in the medical injector 28000. This may urge the adjustment member 28230 to slide and move around the needle 28240 proximally relative to the drug container 28310. The force may be maintained until the adjustment member 28230 moves to position B. This increases the distance that the distal tip of the needle 28240 travels within the target tissue (e.g., ocular tissue), for example, until the distal tip of the needle 28240 is disposed within or near a target region 20 (e.g., the SCS) of the target tissue. In this way, the drug disposed within the drug container 28310 can be delivered to the target region (e.g., the SCS) of the target tissue.

In some embodiments, a needle adjustment assembly may include an adjustment member configured to

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY adjust the length of a needle in discrete increments.

For example, Figures 90A-C show a medical injector 29000 including a medication container 29310, a needle fitting assembly 29200, and a needle 29240 fluidly coupled to the medication container 29310, in a first, second, and third configuration, in accordance with one embodiment. The drug container 29310 may be substantially similar to the drug container 130, 1310, 2310, 3310, or any other drug container 10 described herein. The needle 29240 may include any suitable puncture member, for example, a microneedle, or any other needle described herein.

The needle adjustment mechanism 29200 includes an adjustment member 29230 configured to be engageable by a user 15 to adjust a length of the needle 29240, for example, to control a distance that a distal tip of the needle 29240 travels within a target tissue. By way of example, adjustment member 29230 may be configured to move in discrete increments, e.g., 20 increments of 100 microns such that the length of needle 29240 may be digitally adjusted. For example, as shown in the first configuration of Figure 90A, the needle may have a first length Lx (e.g., about 750 microns) measured from a distal tip 25 of the needle to a distal end of the needle container.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY medicament 29310, or a hub (e.g., any of the hubs described herein) coupled to the distal end of the medicament container 29310. The length Li may be sufficient to insert the distal tip of the needle 29240 into a target tissue such that the distal tip is disposed short of a target region (e.g., the SCS) of the target tissue (e.g., ocular tissue). The adjustment member 29230 may be engaged, for example, pressed into the medicament chamber by a first increment 10 by applying a force F on the adjustment member 29230. This may increase the length of the needle 29240 to a second length L.₂ (e.g., about 850 microns), as shown in Figure 90B measured from the distal tip of needle 29240 to the distal end of drug container 29310, or a hub, (e.g., any of the hubs described herein) coupled to the distal end of drug container 29310. The second length L₂ may be sufficient to insert the distal tip of the needle 29240 deeper into the target tissue but still insufficient to position the distal tip of the needle 29240 in the target tissue. The adjustment member 29230 may be engaged a second time by applying the force F again to the adjustment member 29230. This may further increase the length of the needle 29240 to a third length L₃ (for example, approximately 950 microns) tip measurement

<img file="MX372859B_D0237.tif" />

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244 distal end of needle 29240 to the distal end of drug container 29310, as shown in Figure 90C. The third length L₃ It may be sufficient to insert the distal tip of the needle 29240 deeper into the target tissue such that the distal tip of the needle 29240 is disposed within the target region (e.g., the SCS) of the target tissue. In this way, the delivery of the medicament contained within the medicament container 29310 can be initiated at the target region (e.g., the SCS) of the target tissue, for example, by an injection assembly included in the medical injector 29000.

In some embodiments, a medical injector may include a needle adjustment mechanism configured to allow adjustment of a length of a needle included in the medical injector in a small series of qualitative increments. For example, Figure 91 shows a medical injector 30000 including a needle adjustment mechanism including an adjustment member 30230, and a needle 30240 fluidly coupled to a medicament container. The adjustment member 30230 is slidably disposed within a side wall of a housing of the medical injector 30000. The adjustment member 30230 may be configured to be moved between three discrete positions corresponding to a short length, an intermediate (medium) length, and a long length of the needle emerging from one end.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY distal of the medical injector 30000. The needle adjustment mechanism may include other components such as, for example, notches, grooves, grooves, detents, a locking ball, a biasing member, or any other component configured to allow the adjustment member 30230 to be moved in discrete increments as described herein.

In some embodiments, a medical injector may include a hub configured to allow adjustment of a length of a needle inserted into a target tissue. For example, Figures 92A and 92B show a portion of a medical injector 31000 including a housing 31110, a hub 31270, and a needle 31240, in accordance with one embodiment. Needle 31240 is fixedly coupled to a distal end of housing 31110, for example, fluidly coupled with a drug container disposed within housing 31110. Hub 31270 is coupled to a distal end portion of housing 31110 such that the distal end portion is movable within

0 of a passageway defined by hub 3127 0. In addition, the distal end portion of hub 31270 may define a curved surface configured to conform to a curved surface of a target tissue, for example, an eye. Housing 31110 includes a first ridge 31114a and a second ridge 31114b configured to be paired

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY disposed within recesses 31272 defined in an inner surface of hub 31270. While shown as including two ridges, housing 31110 may include any number of ridges disposed thereon e.g. 3, 4, 5, or even 5 more. Furthermore, hub 31270 may be formed from a flexible material, e.g. rubber, plastics, polymers, or any other flexible material described herein. This may allow the ridges 31114 to slide out of the recesses 31272 in the channel defined by the hub 31270 by application of a force to the housing 31110, in this way either the first recesses 31114a or the second recesses 31114b may be mated with the recesses 31272 to adjust the length of the needle 31240.

For example, as shown in Figure 92B, in a first configuration, the hub 31270 may be disposed in a conjunctiva of an eye such that the curved surface of the distal end portion of the hub 31270 conformally contacts the curved conjunctiva. In the first configuration, the first ridge 31114a may be disposed in the recesses 31272 such that a distal tip of the needle 31240 is not inserted into the eye. A force may be exerted on the housing 31110 to displace the housing 31110 within the channel defined by the hub 31270 while maintaining the curved surface of the hub 31270 in contact with the conjunctiva. This may drive the injector

<img file="MX372859B_D0240.tif" />

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247 31000 in a second configuration in which the second ridge 31114b is disposed within the recesses 31272. Movement of the housing 31110 may also urge the needle 31240 to move within the channel 5 defined by the hub 31270 until a distal tip of the needle 31240 pierces the eye. The distal tip of the needle 31240 may continue to travel in the tissue of the eye until the second ridge 31114b is disposed in the recesses 31272. In some embodiments, the distal tip of the needle 31240 may be disposed within a target region, e.g., the SCS in the second configuration. In some embodiments, the distal tip of the needle 31240 may be disposed near but not within the target region, e.g., the SCS in the second configuration.

SCS of the eye. In such embodiments, the user may increase the force on the housing 31110 to insert the distal tip of the needle 31240 further into the eye, for example, by flexing the side walls of the hub, such that the distal tip of the needle 31240 may be disposed within the target region (e.g., the SCS) 20 of the target tissue.

In some embodiments, a medical injector may include a hub configured to contact an external surface of the target tissue and flex or bend to allow a needle included in the medical injector to be inserted into the target tissue. For example, Figure 93A

248 shows a perspective view of a portion of a medical injector 32000. The medical injector includes a hub 32270, a drug container 32310, and a needle 32240 that can be fluidically coupled to a drug container included in the medical injector 32000. The hub 33270 is coupled to a distal end portion of the drug container 3231Q. The hub 32270 has a hemispherical or semi-hemispherical shape and defines a region therein. The hub 32270 is configured to be disposed at the distal end portion of the housing 32110 such that the needle 32240 is disposed within the region defined by the hub 32270. A distal end surface of the hub 32240 is configured to contact an external surface of a target tissue, for example, the conjunctiva of an eye. Furthermore, the hub 32270 may be formed from a flexible material, e.g., rubber, plastic, polymers, silicone, or any flexible material described herein or a combination thereof. The hub 32270 is configured to flex or bend, e.g., upon application of a force to the medication container 32110. Bending or otherwise flexing may reduce the distance between a distal tip of the needle 32240 and the target tissue, such that the distal tip of the needle 32240 may be disposed within the target tissue.

For example, Figures 93B and 93C show the

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY medical injector 32000 in a first configuration and a second configuration, respectively, in the first configuration, the distal end surface of the hub 32270 is disposed in a target tissue, for example, the conjunctiva of the eye such that a distal tip of the needle 32240 is distal from the outer surface of the target tissue. In other words, in the first configuration, no force is exerted on the hub 32270 such that the hub 32270 is not bent, and the needle 32240 is not inserted into the target tissue. In the second configuration, a force may be applied to the drug container 32310, or any other portion of the medical injector 32000 such that the hub flexes or otherwise bends, reducing the distance between the distal tip of the needle 32240 and the outer surface of the target tissue. The force may be maintained until the distal tip of the needle pierces the target tissue and is disposed within a target tissue (e.g., the SCS) of the target tissue (e.g., an eye).

In some embodiments, a medical injector may include a lancing member included in a medical injector that may be configured to detect light to determine the insertion depth of the lancing member. For example, Figures 94A and 94B show a portion of a lancing member 32240 that may be included in a medical injector, e.g., medical injector 100, 1000,

<img file="MX372859B_D0242.tif" />

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2000, or any other medical injector described herein, in a first configuration and a second configuration, respectively, in accordance with one embodiment. The puncture member 32240 may be configured to communicate light from the target tissue to a light detector, for example, a photodiode included in the medical injector. The puncture member 32240 may be formed from any suitable optically transparent material, for example, an optical fiber. A distal end of the optical fiber may be beveled or otherwise formed into a sharp tip for piercing a target tissue. Furthermore, the distal tip may be optically transparent so that the puncture member can communicate light from the target tissue to the light detector. The presence, absence, or otherwise amount of light communicated by the puncture member 32240 to the sensor may be used to determine the depth of insertion and thus, the region of the target tissue in which the distal end of the puncture member 32240 is disposed.

For example, in the first configuration shown in Figure 94A, the distal end of the lancing member 32240 may be disposed in the sclera S of an eye. The sclera S is opaque so no light is communicated from the lancing member 32240 to the light detector. In the second configuration, the distal tip of the lancing member 32240

<img file="MX372859B_D0243.tif" />

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251 It is inserted deeper into the ocular tissue until at least a portion of the distal tip is disposed within the suprachoroidal space SCS which may be the target region for drug delivery. Since the suprachoroidal space SCS is transparent, light entering the eye and striking the retina R also penetrates the suprachoroidal space SCS. Light may be communicated from the distal tip of the lancing member 32240 to the light detector included in the medical injector thereby confirming that the distal tip of the lancing member 32240 is nonetheless disposed in the target region of the eye. In some embodiments, the medical injector including the lancing member 32240 may alert a user that the distal tip of the lancing member 32240 is disposed within the suprachoroidal space SCS using an audible alert (e.g., a beep, an alarm, etc.), a haptic alert (e.g., vibrations, or minor electrical current), or a visible alert (e.g., a light such as, for example, an LED light, or a visual message). In this way, a user can initiate delivery of the medication through the puncture member 32240 only when the distal tip of the puncture member 32240 is within the suprachoroidal space SCS.

In some embodiments, a kit that includes a medical injector for delivering a medication to a region

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY The purpose of a target fabric may include all or parts of the concepts described herein. For example, in some embodiments, a kit may include a medical injector (e.g., medical injector 10, 1000, 2000, 3000, 21000, 5 or any other medical injector described herein), a transfer assembly which may include, for example, an extraction member (e.g., extraction member 21280), a housing that assists in injection (e.g., injection assembly 2100 or any other injection assembly described herein), a needle adjustment mechanism (e.g., needle assembly 3200, or any other needle assembly described herein), a container or vial of a substance, e.g., a drug or any other substance described herein, replacement needles and/or hubs, one or more speculums, swabs, wipes, antibiotic ointments, eye drops, or any other device or apparatus configured to facilitate delivery of the drug to the target tissue, for example, the eye.

For example, Figure 95 shows a speculum 33400 that may be included in a kit that includes a medical injector 33000, in accordance with one embodiment. The medical injector 33000 may be substantially similar to the medical injector 100, 1000, 2000, 3000, or any other medical injector 25 described herein. The speculum 33400 may be

253 configured to be placed on an external surface of the conjunctiva of the eye and open a patient's eyelids. In this way, the speculum 33400 can facilitate access to the surface of the eye such that the medical injector can be used to deliver a medicament to a target tissue of the eye, for example, the SCS. The speculum 33400 can include an ergonomic handle, which can be comfortably gripped by a user during use. The speculum 33400 also includes a cavity 33410 configured to receive at least a portion of the medical injector 33000. In use, a user may place the speculum 33400 on the conjunctiva of the eye such that the eyelids are forced open.

Furthermore, the cavity 33410 may be located in a target portion of the eye. The user may dispose a distal end portion of the medical injector 33000 in the cavity 33410 and deliver the medicament to a target region (e.g., the SCS) of the eye. In some embodiments, the cavity 33410 may be oriented such that a centerline of a delivery passage of the medical injector 33000 and a tangent to the surface line of a target surface of the eye (e.g., the conjunctiva, sclera, and/or suprachoroidal space SCS) define an entry angle of between about 75 degrees and about 105 degrees, e.g., about 90 degrees. However, cavity 33410 may be configured to prevent

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254 lateral movement of the medical injector so that the centerline of the needle remains substantially normal to the target surface during drug delivery.

In some embodiments, a speculum may include 5 markings to allow measurement of a size, radius, diameter, or other cross-section of an eye. For example, Figure 96 shows a speculum 34400 that may be included in a kit that includes a medical injector (e.g., medical injector 100, 1000, 2000, 3000, or any other medical injector described herein). The speculum 34400 includes two arms. A distal end portion of each of the arms is configured to be disposed on the first and second eyelids. The distal end portion can be moved apart to open the eyelids and allow access to the surface of the eye. The distal portions also include a plurality of markings or indicia. The markings can be used to measure a size of the eye, for example, a size, radius, diameter, or otherwise, a cross-section of the eye. Information on eye size can be used to determine, for example, the thickness of individual layers, e.g., the sclera and SCS. In this way, a user can predict how far a needle needs to be penetrated into the eye such that a distal tip of the needle is disposed in a target region (e.g., the SCS) of the eye.

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255

In some embodiments, a speculum may include mounting features for mounting a medical injector. Referring now to Figure 97, a speculum 35400 includes a plurality of arms configured to open a patient's eyelids and provide access to the eye. The speculum 35400 includes a mount 35410 configured to receive a mounting member 35114 included on a medical injector 35000. The medical injector 35000 may be substantially similar to the medical injector 100, 1000, 2000, 3000, or any other medication container described herein. The mounting member 35410 may include any suitable mounting features, for example, a magnet, threads, snap-fit mechanism, friction-fit mechanism, or any other suitable mounting mechanism configured to mount the medical injector 35000 via the mounting member 35114. In some embodiments, the mount 35114 may include a magnet. In such embodiments, the mounting member 35114 may be formed from a magnetic material, e.g., a ferrous material, such that the mounting member 35114 may be coupled to the mount 35410 via magnetic coupling. In use, the speculum 35400 may be disposed on an eye of a patient. Each arm of the speculum 35400 may be used to open an eyelid of the patient to allow access to the eye. The 35000 medical injector can be mounted on the 35410 mount

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY by means of mounting feature 35114, for example, by magnetic coupling. The medical injector mount 35000 can prevent inadvertent movement of the medical injector 34000 during medication injection, thereby minimizing the risk of eye injury. Furthermore, the speculum 35400 may reduce the risk of user error by positioning the medical injector 35000 to the user so that the user can focus on delivering the medicament to a target region of the eye preferably by correctly positioning the medical injector 35000 in the eye.

In some embodiments, a speculum may include a single-piece speculum. For example, Figures 98A show a single-piece speculum 36400 configured to be disposed on a surface of an eye and open the patient's eyelids. The speculum 36400 defines a cavity 36410 configured to receive at least a portion of a medical injector, for example, the medical injector 33000 or any other medical injector described herein. For example, as shown in Figure 98B, the speculum 36400 may be disposed in the eye such that the cavity 36410 is disposed over a target location of the eye. At least a portion of the medical injector 33000 is then disposed in the cavity 36410 thereby positioning the medical injector 33000 over the target location of the eye.

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Mexican Institute of Industrial Property to supply the drug to a target region within the target location.

Figure 99 shows a schematic flow diagram of a method 500 for delivering a medicament to a target tissue using a medical injector including a hub having a convex distal end surface (e.g., hub 7270, 8270, or hub 9720), coupled thereto. The medical injector may include any of the medical injectors described herein. The method includes inserting a distal end portion of a needle of a medical injector into a target tissue to define a delivery passage within the target tissue 502. The needle may include any suitable puncture member, for example, a microneedle (e.g., a 27 gauge needle, a 30 gauge needle, or even smaller), or any other puncture member described herein. In some embodiments, the target tissue may be ocular tissue, including the conjunctiva, sclera, and suprachoroidal space. In some embodiments, insertion is performed such that the centerline of the delivery passage and a tangent from the surface line to the target surface define an entry angle of between about 75 degrees and about 105 degrees, e.g., about 90 degrees. In some embodiments, the insertion may be performed so that the line

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258 The hub 504 is substantially normal to the target surface. This may, for example, minimize tissue damage and provide the shortest path for a distal tip of the needle to reach a target region of the target tissue (e.g., the SCS). The convex surface of the distal end of the hub is then placed in contact with a target surface of the target tissue to fluidically isolate the delivery passage 504. In some embodiments, positioning may include deforming the target surface. For example, the distal end surface of the hub may include a sealing portion configured to contact and define a substantially fluid-tight seal with the target surface, e.g., the conjunctiva of the eye (e.g., as defined with respect to sealing portion 7277 included in hub 7270). In such embodiments, the sealing portion may be substantially approximately symmetrical to a centerline of the needle. In some embodiments, the sealing portion may be convex. In some embodiments, only a portion of the sealing portion may be configured to contact the target surface of the target tissue to form the substantially fluid-tight seal. For example, a circular band of the sealing portion may contact the target surface and form the substantially fluid-tight seal surrounding the line.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY needle center.

Method 500 further includes transmitting, after placement, a substance into the target tissue via needle 506. In some embodiments, the substance may include a medicament such as, for example, a VEGF, a VEGF inhibitor, or a combination thereof. The substance may be disposed within an internal volume of a medicament container included in the medical injector. An actuating rod may be included in the medical injector, which may be configured to be engaged by a user to fluidly communicate the substance from the drug container to the target tissue via the needle. The medication container and actuator rod may be substantially similar to the medication container and/or actuator rod included in system 100, 1000, 2000, 3000, or any other system or apparatus described herein. In some embodiments, the target tissue may be an eye, and the target surface may be a conjunctiva of the eye. In such embodiments, the delivery passageway may extend through a sclera of the eye, such that transmission includes transmitting a substance into at least one of a suprachoroidal space or an inferior portion of the sclera.

In some embodiments, method 500 may include

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Mexican Institute of Industrial Property may also adjust, prior to transmission, a length of the needle extending from the distal end surface of the hub. For example, the medical injector may include a needle assembly, e.g., needle assembly 3200 or any other needle assembly described herein. The needle assembly may be used to adjust the length of the needle extending from the distal end surface of the hub until a distal tip of the needle is disposed within a target region 10, e.g., the SCS of the eye. The substance, e.g., such as the medicament described herein, may then be delivered to the target region of the eye.

The embodiments described herein may be formed or constructed from one or more biocompatible materials. Examples of suitable biocompatible materials include metals, glasses, ceramics, or polymers. Examples of suitable metals include pharmaceutical-grade stainless steel, gold, titanium, nickel, iron, platinum, tin, chromium, copper, and alloys thereof. The polymer may be biodegradable or non-biodegradable. Examples of suitable biodegradable polymers include polylactides, polyglycolides, polylactide-co-glycolides (PLGA), polyanhydrides, polyorthoesters, polyetheresters, polycaprolactones, polyesteramides,

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY poly(butyric acid), poly(valeric acid), polyurethanes and copolymers and mixtures thereof. Examples of non-biodegradable polymers include nylon, polyesters, polycarbonates, polyacrylates, ethylene-vinyl acetate polymers and other acyl substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulfonate polyolefins, polyethylene oxide, blends and copolymers thereof.

The microneedles described herein can be manufactured by a variety of methods. For example, in some embodiments, the hollow microneedle is manufactured using a laser or similar optical energy source. In one example, a microcannula can be cut using a laser to represent the desired microneedle length. The laser can also be used to form single or multiple tip openings. Single or multiple cuts can be made in a single microcannula to form the desired microneedle structure. In one example, the microcannula can be made of metal such as stainless steel and cut using a laser with a wavelength in the infrared region of the light spectrum (0.7-300 pm). Further refinement can be performed using metal electropolishing techniques familiar to those skilled in the art. In another 25 embodiments, the length of the microneedle and the optional bevel

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262 They are formed by a physical grinding process, which, for example, may include grinding a metal cannula against a moving abrasive surface. The manufacturing process may also include precision grinding, microbead blasting, and ultrasonic cleaning to configure the desired precise microneedle tip shape.

A wide range of ocular diseases and disorders can be treated by the methods and devices described herein. Non-limiting examples of ocular diseases include uveitis, glaucoma, diabetic macular edema or retinopathy, macular degeneration, retinoblastoma, and genetic diseases. The methods described herein are particularly useful for the local delivery of drugs that need to be administered to the posterior region of the eye, for example the retinochoroidal tissue, macula, and optic nerve in the posterior segment of the eye. In one embodiment, the delivery methods and devices described herein can be used in gene-based therapy applications. For example, the methods can administer a fluid drug formulation into the suprachoroidal space to deliver selected DNA, RNA, or oligonucleotides to target ocular tissues.

Microneedles can be used to direct

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263 delivery to specific tissues or regions within the eye or nearby tissue. In various embodiments, the methods can be designed to deliver drug specifically to the sclera, choroid, Brueh's membrane, retinal pigment epithelium, subretinal space, retina, macula, optic disc, optic nerve, ciliary body, trabecular meshwork, aqueous humor, vitreous humor, and other ocular tissues or nearby tissues in need of treatment.

A wide range of drugs can be formulated for delivery to ocular tissues using the systems and devices described herein. However, any of the delivery devices and/or methods described herein may involve, include, and/or contain any of the drugs described herein. For example, in some embodiments, the drug containment chamber 1310, 2310, 3310, or any other drug containment chamber may contain any of the drugs and/or formulations described herein.

As used herein, the term "drug" refers to any prophylactic, therapeutic, or diagnostic agent (e.g., a contrast agent). The drug may be selected from any suitable protein, peptide, or mixture thereof, which may be naturally occurring, synthesized, or recombinantly produced.

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Representative examples of drug types for delivery to ocular tissues include antibodies, antiviral agents, chemotherapeutic agents (e.g., topoisomerase inhibitors), analgesic agents, anesthetics, aptamers, antihistamines, anti-inflammatory agents, and antineoplastic agents. In one embodiment, the drug is triamcinolone or triamcinolone acetonide.

The term antibody is intended to broadly refer to any immunological binding agent such as IgG, IgM, TgA, IgD, and IgE. An antibody may be monoclonal or polyclonal, and in one embodiment, is a humanized antibody. The term antibody is also used to refer to any antibody-like molecule having an antigen-binding region, and includes antibody fragments such as Fab', Fab, F(ab')₂, single domain antibodies (DABs), Fv, scFv (single chain Fv), and engineered multivalent antibody fragments such as diantibodies, triantibodies, and multiantibodies. Techniques for preparing and using various antibody-based constructs and fragments are well known in the art (see, e.g., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988; incorporated herein by reference).

Non-limiting examples of specific drugs and drug classes include β-adrenoceptor antagonists

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY (e.g., carteolol, cetamolol, betaxolol, levobunolol, metipranolol, timolol), miotics (e.g., pilocarpine, carbachol, physostigmine), sympathomimetics (e.g., adrenaline, dipivefrin), carbonic anhydrase inhibitors 5 (e.g., acetazolamide, dorzolamide), topoisomerase inhibitors (e.g., topotecan, irinotecan, camptothecin, lamelarin D, etoposide, teniposide, doxorubicin, miloxantrone, amsacrine), prostaglandins, anti-microbial compounds, including anti-bacterial and anti-fungal (e.g., chloramphenicol, chlortetracycline, ciprofloxacin, franiicetin, fusidic acid, gentamicin, neomycin, norfloxacin, ofloxacin, polymyxin, propamidine, tetracycline, tobramycin, quinolines), antiviral compounds (e.g., acyclovir, eidofovir, idoxuridine, interferons), aldose reductase inhibitors, anti-inflammatory and/or anti-allergy compounds (e.g., steroidal compounds such as betamethasone, clobetasone, dexamethasone, fluorometholone, hydrocortisone, prednisolone and non-steroidal compounds such as antazoline, bronifenae, diclofenac, indomethacin, lodoxamide, saprofen, sodium cromoglycate), artificial tear/dry eye therapies, local anesthetics (e.g., amethocaine, lignocaine, oxbuprocaine, proxymetacaine), cyclosporine, diclofenac, urogastrone and growth factors such as epidermal growth factor 25, mydriatics and cycloplegics,

<img file="MX372859B_D0257.tif" />

266

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY mitomycin C, and collagenase inhibitors and treatments for age-related macular degeneration such as pegagtanib sodium, ranibizumab, aflibercept and bevacizumab.

In one embodiment, the drug is an integrin antagonist, a selectin antagonist, an adhesion molecule antagonist (e.g., intercellular adhesion molecule (ICAM)-1, ICAM-2, ICAM-3, platelet endothelial adhesion molecule (PCAM), vascular cell adhesion molecule (VCAM)), a leukocyte adhesion-inducing cytokine, or a growth factor antagonist (e.g., tumor necrosis factor-α (TNF-α), interleukin-ΐβ (IL-β), monocyte chemotactic protein-1 (MCP-1), or a vascular endothelial growth factor (VEGF) inhibitor). In some embodiments, a vascular endothelial growth factor (VEGF) inhibitor is administered with one of the microneedles described herein. In some embodiments, two drugs are delivered by the methods described herein. The compounds may be administered in one formulation, or administered serially, in two separate formulations. For example, both a VEGF inhibitor and VEGF are provided. In some embodiments, the VEGF inhibitor is an antibody, for example a humanized monoclonal antibody. In further embodiments, the VEGF antibody is bevacizumab. In another embodiment, the VEGF inhibitor is ranibizumab, aflibercept, or

<img file="MX372859B_D0258.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY pegaptanib. In still other embodiments, the devices and methods described herein can be used to deliver one or more of the following VEGF antagonists: AL8326, 2C3 antibody, AT001 antibody, HyBEV, bevacizumab 5 (Avastina), ANG3070, APX003 antibody, APX004 antibody, ponatinib (AP24534), BDM-E, VGX100 antibody (VGX100 ORCADIAN), VGX200 (c-fos induced by morioclonal growth factor antibody), VGX300, COSMIX, DLX903/1008 antibody, ENMD2076, Sutent (sunitimb malate), INDUS815C, 10 R84 antibody, KD019, NM3, allogeneic mesenchymal precursor cells combined with an anti-VEGF agent or antibody, MGCD265, MG516, VEGF receptor kinase inhibitors, MP0260, NT503, anti-DLL4/VEGF bispecific antibody,

PAN90806, Palomid 529, BD0801 antibody, Volasertib (BI6727), CEP11981, KH903, Lenvalinib (E7G80), terameprocol (EM 1421)

Carboxyamidotriazole orotar, hydroxychloroquine, limfanib (ABT869, RG3635), Iluvien (fluocinolone acetonide), ALG1001, AGN15G998, DARPin MP0112, AMG386, ponatinib (AP24534), AV101, Vargatef (nintedanib), BMS690514, KH902, golvatinib (E7050), 25 Afmitor (everolimus), Dovitinib lactate (TKJ258, CHIR258),

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0RA1O1, ORA102, Axitinib (Inlyta, AG013736), Plitidepsin (Aplidin), Lenvaiinib mesylate, PTC299, aflibercept (Zalirap, Eylea), pegaptanib sodium (Macugen, LI900015), Visudyne (verteporfin), bucillamine (Rimatil, Lamín, Brimani, Lamit, 5 Boomiq), R3 antibody, AT001/r84 antibody, troponin (BLS0597), EG3306, vatalanib (PTK787), BmablOO, GSK2136773,

Anti-VEGFR Alterase, Avila, CEP7055, CLT009, ESBA903, HuMax-VEGF Antibody, GW654652, HMPL010, GEM220, HYB676, JNJ

17029259, TAK593, XtendVEGF antibody, Nova21012, Nova21013, 10 CP564959, Smart Anti-VEGF antibody, AG028262, AG13958,

CVX241, SU14813, PRS055, PG501, PG545, PTI101, TG100948,

ICS283, XL647, Enzastaurin hydrochloride (LY317615), BC194, Quinolines, COT601M061, COT604M062, MabionVEGF, SIR-Sferes coupled to anti-VEGF antibody or VEGF-R, Apatinib (YN968D1), 15 and AL3818. Furthermore, delivery of a VEGF inhibitor or VEGF antagonist using the microneedle devices and methods discussed herein may be combined with one or more agents listed herein or with other agents known in the art.

In one embodiment, the supply of an antagonist

VEGF to the suprachoroidal space of the eye using the devices and methods discussed herein is used to treat, prevent and/or ameliorate a disease or disorder selected from leukemia, relapsed/refractory leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia,

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Mexican Institute of Industrial Property relapsed or refractory acute myeloid leukemia, atopic dermatitis, recurrent or metastatic urothelial carcinoma, advanced urothelial carcinoma, blood disorders, myelofibrosis, brain tumor, glioblastoma, glioma, meningioma, cancer, carcinomatous meningitis (neoplastic meningitis), choroidal neovascularization (CNV), subfoveal choroidal neovascularization, chronic lymphocytic leukemia, chronic myelogenous leukemia, Refractory chronic myelogenous leukemia, colon cancer, colorectal cancer, 10 degenerative nerve diseases, Neurodegenerative diseases, diabetic macular edema, visual impairment due to diabetic macular edema, diabetic retinopathy, dry eye syndrome (inflammation and damage of corneal tissue of the dry eye), endometrial cancer, 15 eye diseases, eye diseases, ocular neovascularization, eye cancer, eurofibromatosis Type II, head and neck cancer, Hematologic malignancies, Kaposi's sarcoma, Hepatocellular carcinoma, Lung cancer, Macular degeneration, Age-related macular degeneration 20, Wet age-related macular degeneration, (wet) Neovascular age-related macular degeneration (AMD)), Subfoveal Neovascular age-related macular degeneration, Macular edema, Macular edema associated with Retinal Vein Occlusion

Branched, macular edema after vein occlusion

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270

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY retinal, macular edema with retinal vein occlusion (RVO), multiple myeloma, relapsed or refractory multiple myeloma, multiple sclerosis, myopia, pathological myopia, neuroendocrine tumor, carcinoid tumor, neuroendocrine tumor,

Non-Hodgkin lymphoma, Diffuse large B-cell lymphoma, Non-small cell lung cancer, Non-squamous non-small cell lung cancer, Non-small cell lung adenocarcinoma, Squamous non-small cell lung cancer, Corneal graft rejection, Osteoarthritis, Recurrent symptomatic malignant ascites, Peripheral T-cell lymphoma, Androgen-independent psoriasis, Pulmonary fibrosis, Idiopathic pulmonary fibrosis, Respiratory diseases, Retinal detachment, Retinal disorders, retinitis pigmentosa, retinal vein occlusion, branch retinal vein occlusion, central retinal vein occlusion, rheumatoid arthritis, sarcoma, alveolar soft part sarcoma, soft tissue sarcoma, scleroderma/systemic sclerosis, solid tumors, refractory germ cell tumors, thyroid cancer, differentiated or medullary thyroid cancer, and West Syndrome (Infantile Spasm).

In certain embodiments, the drug delivered to the suprachoroidal space using the devices and methods discussed herein is rapamycin (Sirolimo, Rapamune).

In one embodiment, the devices (e.g., devices

<img file="MX372859B_D0262.tif" />

271

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY (microneedle) and methods discussed herein are used in conjunction with rapamycin to treat, prevent, and/or ameliorate a wide range of diseases or disorders including, but not limited to: Abdominal neoplasms, acquired immunodeficiency syndrome 5, acute coronary syndrome, acute lymphoblastic leukemia, acute myelocytic leukemia, acute nonlymphoblastic leukemia, adenocarcinoma, adenoma, adenomyoepithelioma, adnexal diseases, anaplastic astrocytoma, anaplastic large cell lymphoma, anaplastic plasmacytoma 10, anemia, angina pectoris, angioimmunoblastic lymphadenopathy with dysproteinemia, angiomyolipoma, arterial occlusive diseases, arteriosclerosis, astrocytoma, atherosclerosis, autoimmune diseases, B-cell lymphomas, blood clotting disorders, blood protein disorders, bone cancer, bone marrow diseases, brain diseases, brain neoplasms, breast neoplasms, bronchial neoplasms, carcinoid syndrome, carcinoid tumor, carcinoma, squamous cell carcinoma, central nervous system diseases, central nervous system neoplasms, choroidal diseases, Choroid plexus neoplasms, choroidal neovascularization, choroiditis, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic myeloproliferative disorders, chronic neutrophilic leukemia, carcinoma of the cell

<img file="MX372859B_D0263.tif" />

272

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Mexican Institute of Industrial Property clear cell kidney, colonic diseases, colonic neoplasms, colorectal neoplasms, coronary artery disease, coronary artery disease, coronary occlusion, coronary restenosis, coronary stenosis, coronary thrombosis, cutaneous T-cell lymphoma, diabetes mellitus, digestive system neoplasms, dry eye syndrome, ear diseases, edema, endocrine gland neoplasms, endocrine system diseases, Endometrial neoplasms, endometrial stromal tumors, Sarcoma of

Ewing, rash, eye neoplasms, fibrosis, follicular lymphoma, gastrointestinal diseases, gastrointestinal neoplasms, genital neoplasms, glioblastoma, glioma, gliosarcoma, graft-versus-host disease, hematologic diseases, hematologic neoplasms, bleeding disorders, hemorrhagic disorders, Hodgkin's disease, Hodgkin's lymphoma, homologous degenerative disease, immunoblastic lymphadenopathy, immune deficiency syndromes, Immunoproliferative disorders, infarction, inflammation, intestinal diseases, intestinal neoplasms, ischemia, kidney cancer, kidney diseases, kidney neoplasms, leukemia, B cell, leukemia, lymphoid, liver cancer, liver diseases, lung diseases, lymphatic diseases, lymphoblastic lymphoma, lymphoma, macular degeneration, macular edema, melanoma, oral neoplasms, multiple myeloma, syndromes

<img file="MX372859B_D0264.tif" />

273

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY myelodysplastic, myelofibrosis, myeloproliferative disorders, neuroectodermal tumors, neuroendocrine tumors, neuroepithelioma, neurofibroma, renal cancer, respiratory tract diseases, retinal degeneration, retinal diseases, retinal neoplasms, retinoblastoma, rhabdomyosarcoma, thoracic neoplasms, uveitis, vascular diseases, Waldenstrom's Macroglobulidemia, and wet macular degeneration, in addition, The delivery of rapamycin using the microneedle devices and methods discussed herein may be combined with one or more agents listed herein or with other agents known in the art,

In one embodiment, the drug delivered to ocular tissue, e.g., the sclera or suprachoroidal space, using the microneedle devices and methods discussed herein reduces, inhibits, prevents, and/or ameliorates inflammation. Examples of drugs that reduce, inhibit, prevent, and/or ameliorate inflammation include (but are not limited to): 19AV agonists, 19GJ agonists, 2MD analogs, 4SC101, 4SC102, 57-57, 5-HT2 receptor antagonists,

64G12, A804598, A967079, AAD2004, AB1010, AB224050, abataeept, Abegrin, Abevac, AbGnl34, AbGnl68, Abki, ABN912, ABR215062, ABR224050, Abramune, Abreva, ABS15, ABS4, ABS6, ABT122, ABT325, ΆΒT494, ABT874, ABT963, ABXIL8, ABXRB2,

AC430, Accenetra, Acdeam, ACE772, Acebid, Acebloe,

274 aceclofenac, acetaminophen, chlorzoxazone, serrapeptase, tizanidine hydrochloride, betadex, Aceclogesic Plus, Aceclon, Acecloren, Aceclorism, acecrona, Aceffein, acemetacin, Acenac, Acentroin, Acetal-SP, ibuprofen, Acetyl-

G, dl-lysine acetylsalicylate, acetylsalicylic acid,

Acicot, Acifina, Acik, Aclocen, Acloflam-P, Aclomor, Aclon, A-CQ, ACS15, actarit, Actemra, Actelea lyophilizado, Actifast, Actimab-B, Actiquim, Actirin, Actis PLUS, activated leukocyte cell adhesion molecule antibody, Acular

X, AD452, Adalimumab, Adamts5 Inhibitor, ADC1001, ADCODYCLOFENAC, ADCO-OLDOMINTACIN, Adiodol, Adipoplus, adipose-derived stem and/or regenerative cells, Adizen, Adpep, Advacan, Advagraf, Advel, Adwiflam, AEB071, Aental, Afenac, Affen Plus, Afiancen, Afinitor, Aflamin, Aflazacort, Aflogen, Alloxan, AFM15, AFM16, AFM17, AFM23, Atpred-Dexa, AFX200, AG011, Agafen, aganirsen, AGI1096, Agidex, AGS010, Agudol, A-

Hidrocort, AIK1, ΆΙΝ457, Airtal, AIT110, AJM300, ajuiemic acid, AK106, AL—24—2A1, AL4-1A1, Ala Cort, Alanz, immunoglobulin Albumin, alclometasone dipropionate, ALD518, aldesleukin, Aldoderma, alefacept alemtuzumab, Alequel, Alergolon, Alergosone, Aletraxon, Alfenac, Algason, Algin vek coating, Algioflex, Algirex, Algivin Plus,

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY alicaforsen sodium, Alin, Alinia, Aliviodol, Aliviosin, alkaline phosphatase, ALKS6931, allantoin, Albupen, Almol, Alocrisina, allogeneic endothelial cells, allogeneic mesenchymal precursor cells, allogeneic mesenchymal stem cells 5, alminoprofen, alpha 1 antitrypsin, Alpha 7 nicotinic agonists, alpha amylase, alpha chymotrypsin, alpha fetoprotein, alpha linolenic acid, Alpha-l-antitrypsin, Alpha2Betal integrin inhibitors, Alfacort, Alfafen, alfa-hexidine, alfa-trypsin, Alfintern, 10 omega 3 mobility Alpinamed, Alpoxen, AL-Rel, Alterasa,

ALX006L ALX0761, ALXN1007, ALXN1102, AM3840, AM3876, ΆΜΑΒ, AMAP102, Amason, Ambene, AmbezimG, amcinonide, AME133v,

Amecin, Ameloteks, A-Metapred, Amevive, AMG108, AMG139,

AMG162, AMG181, AMG191, AMG220, AMG623, AMG674, AMG714, 15 AMG719, AMG729, AMG827, Amidol, amifampridin phosphate,

Amifenac, Amimetacin, amiprilose hydrochloride, Amiprofen, Ammofos, Amoflam, AMP 110, Ampikyy, Ampion, ampiroxicam, amtolmetin guacil, AMX256, AN6415, ANA004, ANA506, Anabu,

Anace, Anaflam, Anaflex ACI, Anaida, anakinra, Analgen 20 Arthritis, Anapan, Anaprox, Anavan, Anax, Anco, andrografis,

Aneol, Anergix, Anervax.RA, Anflene, ANG797, Anilixin,

Anmerushin, Annexin 1 peptides, annexin A5, Anodyne, Ansaid, Anspirin, Antarene, Indigo BST2 antibody, Anti C5a MAb, Anti ILT7 antibody, Anti VLA1 antibody, Anti25 alpha 1 antibody, Anti-CD4 802-2, Anti-CD86 monoclonal antibody,

<img file="MX372859B_D0266.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Anti-chemokine, Anti-DC-STGN, Anti-HMGB-1 MAb, Anti-IL-18 MAb, Anti-IL-IR MAb, Anti-IL-IR MAb, Anti-IL23 BRISTOL, Anti-inflammatory Peptides, Anti-interleukin 1 Beta antibody, Anti-LIGHT antibody, Anti-LIGHT antibody, Anti-MIF 5 Antibody, Anti-MIF Antibody, Anti-miR181a, Antioxidant inflammation modulators, Antiphthalamine, AntiRAGE MAb, Antithrombin III, Anti-TIRC-7 MAb, Anusol-HC, Anifen, AP105, AP1089, AP1189, AP401, AP501, Apazone, APD334, Apentac, APG103, Apidone, apilimod mesylate, Apitac, 10 Apitoxin, Apizel, APN Inhibitor, Apo-Azathioprine, ApoDexanietasone, ApoE mimetics, ApoFasL, apo-Indomethacin, apomefenamic, apo-methotrexate, apo-nabumetone, Apo-Napro-NA, apo-Naproxen, aponidin, apo-Phenylbutazone, apo-Piroxicam, apo-Sulin, Apo-Tenoxicam, apo-Tiaprofenic, Apranax, 15 apremilast, apricoxib, Aprofen, Aprose, Aproxen, antibody

APX001, APX007 antibody, APY0201, AqvoDex, AQX108, AQX1125, AQX131135, AQX140, AQX150, AQX200, AQX356, AQXMN100,

AQXMN106, ARA290, Arava, Arcalyst, Arcoxia, Arequin, Arflur, ARG098, ARG301, arginin aescin, arginine deiminase (pegylated), antibody ARGX109, ARGX110, Arheuma, Aristocort,

Aristospan, Ark-AP, ARN4026, Arofen, Aroff EZ, Arolef, Arotal, Arpibru, Arpimune, Arpu Shuangxin, ARQ101, Arrestin SP, Arrox, ARRY162, ARRY371797, ARRY614, ARRY872, ART621, Artamin, Arthfree, Arto Tech, Artrexin, Artrispray, Artrotec, 25 Arthrovas, Artifit, Artigo, Artin, Artinor, Artisid,

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Artoflex, Artren Hipergel, Artridol, Artrilasa, Artrocaptin, Artrodiet, Artrofen, Artropan, Artrosil, Artrosileno, Artrotin, Anrox, Artiflam, Arzerra, AS604850, AS605858,

Asacol, ASA-Grindeks, Asazipam, Aséelo, ASF1096, ASF1096,

ASK8007, ASKP1240, ASLAN003, Asmo ID, Asonep, ASP015K,

ASP2408, ASP2409, Aspagin, Aspeol, Aspicani, Aspirimex, aspirin, AST120, astaxantin, AstroCort, Aszes, AT002 antibody, AT007, AT008 antibody, AT008 antibody, AT010,

AT1001, atacicept, Ataspin, Atepadene, Atgam, ATG-Fresenius, 10 Atrofen, AT1003, atiprimod, ATL1222, ATN103, ATN192, ATR107,

Atri, Atrmin, Arrosab antibody, ATX3105, AU801, auranofin, Aurobin, Auropan, Aurotio, aurothioprol, autologous adipose-derived regenerative cells, Autonec, Avandia, AVE9897, AVE9940, Avelox, Avent, AV13378, Avloquin, AVP13546, 15 AVP13748, AVP28225, AVX002, Axcel Diclofenac, Axcel Papain,

Axen, AZ17, AZ175, Azacortid, AZA-DR, Azafrina, Azamun, Azanin, Azap, Azapin, Azapren, Azaprin, Azaram, Azasan, azathioprine, AZD0275, AZD0902, AZD2315, AZD5672, AZD6703,

AZD7140, AZD8309, AZD8566, AZD9056, Azet, Azintrel, Azithromycin, Az-od, Azofit, Azolid, Azoran, Azulene,

Azulfidine, Azuifm, Bl antagonists, Baclonet, BAF312, BAFF Inhibitor, Bages, Baily SP, Baleston, Baisolona, baminercept alfa, bardoxolon methyl, baricitinib, Barotase, Basecam, basiliximab, Baxmune, Baxo, BAY 869766, BB2827,

BCX34, BCX4208, Becfina, Beclato-C, Beclato-N, Beclolab Q,

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278

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY beclometason dipropionate, Beclorhin, Becmet-CG, Begita, Begti, belatacept, belimumab, Belosalico, Bemetson, Ben, Benevat, Benexam, Benflogin, Benisan, Benlista, Benlista, benorilato, Benoson, benoxaprofen, Bentol, benzydamine hydrochloride, Benzymin, Beofenac, Berafen, Berinert, Berlofen, Bertanel, Bestamina, Bestofen, Beta Nicip, Betacort, Betacorten G, Betafoam, beta-glucan, Betalar, Beta-M, Betamed, Betamesol, betamethasone, Atamphasone dipropionate_F betamethasone sodium, betamethasone sodium phosphate, betamethasone valerate, Betano, Betanex, Betapanten, Betapar, Betapred, Betason, Betasonato, Betasona, Betatrinta, Betaval, Betazon, Betazona, Betesil, Betnecort, Betnesol, Betnovato, Bextra, BFPC13, BFPC18, BFPC21, BFPT6864, BG12, BG9924, BI695500, BI695501, BIA12, Big-Joint-D, antibody

BIIB023, Bi-ksikam, Bingo, BioBee, Bio-Cartilage, Bio-CSinkki, Biodexona, Biofenac, Bioreucam, Biosona, Biosporin, BIRB796, Bitnoval, Bitvio, Bivigam, BKT140, BKTP46, BL2030, BL3030, BL4020, BL6040, BL7060, BLI1300, blisibimod,' Blokium B12, Blokium Gesic, Blokium, BMS066, BMS345541, BMS470539,

BMS561392, BMS566419, BMS582949, BMS587101, BMS817399,

BMS936557, BMS945429, BMS-A, BN006, BN007, BNP166, Bonacort, Bonas, bone marrow stromal cell antigen 2 antibody, Bonflex, Bonifen, Boomiq, Borbit, Bosong, BR02001, B3-FC, Bradykinin Bl receptor antagonists,

Bredinin, Brexecam, Brexin, Brexodin, briakinumab, Brimani,

<img file="MX372859B_D0269.tif" />

279

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY briobacept, Bristaffam, Britten, Broben, brodalumab, Broen-C, bromelains, Bronielin, Bronax, Bropain, Brosiral, Bruace, Brufadol, Brufen, Brugel, Brukil, Brusil, BT061, BTI9, BTK kinase inhibitors, antibody BTT1023, BITT1507, bucillamine, Bucilate, Buco Reigis, bucolome, Budenofalk, budesonide, Budex, Bufect, Bufencon, Bukwang Ketoprofen, Bunida, Bunofen, Busilvex, busulfan, Busulfex, Busulipo, Butartrol, Butarut B12, Butasone, Butazoiidin, Butesone, Butidione, BVX10, BXL628, BYM338, B-Zone, Cl esterase inhibitor, C243, c4462, c5997, CSaQb, c7198, c9101, C9709, c9787, CAB101, Cadherin 11 antibody, Caerulomycin A,

CAL263, Calcort, Calniatel, CAM3001, Antibodies Camelid, Camlox, Camola, Campath, Camrox, Camtenam, canakinumab, Candida albicans antigen, Candin, cannabidiol, CAP1.1,

CAPI.2, CAP2.1, CAP2.2, CAP3.1, CAP3.2, Careram, Carimune, Cariodent Cartifix, CartiJoint, Cartilage, Cartisafe-DN, Cartisina, Cartivit, Cartril-S, Carudol, CaspaCIDe, CaspaCIDe, Casyn, CAT1004, CAT1902, CAT2200, Cataflam, Cathepsin S inhibitor, Catlep, CB0114, CB2 agonist,

CC0478765, CC10004, CC10015, CC1088, CC11050, CC13097,

CC15965, CC16057, CC220, CC292, CC401, CC5048, CC509, CC7085, CC930, CCR1 Antagonist, CCR6 Inhibitor, CCR7 Antagonist, CCRL2 Antagonist, CCX025, CCX354, CCX634, CD Diclofenac,

CD102, CD103 Antibody, CD103 Antibody, CD137 Antibody, CD16 Antibody, CD18 Antibody, CD19 Antibody, Antibody

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280

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

CDId, CD20 antibody, CD200FC, CD209 antibody, CD24, CD3 antibody, CD30 antibody, CD32A antibody, CD32B antibody, CD4 antibody, CD40 ligand, CD44 antibody, CD64 antibody, CDC839, CDC998, CDIM4, CDIM9, Inhibitor

CDK9, CDP146, CDP323, CDP484, CDP6038, CDP870, CDX1135,

CDX301, CE224535, Ceanel, Cebedex, Cebutid, Cecionac, Ceex, CEL2000, Celact, Celbexx, Celeox, Celebiox, Celebrex, Celebrin, Celecox, celccoxib, Celedol, Celestone, Celevex, Celex, CELG4, Cell adhesion molecule antagonists, CellCept, Cellmune, Celosti, Celoxib, Celprot,

Celudex, cenicriviroc mesylate, cenplacel-1, CEP 11004, CEP37247, CEP37248, Cephyr, Ceprofen, Certiean, certolizumab pegol, Cetofenid, Ketoprofen, cetylpyridinium chloride, CF101, CF402, CF502, CG57008, CGEN15001, CGEN15021,

CGEN15051, CGEN15091, CGEN25017, CGEN25068, CGEN40, CGEN54, CGEN768, CGEN855, CGI1746, CGI560, CGI676, Cgtx Peptides, CH1504, CH4051, CH4446, caperonin 10, CC chemokine moiety ligand 2, CC chemokine moiety ligand 2 antibody, CC chemokine moiety ligand 5 antibody, CC chemokine moiety receptor 2 antibody, CC chemokine moiety receptor 4 antibody, CXC chemokine moiety ligand 10 antibody, CXC chemokine moiety ligand 12 aptamer, Chemotaxis Inhibitor, quilmetacin, chitinase 3-like 1, clocodemin, Cloquin, gluconate

281 Chlorhexidine, chloroquine phosphate, choline trisalicylate, magnesium chondroitin sulfate, Chondroscart

CHR3620,

CHR4432, CHR5154, Crisalin, Chuanxinlian, quimapra,

Chymotaso, chymotrypsin, quitmutrip, CI202, CI302,

Cicloderm-C, Ciclopren, Cicporal, Cilamin, Cimzia, quincofen, cinmetacin, cinnoxicam, Cinoderm, Cinolona-S, Cinriza, Cipcorlin, cipemastat, Cipol-N, Cipridanol, Cipzen, Citax F, Citogan, Citoken T, Civamide, CJ042794, CJ14877, antibody monoclonal c^—Kit, cladribine, Clafen, Clanza, Claversal, clazakizumab, Clearoid, Clease, Clevegen, Clevian, Clidol, Clindac, Clinoril, Cliptol, Clobenate, Clobequad, clobetasol butyrate, clobetasol propionate, Clodol, clofarabine, Clofen, Clofenal LP, Clolar, Clonac, Clongamma, clonixin lysine, Clotasoce, Clovacort, Clovana, Cloxin, CLT001, CLT008,

C-MAF Inhibitor, CMPX1023, Cnac, CNDO201, CNI1493, CNTO136, CNTO148, CNTO1959, Cobefen, CoBenCoDerm, Cobix, Cofenac,

Cofenac, COG241, COL179, Colchicine, Colchicus Dispert,

Colquimax, Colcibra, Coledes A, Colesol, Colifoam, Colirest, collagen, type V, Comcort, receptor 1 (3b/4b) complement component, Cls Inhibitors Complement component, complement component C3, complement factor 5a receptor antibody, complement factor 5a receptor antibody, complement factor D antibody, Chondrosulf, Chondroiec, Chondrotin, conestat alfa, connective tissue growth factor antibody, Coolpan, Copaxone,

282

Copiron, Cordefla, Corhidron, Corte S, Cortan, Cortate, CortDome, Cortecetina, Cortef, Corteroide, Corticap, Corticas, Cortic-DS, corticotropin, Cortiderm, Cortidex, Cortiflam, Cortinet M, Cortinil, Cortipiren B, Cortiran, Cortis, 5 Cortisolu, cortisone acetate, Cortival, acetate

Cortona, Cortopin, Cortoral, Cortril, Cortipiren, Cosamine, Cosone, cosintropin, COT Kinase Inhibitor, Cotilam, Cotrisone, Cotson, Covox, Cox B, · COX-2/5-LO inhibitors, Coxeton, Coxflam, Coxicam, Coxitor, Coxtrai, Coxipar,

CP195543, CP412245, CP424174, CP461, CP629933, CP690550,

CP751871, CPSI2364, C-quin, CR039, CR074, CR106, CRA102, CRAC channel inhibitor, CRACM ion channel inhibitor, Cratisone, CRB15, CRC4273, CRC4342, 2methoxyethyl phosphorothioate protein oligonucleotide. C-reactive, CreaVax15 RA, CRH modulators, critical auxiliary, Crocam, Cróhnsvax, Cromogl{icic acid, Cronocorteroid sodium, Cronocorteroid, Cronodicasone, CRTX803, CRX119, CRxl39, CRxl50, CS502, CS670, CS706, CSF1R kinase inhibitors, CSL324, CSL718, CSL742, CT112, CT1501R, CT200, CT2008, CT2009, CT3, CT335, CT340, 20 CT5357, CT637, CTP05, CTP10, CT-P13, CTP17, Cuprenil,

Cuprimin, Cuprindo, Cupripen, Curaquin, Cutfen, CWF0808, CWP271, CX1020, CX1030, CX1040, CX5011, Cx611, Cx621, Cx911, CXC chemokine receptor 4 antibody, anti-CXCL13 antibodies, CXCR3 antagonists, CXCR4 antagonist, Ciathus 1104 25 B, Ciclo-2, Ciclocort, cyclooxygenase-2 inhibitor,

<img file="MX372859B_D0271.tif" />

283

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY cyclophosphamide, Cyclorina, Ciclosporin A prodrug, Ciclosporin A analogue, cyclosporine, Cirevia, Cirin CLARIS, CYT007TNFQb, CYT013lLlbQb, CYT015IL17Qb, CYT020TFQb, CYT107, CYT387, CYT99007, cytokine inhibitors, Cytopan, 5 Citoreg, CZC24832, D1927, D9421C, daclizumab, danazol,

Danilase, Dantes, Danzen, dapsone, Dase-D, Daipro, Daipro Alta, Dairun, Dazen, DB295, DBTP2, D-Cort, DD1, DD3, DE096, DE098, Debio0406, Debio0512, Debio0615, Debio0618, Debiol036, Decaderm, Decadrale, Decadron, Decadronal, Decalon, Decan, 10 Décason, Decdan, Decilona, Declofen, Decopen, Decorex, Decorten, Dedema, Dedron, Deexa, Defcort, De-flam, Deilamat, Deflan, Deflanil, Defiaren, Deflaz, deflazacort, Defnac, Defnalona, Defnil, Defosalic, Defsure, Defza, Dehydrocortison, Dekort, Delagil, delcasertib, delmitide, 15 Delficort, Deltacorsolona, Deltacortril, Deltafluorene, Deltasolona, Deltasone, Deltastab, Deltonin, Demarin, Demisone, Denebola, deniieukin diftitox, denosumab, Denzo, Depocortin, Depo-medrol, Depomethotrexate, Depopred, Deposet, Depirin, Derinase, Dermol, Dermolar, Dermonate, Dermosone, 20 Dersone, Desceto, desonide, deoxycorticosterone acetate, Deswon,' Dexa, Dexabene, Dexacip, Dexacort, Dexacortisona, Dexacotisii, Dexadic, Dexadrin, Dexadron, Dexafar, Dexahil, Dexalab, Dexalaf, Dexalet, Dexalgen, Dexallion, Dexalocal, Dexalorse, Dexa-M, Dexamecortin, Dexamed, Dexamedis, 25 Dexameral, Dexameta, Dexamethasone, dexamethasone acetate,

<img file="MX372859B_D0272.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

284 dexamethasone palmitate, dexamethasone phosphate, dexamethasone sodium metasulfobenzoate, dexamethasone sodium phosphate, Dexamine, Dexapanten, Dexa-S, Dexason, Dexatab, Dexatopic, Dexaval, Dexaven, Dexazoiidin, Dexazone, 5 Dexazono, Dexcor, Dexibu, dexibuprofen, Dexico, Dexifen,

Deximune, dexcetoprofen, dexcetoprofen trometamol, Dexmark, Dexomet, Dexon I, Dexonalin, Dexonex, Dexini, Dexoptifen, Dexpin, Dextan-Plus, dextran sulfate, Dezacor, Dfz, diacerein, Diannexin, Diastone, Dicarol, Dicasona, Dicknol, 10 . Diclo, Diclobon, Diclobonse, Diclobonzox, Diciofast,

Diclofen, diclofenac, diclofenac beta-dimethylaminoethanol, diclofenac deanol, diclofenac diethylamine, diclofenac epolamine, diclofenac potassium, diclofenac resinate, diclofenac sodium, Diclogen AGIO, Diclogen Plus, Diclokim, 15 Diclomed, Diclo-NA, Diclonac, Dichloramin, Dichloran, Dichloro,

Dichlorism, Diclotec, Diclovit, Diclowal, Diclozem, Dico P, Dicofen, Dicoliv, Dicorsona, Dieron, Dicser, Difena,

Diffutab, diflunisal, dilmapimod, Dilora, dimethyl sulfone, Dinac, D-Indomethacin, Dioxaflex Protect, Dipagesico,

Dipenopen, Dipexin, Dipro AS, Diprobeta, Diprobetasone,

Diproklenat, Dipromet, Dipronova, Diprosone, Diprovate,

Diproxen, Disannin, Diser, Disopain, Dispain, Dispercam, nystamina, DÍZOX, DLT303, DLT404, DM199, DM99, DM19523, dnaJPl, DNX02070, DNX04042, DNX2000, DNX4G00, docosanol,

Docz-β, Dolamida, Dolaren, Dolchis, Dolex, Dolflam, Dolfre,

<img file="MX372859B_D0273.tif" />

285

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Dolgit, Dolmax, Dolmina, Dolo Ketazon, Dolobest, Dolobid, Doloc, Dolocam, Dolocartigen, Dolofit, Dolokind, Dolomed, Dolonac, Dolonex, Dolotren, Dolozen, Dolquina, . DomOlOO, Dom0400, Dom0500, Domet, Dometon, Dominadol, Dongipap,

Donica, Dontisanin, doramapimod, Dorixina Relax, Dormelox,

Dorzine Plus, Doxatar, Doxtran, DP NEC, DP4577, DP50, DP6221,

D-Penamine, DPIV/APN inhibitors, DR1 inhibitors, DR4 inhibitors, DRA161, DRA162, Drenex, DRF4848, DRL15725, Drossadin, DSP, Duexis, Duo-Decadron, Duoflex, Duonase,

DV1079, DV1179, DWJ425, DWP422, Dimol, DYN15, Dinapar,

Dismen, E5090, E6070, Easy Dayz, Ebetrexat, EBI007, EC0286, EC0565, EC0746, Ecax, Echinacea purpurea extract, ECNaprosyn, Econac, Ecosprin 300, Ecosprin 300, Ecridoxan, eculizumab, Edecam, efalizumab, Efcortesol, Effigel, Eflagen, 15 Efridol, EGFR Antibody, EGS21, elFSAl siRNA, Ekarzin, elafin, Eldoflam, Elidel, Eliflam, Elisona, Elmes, Elmetacin, ELND001, ELND004, elocalcitol, Elocom, elsibucol, Emanzen, Emecort, Emifen, Emifenac, emorpházone, Empynasa, emricasan, Erntor, Enable, Enbrel, Enceid, EncorStat, Encortolon,

Encorton, Endase, Endogesic, Endoxan, Enkorien, Ensera,

Entocort, Enzylan, Epanova, Eparang, Epatec, Epicotil, epidermal growth factor receptor 2 antibody, epidermal growth factor receptor antibody, Epidixone, Epidron, Epiklin, EPPA1, epratuzumab, 25 EquiO, Erac, Erazon, ERB041, ERB196, Erdon, EryDex, subunit

<img file="MX372859B_D0274.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

286 of enterotoxin B escherichia coil, Esein, ESelectin Antagonists, Esfenac, ESN603, esonartmod, Esprofen, estetrol, Estopein, Estrogen Receptor beta agonist, etanercept, etaracizumab, ETC001, ethanol propolis extract, ETI511, etiprednol 5 dicloacetate, Etodin, Etodine, EtodOl, etodolac, Etody, etofenamate, Etol Fort, Etolac, Etopin, etoricoxib, Etorix, Etosafe, Etova, Etozox, Etura, Eucob, Eufans, eukaryotic translation initiation factor 5 oligonucleotide, Eitnac, Eurocox, Eurogesic, 10 everolimus, Evinopon, EVT401, Exaflam, EXEL9953, Exicort,

Expen, Extra Feverlet, Extrapan, Extrauma, Exudasa, F16, F991, Faleam, Falcol, Falzy, Faibovil, Farcometacin,

Farnerate, Farnezone, Farnezone, Farotrin, fas antibody, Fastflam, FasTRACK, Fastum, Fauldmetro, antibody 15 FcgammaRlA, FE301, Febrofen, Febrofid, feibinac, Feldene, Feldex, Feloran, Felxicam, Fenac, Fenacop, Fenadol, Fenafian, Fenarrsic, Fenaren, Fenaton, Fenbid, fenbufen, Fengshi

Gutong, Fenicort, Fenopina, fenoprofen calcium, Fenopron, Fenris, Fensupp, Fenxicam, fepradinol, Ferovise, Feverlet, 20 fezakinumab, FG3019, FHT401, FHTCT4, FID 114657, figitumumab, Filexi, filgrastim, Filiase, Final, Findoxin, hydrochloride fingolimod, firategrast, Firdapse, Fisiodar, Fivasa, FK778, Flacoxto, Fladalgin, Flagon, Flamar, Flamcid, Flamfort, Flamida, Flaminase, Flamirex Gesic, Flanid, Flanzen, Fiaren, 25 Fiaren, Flash Act, Flavonoid Anti-inflammatory Molecule,

<img file="MX372859B_D0275.tif" />

287

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Flebogamma DIF, Flenac, Flex, Flexafen 400, Flexi, Flexidol, Flexium, Flexon, Flexono, Flogene, Flogiatrin B12, Flogomin, Flogoral, Flogosan, Flogoter, Flo-Pred, Flosteron, Flotrip Forte, Fit3 inhibitors, fluasterone, Flucam, Flucinar, 5 fludrocortisone acetate, aluminum flufenamate, flitmetasone, Flumidon, flunixin, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortolone, Fluonid, fluorometholone, Flur, flurbiprofen, Fluribee, Flurometholone, Flutal, fluticasone, fluticasone propionate, Flutizone, 10 Fluzone, FM101 antibody, fms-related tyrosine kinase 1 antibody, Folitrax, fontolizumab, formic acid, Fortecortin, Fospeg, fostamatimb disodium, FP1069, FP13XX, FPA008, FPA031, FPT025, FR104, FR167653, Framebin, Prime,

Froben, Frolix, FRQUNT inhibitors, Fubifen PAP, Fucol 15 ibuprofen, Fulamotol, Fulpen, Fungifin, Furotalgin, sodium fusidate, FXQ02, FX141L, FX201, FX300, FX87L, modulators

Galectin, Gallium maltolate, Gamimune N, Gammagard, GammaI.V., GammaQuin, Gamma-Venin, Gamunex, Garzen, Gaspirin, Gattex, GBR500, GBR500 antibody, GBT009, G-CSF, GED0301, 20 GED0414, Gefenec, Gelofen, Genepril, Gengraf, Genimune,

Geniquin, Genotropin, Genz29155, Gerbin, Gerbin, gevokizumab, GF01564600, Gilenia, Gilenya, givinostat, GL0050, GL2045, glatiramer acetate, Globulin, Glorto Forte, Glovaiox, Glovenin-L GLPG0259, GLPG0555, GLPG0634, GLPG0778, GLPG0974, 25 Gluco, Glucocerin, glucosamine, glucosamine hydrochloride,

<img file="MX372859B_D0276.tif" />

288

IMPI

Mexican Institute of Industrial Property glucosamine sulfate, Glueotina, Gludex, Glutilage, GLY079, GLY145, Glycanic, Glycefort up, Giygesic, Glysopep, GMCSF Antibody, GMI1010, GMI1011, GMI1043, GMR321, GN4001, Goanna Salve, Goflex, gold sodium thiomalate, golimumab, 5 GP2013, GPCR modulator, GPR15 Antagonist, antagonist

GPR183, GPR32 antagonist, GPR83 antagonist, G protein-coupled receptor antagonists, Graceptor, Graflac, granulocyte colony-stimulating factor antibody, granulocyte macrophage colony-stimulating factor antibody, Gravx, GRC4039, Grelyse, GS101, GS9973, GSC100, GSK1605786, GSK1827771, GSK2136525, GSK2941266, GSK315234,

GSK681323, GT146, GT442, Gucixiaotong, Gufisera, Gupisone, Gusperimo hydrochloride, GW274150, GW3333, GW406381,

GW856553, GWB78, GXP04, Gynestrel, Haloart, Halopredone acetate, Haloxin, HANALL, Hanall Soludacortina, Havisco, Hawon Bucilamine, HB802, HC31496, HCQ 200, HD 104, HD203,

HD205, HDAC inhibitor, HE2500, HE3177, HE3413, Hecoria,

Hectomitacin, Hefasolon, Helen, Helenil, HemaMax, Hematom, Hematopoietic stem cells, Hematrol, Hemner, Hemril, Heparinoid, Heptax, HER2 Antibody, Herponil, hESC-derived dendritic cells, hESC-derived hematopoietic stem cells, Hespercorbin, Hexacorton, Hexadrol, Hexetidine, Hexoderm, Hexoderm Salic, HF0220, HF1020, HFT-401, hG-CSFR ED Fe, Hiberna, Frame Antibody

1 d ehigh mobility, Hiloneed, Hinocam, hirudin, Hirudoid,

<img file="MX372859B_D0277.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

289

Hison, Histamine H4 Receptor Antagonists, Hitenercept, Hizentra, HL036, F1L161, HMPL001, HMPL004, HMPL004, HMPL011, HMPL342, HMPL692, Honey Bee Venom, Hongqiang, Hotemin, HPH116, HT1101, HuCAL Antibody, Human Adipose Mesenchymal Stem Cell 5, Monoclonal Antibody Class

II anti-MHC, Human Immunoglobulin, Human Placental Tissue Hydrolysate, HuMaxCD4, HuMax-TAC, HumetonA, Humicade, Humira, Betamethasone Sodium Phosphate Huons, Dexamethasone Sodium Phosphate Huons, Piroxicam Huons, Talniflumate 10 Huons, Hurofen, Huruma, Huvap, HuZAF, HX02, Hyalogel, Sodium Hyaluronate, Hyaluronic Acid, Hyaluronidase, Hyaron, Hycocin, Hycort, Fly-Cortisone, Hydrocortisone, Hydrocortisone Acetate, Hydrocortisone Butyrate, Hydrocortisone Hemisuccinate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate 15, Hidrocortistab, Hidrocortone,

Hydrolin, Hydroquine, Hydro-Rx, Hydrosone HIKMA, Hydroxychloroquine, Hydroxychloroquine Sulfate, Hyiase

Dessau, HyMEX, Hypen, HyQ, Hysonate, HZN602, IM75,

IAP inhibitors, Ibaigin, Ibalgin, Ibex, ibrutinib, 20 IBsolvMIR, Ibu, Ibucon, Ibudolor, Ibufen, Ibuflam, Ibuflex,

Ibugesic, Ibu—Hepa, Ibukim, Ibumal, Ibunal, Ibupental, Ibupril, ibuprof, ibuprofen, Ibuscent, Ibusoft, Ibusuki

Penjeong, Ibususpen, Ibutard, Ibutop, Ibutop, Ibutrex,

IC487892, ichtammol, ICRAC blocker, IDEC131, IDECCE9.1, 25 Ides, Idicin, Idizona, IDN6556, Idometina, IDR1, Idyl SR,

<img file="MX372859B_D0278.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

290

Ifen, iguratimod, IK6002, IKK-beta inhibitor, IL17 Antagonist, IL-17 Inhibitor, IL-17RC, IL18, ILlHyl, IL1R1,

Adnectin IL-23, IL23 Inhibitor, IL23 Receptor Antagonists, IL-31 mAb, IL-6 Inhibitor, IL6Qb, Hacox, Ilaris, ilodecakin, ILV094, ILV095, Imaxetil, IMD0560, IMD2560,

Imesel Plus, Iminoral, Immodin, IMMU 103, IMMU 106, Immucept, Immufina, Inimunex Syrup, immunoglobulin, immunoglobulin G, Immunoprin, ImmunoRel, Immurin, IMO8400, IMP731 antibody, Implanta, Imunocell, Imuran, Iniurek, Imusafe, Imusporin,

Imutrex, IN0701, Inal, INCB039110, INCB18424, INCB28050,

INCB3284, INCB3344, indexon, Indie, Indo, Indo-A, Indobid,

Indo-Bros, Indocaf, Indocarsil, Indocid, Indocin, Indomehotpas, Indomen, Indomet, Indomethacin, indomethacin,

Indometasone, Indométin, Indomin, Indopal, Indoron, indotroxin, INDUS830, INDUS83030, Infladase, Inflamac, Inflammasome inhibitor, inflavis, Inflaxen, Inflectra, infliximab, Ingalipt, inicox dp, Inmecin, Inmunoartro,

Innamit, InnoD06006, INO7997, Inocin, Inoten, Inovan, Inpra, Inside Pap, Insider-P, Instacil, Instracool, Iniafenac,

Intaflam, Inteban, Inteban Spatula, integrin, alpha 1 antibody, integrin, alpha 2 antibody, intenurse, inferred alpha, inferred beta-la, inferred gamma, inferred gamma antibody, Interking, interleukin 1 Hyl, interleukin 1 antibody, interleukin 1 receptor antibody, interleukin 1, beta antibody, interleukin 10, antibody

<img file="MX372859B_D0279.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

91 interleukin 10, interleukin 12, interleukin 12 antibody, interleukin 13 antibody, interleukin 15 antibody, interleukin 17 antibody, interleukin 17 receptor C, interleukin 18, interleukin 18 binding protein, interleukin 18 antibody, interleukin 2 receptor, alpha antibody, interleukin 20 antibody, interleukin 21 mAb, interleukin 23 aptamer, interleukin 31 antibody, interleukin 34, interleukin 6 inhibitor, interleukin 6 antibody, interleukin 6 receptor antibody, interleukin 7, interleukin 7 receptor antibody, interleukin 8, interleukin 8 antibody, interleukin-18 antibody, Intidrol, Intradex, Intragam P, Intragesic, Infraglobin F, Intratect, Inzel, lomab B, IOR-T3, TP751, IPH2201, IPH2301, IPH24, IPH33, IPT145, Ipocort, IPP201Q07, 15 I-Profen, Iprox, Ipson, Iputon, IRAK4 inhibitor, Iremod,

Irtonpison, IRX3, IRX5183, ISA247, ISIS104838, ISIS2302,

ISISCRPRx, Ismafron, IsoQC inhibitor, Isox, ITF2357, Iveegam EN, Ivepred, IVIG-SN, IW001, Izilox, J607Y, J775Y, JAK inhibitor, JAK3 inhibitor, JAK3 kinase inhibitor, JI3292, 20 JI4135, Jinan Lida, JNJ10329670, JNJ18003414, JNJ26528398,

JNJ27390467, JNJ28838017, JNJ31001958, JNJ38518168,

JNJ39758979, JNJ40346527, JNJ7777120, JNT-Plus, Joflam, Joint Glucosamine, Jointec, Jointstem, Joinup, JPE1375, JSM10292, JSM7717, JSM8757, JTE051, JTE052, JTE522, JTE607, Jusgo,

K412, K832, Caflam, KAHR101, KAHR102, KAI9803, Calimin, Kam

<img file="MX372859B_D0280.tif" />

292

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Predsol, Cameton, KANAb071, Cappaproct, KAR2581, KAR3000,

KAR3166, KAR4000, KAR4139, KAR4141, KB002, KB003, KD7332,

Ke298 trometbamine, Cetoselect, Ketotop, Cetovail, Cetricin, Cetroc, Cetum, Keyi, Keyven, KF24345, KFenac, K-Fenak, K-Gesic, Cifadene, Cilcort, Cildrol, KIM127, 10 Cimotab, Kinase 4SC Inhibitor, Kinase N, Cincort,

Cindorase, Cineret, Cineto, Citadol, Citex, Citolac, KLK1 Inhibitor, Clofen-L, dotaren, KLS-4()or, KLS-40ra, KM277, Knavon, Codolo orahase, Cohakusanin, Coide, Coidexa, Coibet, Cognac, Condro, Condromin, Conshren, Comab, Cordexa,

Cosa, Cotase, KPE06001, KRP107, KRP203, KRX211, KRX252,

KSB302, K-Sep, Kv 1.3 Blocker, Kvl.3 4SC, Kvl.3 inhibitor, KVK702, Cynol, L156602, Labizona, Labohidro, Labopen, Lacoxa, Laniin, Lamit, Lanfetil, laquinimod, larazotide acetate, LAS186323, LAS187247, LAS41002, Laticort, LBEC0101, LCP3301, 20 LCP-Siro, LCP-Tacro, LCsA, LDP392, Leap-S, Ledercort,

Lederfen, Lederlon, Lederspan, Lefenina, leflunomide, Leflux, Lefno, Lefra, Leftosa, Leftimida, Lefumodin, Lefva, lenalidomide, lenercept, LentiRA, LEO15520, Leodase,

Leucinae, antagonist of the antigen-1 function associated with 25 Leukocyte, antibody of 4 members of the subfamily A of the

<img file="MX372859B_D0281.tif" />

293

IMPI

Mexican Institute of Industrial Property leukocyte immunoglobulin-like receptor, Leukotroa, leuprolide acetate, levalbuterol, levomenthol, Antagonist

LFA-1, LFA451, LFA703, LFA878, LG106, LG267 inhibitors,

Inhibitors LG688, LGD5552, Li Life, LidaMantle, Lidex, 5 lidocame, lidocame hydrochloride, Lignocaine hydrochloride,

LIM0723, LIM5310, Limetason, Limus, Limustin, Lindac,

Linfonex, Acute Linola, Lipcy, lisophilin, Listran, Liver Loracort, Lorcam, Lorfenamin, Lorinden

Lotio, Lorncrat, lornoxicam, Lorox, losmapimod, loteprednol etabonate, Loteprednol, Lotirac, Low Molecular Ganoderma Lucidum Polysaccharide, Loxafen, Loxfenine, Loxicara, 15 Loxofen, Loxonal, Loxonin, loxoprofen sodium, Loxoron,

LPI83A1, LP183A2, LP204A1, LPCN1019, LT1942, LT1964, LTNS101,

LTNS103, LTNS106, LTNS108, LTS1115, LTZMP001, Lubor, lumiracoxib, Lumitect, LX2311, LX2931, LX2932, LY2127399,

LY2189102, LY2439821, LY294002, LY3009104, LY309887,

LY333013, lymphocyte activation gene 3 antibody,

Lymphoglobulin, Lyser, Lysine Aspirin, Lysobact, Lysoflam, Lysozyme Hydrochloride, M3000, M834, M923, mAb hG-CSF,

MABP1, macrophage migration inhibitory factor antibody, Maitongna, Majamilu prolongatu, class 25 II DR antibody of major histocompatibility complex, antibody

<img file="MX372859B_D0282.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

294 Major hydrocompatibility complex class II, Malidens, Malival, Marman-binding lecithin, serine protease antibody^-2 mannan-binding lecithin-associated, MapKap Kinase 2 Inhibitor, maraviroc, Marlex, masitinib, 5 Maso, MASP2 antibody, MAT304, Matrix Metalopro.tease Inhibitor, mavrilimumab, Maxiflam, Maxilase, Maximus, Maxisona, Maxius, Maxpro, Maxrel, Maxsulid, Maxyl2, Maxy30, MAXY4, Maxy735, Maxy740, Mayfenamic, MB11040, MBPY003b, MCAF5352A, McCam, McRofy, MCS18, MD707, MDAM, MDcort,

MDR06155, MDT012, Mebicam, Mebuton, meclofenamate sodium.

Meclofen, Mecox, Medacomb, Medafen, Medamol, Medesone,

MED1I070, MEDI5117, MEDI541, MEDI552, MEDI571, Medicox,

Mediten, Medisolu, Medixon, Mednisol, Medrol, Medrolon, Medroxyprogesterone acetate, Mefalgine, Mefenamic acid, 15 Mefenix, Mefentane, Meflen, Mefnetra forte, Meftagesic-DT, Meftal, Megakaryocyte Growth and Development Factor, Megaspas, Megaster, Megestrol acetate, Meite, Meksun, Melbrex, Melcam, Melcam, Melflara, Melic, Mélica, Melix, Melocam, Melocox, Mel-One, Meloprol, Melosteral, Melox,

Meloxan, Meloxicam, Meloxic, Menoxicam, Meloxifen, Meloxin, Meloxiv, Meipred, Melpros, Melurjin, Menamina, Menisona, Mentomceto, Mentoneurin, Mentocin, Mepa, Mefaren, Meprednisone, Mepresso, Mepsolone, Mercaptopurine, Mervan, Mesadorone, Mesalamine, Mesasal, Mesatec, Mesenchymal Stem Cells 25, Mesipol Mesenchymal Stem Cells,

<img file="MX372859B_D0283.tif" />

295

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Mesren, Mesulan, Mesulid, Metacin, Metadaxane, Metaflex, Metalcaptase, metalloenzyme inhibitors, Metapred, Metax, Metaz, Meted, Metedic, Metacin, Metaderm, Metasone,

Methotrax, methotrexate, methotrexate sodium, Metpred, 5-Methyl prednisolone acetate, methyl salicylate, methyl sulfonyl methane, Metilon, Methylpred, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisolone succinate, Methylprednisolone, Metisol, Metindol, Metoart, Metoject, 10 Metolato, Metoral, Metosina, Metotab, Metracin, Metrex, metronidazole, Metipred, Mevamox, Mevedal, Mevilox, Mevin SR, Mexilal, Mexfarm, Mext, Mextran, MF280, M-FasL, MHC class II beta chain peptide, Micar, Miclofen, Miclofenac, Mycophenolate Mofetil, Micosone, Microdase, microRNA 181a-2 oligonucleotide, MSI inhibitors, MTFQb, MIKA-Ketoprofen,

Mikamethane, milodistim, Miltax, Minafen, Minalfen, Minalfeno, Minesulina, Minocort, Mioflex, Miolox, Miprofen, Miridacin, Mirloks, Misocio, Misolenac, MISTB03, MISTB04, Mitilor, mizoribme, MK0359, MK0812, MK0873, Inhibitors MK2, MK50, 20 MK8457, MK8808, MKC204, MLN0002, MLN0415, MLN1202, MLN273,

MLN3126, MLN3701, MLN3897, MLNM002, MM093, MM7XX, MN8001,

Mobic, Mobicam, Mobicox, Mobifen Plus, Mobilat, Mobitil, Mocox, Modigraf, Modrasone, Modulina, Mofecept, Mofetil, mofezolac sodium, Mofilet, Molace, molgramostim, Molslida, 25 Momecin, Momen Gele, Moment 100, Momesone, Momesun,

<img file="MX372859B_D0284.tif" />

296

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Mometamed, mometasone, mometasone furoate, Monimate, alphaiuminol monosodium, Mopik, MOR103, MOR104, MOR105, MOR208 antibody, MORAb022, Moricam, morniflumate, Mosuolit, Motoral, Movaxina, Moverr, Moverx, Movix, Movoxicam, Mox Forte, Moxen, 5 moxifloxacin hydrochloride, Mozobil, MP, MP0210, MP0270,

MP1000, MP1031, MP196, MP435, MPA, mPGES-1 inhibitor, MPSS, MRX7EAT, MSL, MT203, MT204, mTOR inhibitor,

MTRX1011A, Mucolase, Multicort, MultiStem, muramidase, muramidase, muramidase hydrochloride, muromonab-CD3, Muslax, 10 Muspinil, Mutaze, Muvera, MX68, Mycept, Mycoceli, Mycocept,

Micofenolatmofetil Aetavis, Micofel, Micofit, Micolato, Micoldosa, Micomun, Miconol, mycophenolate mofetil, maycophenolate sodium, mycophenolic acid, Micotil, myeloid progenitor cells, Myfenax, Myfetil, Myfortic, Mygraft, 15 Myocrisin, Miocrisin, Miprodol, Misone, nab-Ciclosporin, Nabentac, nabiximols, Nabton, Nabuco, Nabucox, Nabuflam, Nabumet, nabumetone, Nabuton, Nac Plus, Nacta, Nacton, Nadium, Naklofen SR, NAL1207, NAL1216, NAL1219, NAL1268, NAL8202, Nalfon, Nalgesina S, namilumab, Namsafo, Nandrolone, 20 Nanocort, Nanogam, Nanosomal Tacrolimus, Napageln, Napilac,

Naprelan, Napro, Naprodil, Napronax, Napropal, Naproson, Naprosina, Naproval, Naprox, naproxen, naproxen sodium, Naproxina, Naprozen, Narbon, Narexsina, Naril, Nasida, natalizumab, Naxdom, Naxen, Naxin, Nazovel, NC2300, ND07,

NDC01352, Nebumetone, NecLipGCSF, Necsulide, Necsunim,

<img file="MX372859B_D0285.tif" />

297

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Nelsid-S, Neo Clobenate, Neo Swiflox FC, Neocoilan, Neo-Drol, Neo-Eblimon, Neo-Hidro, Neopianta, Neoporina, Neopreol, Neoprox, Neoral, Neotrexate, Neozen, Nepra, Nestacort, Neumega, Neupogen, Neuprex, Neurofenac, Neurogesic, Neurolab, 5 Neuroteradol, Neuroxicam, Neutalina, neuirazumab, Neuzym, New

Panazox, Newfenstop, NewGam, Newmafen, Newmatal, Newsicam, NEX1285, sFcRTIB, Despuésomab, NF-kappaB inhibitor, NF-kB inhibitor, NGD2000I, NHP554B, NHP554P, NI0101 antibody, NI0401, NIOSO1 antibody, NI070I, NI071, NI1201 antibody, NI1401, 10 Nicip, Niconas, Nicool, NiCord, Nicox, Nillumato, Nigaz,

Nikam, Nilitis, Nimace, Nimaid, Nimark-P, Nimaz, Nimcet Juicy, Nime, Niraed, Nimepast, nimesulide, Nimesuhx, Nimesukm, Nimica Plus, Nimkul, Nimlin, Nimnat, Nimodol, Nimpidase, Nimsaid-S, Nimser, Nimsy-SP, Nimupep, Nimusol, 15 Nimutal, Nimuwin, Nimvon-S, Nincori, Niofen, Ñipan, Nipent,

Nise, Nisolona, Nisopred, Nisoprex, Nisulid, nitazoxanide, Nitcon, nitric oxide, Nizhvisal B, Nizon, NL, NMR1947, NN8209, NN8210, NN8226, NN8555, NN8765, NN8828,

NNC014100000100, NNC051869, Noak, Nodevex, Nodia, Nofenac,

Notlagma, Noflam, Noflamen, Noflux, Nonbacterial tetracyclines, Nonpiron, Nopaina, Normferon, Notpel, Notritis, Novacort, Novagent, Novarina, Novigésico, NOXA12, NOXD19,

Noxen, oxon, NPI1302a—3, NPI1342, NPI1387, NPI1390, NPRCS1, NPRCS2, NPRCS3, NPRCS4, NPRCS5, NPRCS6, NPS3, NPS4, nPT-ery,

NU3450, nuclear factor p65 subunit oligonucleotide

<img file="MX372859B_D0286.tif" />

298

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

NF-kappa-B, Nucort, Nulojix, Numed-Plus, Nurokind Orto, Nusona-H, Nutrikemia, Nuvion, NV07alfa, NX001, Nyclobato, Nyox, Nysa, Obarcort, OC002417, OC2286, ocaratuzumab,

OCTSG815, Oedemasa, Oedemasa-D, ofatumumab, Ofgil-O, Ofvista, 5 OHR118, OKi, Ocifeno, Oksamen, Olai, olokizumab, Omeprosa E,

Omnacortil, Omneed, Omniclor, Omnigel, Omniwel, onercept,

ONO4057, ONS1210, ONS1220, Ontac Plus, Ontak, ONX0914,

OPC6535, opebacan, ΟΡΝ1Ό1, OPN201, OPN302, OPN305, OPN401, oprelvecin, OPT66, Optifer, Optiflur, OptiMIRA, Grabase Hca, 10 Oradexon, Oraflex, OralFenac, Oralog, Oralpred, Ora-sed,

Orasone, orBec, Orbona forte, Orel, ORE10002, ORE10002,

Orencia, Org214007, Org217993, Org219517, Org223119,

Org37663, Org39141, Org48762, Org48775, Orgadrone, Ormoxen,

Orofen Plus, Oromilasa Biogaran, Ortal Forte, Orto Flex, 15 Ortoclon OKT3, Ortofen, Ortoflam, Ortbogesic, Ortoglu, Orto-, Ortomac, Orto-Plus, Ortinims, Ortofen, Orudis, Omvail, OS2, Oscart, Osmetona, Ospaina, Ossilife, Osteiox, Osteluc, Osteocerina, osteopontin, Osteral, otelixizumab, Otipax, Ou Ning, OvaSave, 0X40 Ligand Antibody, Oxa, Oxagesic CB, 20 Oxalgina DP, oxaprozin, OXCO, Oxeno, Oxib MD, Oxibut,

Oxicam, Oxiklorina, Oximal, Oxinal, oxyphenbutazone, Oxyphenbutazone, ozoralizumab, peptide P13, P1639, P21,

P2X7 Antagonists, p38 Alpha Inhibitor, p38 Antagonist, p38 MAP Kinase Inhibitor, p38alpha MAP Kinase Inhibitor, 25 P7 Peptide, P7170, P979, PA401, PA537, Pabi-Dexamethasone,

299

PAC, PAC10649, paclitaxel, Painoxam, Paldon, Palima, pamapimod, Pamatasa, Panafcort, Panafcortelone, Panewin, PanGraf, Panimun Bioral, Panmesone, Panodin SR, Panslay, Panzem, Panzem NCD, PAP1, papain, Papirzina, Pappen K Pap, 5 Paptinim-D, paquinimod, Antagonist PAR2, Paracetamol, Paradic, Parafen TAJ, Paramidin, Paranac, Parapar, Parci, parecoxib, Parixam, Parry-S, Partaject Busulfan, pateclizumab, Paxceed, PBI0032, PBI1101, PBI1308, PB11393,

PBI1607, PBI1737, PB12856, PBI4419, PBI4419, P-Cam, PCI31523, 10 PCI32765, PCI34051, PCI45261, PCI45292, PCI45308, PD360324,

PD360324, PDA001, PDE4 inhibitor, PDE-TV inhibitor, PDL241 antibody, PDL252, Pediapred, Pefree, pegacaristim, Peganix, Peg-Interleukin 12, pegsunercept, Pegsunercept, Pegylated arginine deiminase, peldesin pelubiprofen

Penacle, penicillamine, Penosiop, Pentalgin, Pentasa, Pentaud, pentostatin, Peon, Pepdase, Pepser, Peptirase, Pcpzen, Pepzol, Percutalgin, Periochip, Peroxisome Proliferator Activated Receptor Gamma Modulators, Peticene, PF00344600, PF04171327, PF04236921, PF04308515, PF052309O5,

PF05280586, PF251802, PF3475952, PF3491390, PF3644022,

PF4629991, PF4856880, PF5212367, PF5230896, PF547659,

PF755616, PF9184, PG27, PG562, PG760564, PG8395, PGE3935199, PGE527667, PH5, PH797804, FA408, Farmiaga Mefenamic Acid, Farmiaga Meloxicam, Feldin, Fenocept, Phenylbutazone,

PHY702, delta PI3K inhibitor, Gamma/Delta PI3K inhibitor,

<img file="MX372859B_D0287.tif" />

300

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

PI3K inhibitor, Picalm, pidotimode, picetoprofen, Pilelife, Pilopil, Pilovato, pimecrolimo, Pipetkanen, Piractam, Pirexil, Pirobet, Piroc, Pirocam, Pirofel, Pirogel, Piromed, Pirosol, Pirox, Piroxeno, Piroxicam, piroxicam betadex, Piroxifar, Piroxil, Piroxim, Pixim, Pixicin, Theta PKC Inhibitor, PL3100, PL5100 Diclofenac, Placenta Polypeptide,

Plaquenil, plerixafor, Plocfen, PLR14, PLR18, Plutin, PLX3397, PLX5622, PLX647, PLX-BMT, pms-Diclofenac, pmsIbuprofen, pms^-Leflunomide, pms-Meloxicam, pms^-Piroxicam, pms-Prednisolone, pms^-Sulfasalazine, pms-Tiaprofenic, PMX53, PN0615, PN100, PN951, podofilox, POL6326, Polcortolone,

Poliderm, Poligam S/D, Poliflogina, Poncif, Ponstan, Ponstil Forte, Porina-A Neoral, Potaba, potassium arainobenzoate, Potencort, Povidone, povidone iodine, pralnacasan, Prandina, Prebel, Pr ecodil, Precortisil Forte, Precortil, Predfoam, Predicort, Predicorten, Predilab, Predilona, Predmethyl, Predmix, Predna, Prednesol, Predni, prednicarbate, Prednicort, Prednidib, Prednifarma, Prednilasca, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone sodium succinate, prednisolone sodium succinate, prednisone, prednisone acetate, Prednitop, Prednol-L, Prednox, Predona, Predonema, Predsol, Predsolona, Predsona, Predval, Preflam, Prelon, Prenaxol, Prenolone, Preservex, Preservin, Presol, Preson, Prexige, Priliximab, Primacort, Primmuno, Primofenac, prinaberel,

<img file="MX372859B_D0288.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

301

Privigen, Prixam, Probuxil, Procaina, Proquimal, Procider-EF, Proctocir, Prodasa, Prodel B, Prodent, Prodent Verde, Proepa, Profecom, Profenac L, Profenid, Profenol, Proflam, Proflex, Progesic Z, proglumetacin, proglumethacin maleate,

Prograf, Prolase, Prolixan, Promethazine hydrochloride,

Promostem, Promane, PronaB, pronase, Pronat, Prongs, Pronisone, Prontoflam, Propaderrn-L, Propodezas, Propolisol, Proponol, propyl nicotinate, Prostaloc, Prostapol, Protacin, Protasa, Protease Inhibitors, Protectan,

Proteinase-activated Receptor 2 Inhibitor, Protofen,

Protein, Proxalyoc, Proxidol, Proxigel, Proxil, Proxim, Prozym, PRT062070, PRT2607, PRTX100, PRTX200, PRX106,

PRX167700, Prisolona, PS031291, PS375179, PS386113, PS540446, PS608504, PS826957, PS873266, Psorid, PT, PT17, PTL101,

Transfer Factor P Peptides, PTX3, Pulminiq, Pulsonid, Purazen, Pursin, PVS40200, PX101, P106491, PX114, PXS2000, PXS2076, PYM60001, Piralvex, Piranim, pyrazmobulazone, Pirenol, Piricam, Pirodex, Piroxi-Kid, QAX576, Qianbobiyan, QP11002, QR440, qT3, Quiacort, Quidofil, 20 R107s, R125224, R1295, R132811, R1487, R1503, R1524, R1628,

R333, R348, R548, R7277, R788, rabeximod, Radix Isatidis,

Radofen, Raipeck, Rambazol, Randazim, Rapacan, Rapamuna, Raptiva, Ravax, Rayos, RDEA119, RDEA436, RDP58, Reactin, Rebif, REC200, Recartix-DN, receptor for advanced glycation end products 25 antibody, Reclast,

<img file="MX372859B_D0289.tif" />

302

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Reclofen, Recombinant HSA-T1MP-2, Recombinant human alkaline phosphatase, Recombinant Gamma Interferon, Recombinant human alkaline phosphatase, Reconil, Rectagel HC, Recticina, Recto Menaderm, Rectos, Redipred, Redolet, 5 Refastina, Regenica, REG 88, Relafen, Relaxib, Relev, Relex,

Relifen, Relifex, Relitch, Rematof, remestemcel-1, Remesulido, Remicade, Remsima, Remsima, Remsima, ReN1869, Renacept, Renfor, Renodapt, Renodapt-S, Renta, Reosan, Repare-AR, Reparilexin, reparixin, Repertaxin, Repisprina, 10 Resochin, Resol, resolvin El, Resurgil, Re-tin-colloid,

Retoz, Reumacap, Reumacon, Reumadolor, Reumador, Reumanisal, Reumazina, Reumel, Reumotec, Reuquinol, revamilast, Revascor, Reviroc, Revlimid, Revmoksikam, Rewalk, Rexalgan, RG2077, RG3421, antibody RG4934, RG7416, RG7624, Reila, rheoma,

Reprox, Reudcinolone, Reufen, Reugesia, Reumacid, Reumacort,

Reumatrex, Reumesser, Reumid, Reumon, Reúmox, Reuoxib, Rewlin, Rucina, RuDex, Rulef, Ribox, Ribunal, Ridaura, rifaximin, rilonacept, rimacalib, Rimasa, Rimato, Rimatil, Rimesid, risedronate sodium, Ritatamina, Rito, Rituxan, 20 rituximab, RNS60, RO1138452, Ro313948, RO3244794, RO5310074,

Rob803, Rocamix, Rocas, Rofeb, rofecoxib, Rofee, Rofewal, Roficip Plus, Rojepen, Rokam, Rolodiquim, Romacox Fort, Romatim, romazarit, Ronaben, ronacaleret, Ronoxcina, ROR Gamma T antagonist, ROR gamma t inverse agonists, 25 Rosecin, rosiglitazone, Rosmarinic acid, Rotan, rotate,

<img file="MX372859B_D0290.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

303

Rotem, Roxam, Roxib, Roxicam, Roxopro, Roxigina DT, RP54745, RPT78, RPI78M, RPI78M, RPIMN, RQ00000007, RQ00000008, RTA402, R—Tyflam, Rubicalm, Rubifen, Ruma pap, Rumalef, Rumidol, Rumifen, Runomex,russialatido acetate, ruxolilinib, RWJ445380, RX10001, Rycloser MR, Rydol, SIP receptor agonists, SIP receptor modulators, S1P1 agonist, S1P1 receptor agonist, S2474, S3013, SA237, SA6541, Saaz, S-adenosylL-methionine-sulfate-p-toluene sulfonate, Sala, Salazidine, Salazine, Salazopyrine, Saleen, Salicam, salsalate, Sameron, SAN300, Sanaven, Sandimmun, Sandoglobulin, Sanexon, SangCya, SAR153191, SAR302503, SAR479746, Sarapep, sargramostim,

Sativex, Savantac, Save, Saxizon, Sazo, SB1578, SB210396,

SB217969, SB242235, SB273005, SB281832, SB683698, SB751689, SBI087, SC080036, SC12267, SC409, Scaflam, SCD ketoprofen, SCIO323, SCIO469, SD-15, SD281, antibody SDP051, Sd-rxRNA, secukinumab, Sedase, Sedilax, Sefdene, Seizima, SEL113, Seladina, Selecox, P-selectin ligand antibody, glucocorticoid receptor agonists, Selectofen, Selectin, SelKl antibody, Seloxx, Selspot, Selzen, Selzenta, Selzentry, semapimod, semapimod hydrochloride, semparatida, Semparatida, Senafen, Sendipen, Senterlic, SEP 119249, Sepdase, Septirosa, Seractil, Serafen-P, Serase, Seratid D, Seratiopeptidase, Serato-M, Seratoma Forte, Serazime, Serezon, Sero, Serodase, Serpicam, Serra, serrapeptase, Serratin, Serratiopeptidase, Serrazime,

<img file="MX372859B_D0291.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

304

Servisona, Seven EP, SGI1252, SGN30, SGN70, SGX203, Shark Cartilage Extract, Sheril, Shield, Shrfazen, ShifazenFort, Shincort, Shincort, Shiosol, SI1K186, Shuanghuangxiaoyan, SI615, SI636, Sigmasporin, Sigmasporin, 5 SIM916, Simpona, Simulect, Sinacort, Sinalgia, Sinapol,

Sinatrol, Sinsia, siponimod, Sirolim, sirolimo, Siropan,

Sirota, Sirova, sirukumab, Sistal Forte, SKF105685,

SKF105809, SKF106615, SKF86002, Skinalar, Skynim, Skytrip, SLAM family member 7 antibody, Slo-indo, SM101, SM201 antibody, SM401, SMAD family member 7 oligonucleotide, Anti-IL-12 SMART antibody, SMP114, SNO030908, SNO070131, sodium aurothiomalate, sodium chondroitin sulfate, sodium deoxyribonucleotide, sodium gualenate, sodium naproxen, sodium salicylate, Sodixene, Sofeo, Soleten, Solhydrol, Solicam, Soliky, Soliris, Sol-Melcort,

Solomet, Solondo, Solona, Solu-Cort, Soiu-Cortef, SoluDecortina H, Solufen, Solu-Ket, Solumark, Solu-Medrol, Solupred, Somal¡gen, somatropin, Sonap, Soné, sonepcizumab, Sonexa, Sonim, Sonim P, Soonil, Soral, Sorenil, 20-sotrastaurin acetate, SP—10, SP600125, Espanidin, SP-Cortil,

SPD550, Spedace, sperm adhesion molecule 1, Espictol, spleen tyrosine kinase oligonucleotide, Esporin, nSprin, SPWF1501, SQ641, SQ922, . SR318B, SR9025, -SRT2104,

SSR150106, SSR180575, SSS07 antibody, STI959, STA5326, stabilin 1 antibody, Estacort, Estalogesic, stanozolol,

<img file="MX372859B_D0292.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

305

Estaren, Estarmelox, Estedex IND-SWIFT, Estelara, Estemina, Estenirol, Esterapred, Esteriderm S, Esterio, Esterisona, Esteren, helianthus stichodactyl peptide, Estickzenol A,

Estiefcortil. Stimulate, STNM01, Stored-Operated Calcium 5-Channel (SOCC) Modulator, STP432, STP900,

Estratasina, Estridimune, Estrigraf, SU Medro!, Subreum, Subuton, Succicort, Succimed, Sulan, Sulcolon, Sulfasalazina

Heyl, Sulfasalazine, sulfasalazine, Sulfovit, Sulidac, Sulide, sulindac, Sulindex, Sulinton, Sulfafina, Sumilu,

SU597, Suprafen, 'Supretic, Supsidine, Surgam, Surgamine,

Surugamu, Suspen, Suton, Suvenyl, Sitwei, SW Dexasone, Syk Family Kinase Inhibitor, Synl002, Synacran, Synacthen, Synalar C, Synalar, Synavive, Synercort, Sypresta, T cell surface molecule antibody that induces cytokine 15, T cell receptor antibody, T5224,

T5226, TA101, TA112, TA383, TA5493, tabalumab, Tacedin,

Tacgraf, TACIFcS, Tacrobell, Tacrograf, Tacrol, tacrolimo, Tadekimg alfa, Tadoiak, TAFA93, Tafirol Artro, Taizen, TAK603, TAK715, TAK783, Takfa, Taksta, talarozole, Talfin,

Talmaina, talmapimod, Talmea, Talnif, tainiflumate, Talos, Talpaina, Talumat, Tamalgen, Tamcetona, Tamezoan, Tandrilax, tannins, Tannosynt, Tantum, tanzisertib, Tapaina-beta, Tapoeina, Tarenac, tarenflurbil, Tarimus, Tarproxeno, Tauxib, Tazomust, TBR652, TC5619, T-cells, immune response regulator 1, ATPase, H + transport, antibody

<img file="MX372859B_D0293.tif" />

306

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

A3 lysosomal VO subunit, TCK1, T-cort, T-Dexa, Tecelac, Tecon, teduglutide, Teecort, Tegelin, Tementil, temoporfin, Tencam, Tendrone, Tenefuse, Tenfly, tenidap sodium, Tenocam, Tenofiex, Tenoksan, Tenotil, tenoxicam, Tenoxim, Tepadin, Teracort, Teradol, tetomilast, TG0054, TGI 060, TG20, TG20, tgAAC94, Cytokine Synthase Inhibitor

Thl/Th2, Th-17 cell inhibitors, Thalide, thalidomidep, Talomid, Temisera, Tenil, Terafectin, Terapiace, thiarabine, Thiazolopyrimidines, thioctic acid, thiotepa, THR090717, 10 THR0921, Treenofen, Trombate Til, thymic peptide,

Thymodepressin, Timogam, Thymoglobulin, Thymogiobulin, Thymic peptides Timoject, Thymoinodulin, Thymopentin, Thymopolypeptides, Tiaprofenic acid, Tibezonium iodide, Ticoflex, Tilmacoxib, Tilur, T-immune, Timocon, Thiorase, 15 Tissop, TKB662, TL011, TLR4 antagonists, inhibitor of

TLR8, TM120, TM400, TMX302, TNF alpha inhibitor, TNF alpha-TNF receptor antagonists, TNF antibody, TNF receptor superfamily antagonists, TNF TWEAK Bi-Specific, TNF-Cinoid, TNFqb, TNFR1 antagonist, TNR001, TN100, TNX224, TNX336, TNX558, tocilizumab, tofacitinib, Tokuhon happ, TOL101, TOL102, Tolectin,

ToleriMab, Tolerostem, Tolindol, Toll-like receptor 4 antibody, toll-like receptor antibody, tolmetin, Tongkeeper, Tonmex, Topflame, Topicort, Topleucon, 25 Topnac, Toppin Ichtamol, toralizumab, Toraren, Torcoxia,

<img file="MX372859B_D0294.tif" />

307

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Toroxx, Tory, Toselac, Totaril, Toucb-med, Toucbron, Tovok, Toxic apis, Toyolyzom, TP4179, TPCA1, TPI526, TR14035, Tradil Fort, Traficet-EN, Tramace, tramadol hydrochloride, tranilast, Transimune, Transporina, Tratul, Trexall, 5 Triacort, Triakort, Trialon, Triam, triamcinolone, triamcinolone acetate, triamcinolone acetonide, triamcinolone acetonide, triamcinolone hexacetonide, Triamcort, Triamsicort, Trianex, Tricina, Tricort, Tricortone, TricOs T, Triderm, Trilac, Trilisato, Trinocort, 10 Trinolone, Triolex, triptolide, Trisfen, Trivaris, TRK170,

TRK530, Trocade, (rolamine salicylate, Trolovol, Trosera, Trosera D, Troycort, TRX1, TRX4 antibody, Trymoto, TrymotoA, TT301, TT302, TT32, TT32, TT33, TT1314, tumor necrosis factor, tumor necrosis factor 15-2-methoxyethyl phosphorothioate oligonucleotide, tumor necrosis factor antibody, tumor necrosis factor receptor superfamily member IB antibody, Tumor necrosis factor receptor superfamily 20 oligonucleotide IB, Tumor necrosis factor superfamily member 12 antibody, Tumor necrosis factor superfamily member 4 antibody, Tumor protein p53 oligonucleotide, Tumor necrosis factor alpha antibody, TuNEX, TXA127, TX-RAD, TYK2 inhibitors, Tysabri,

<img file="MX372859B_D0295.tif" />

308

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ubidecarenone, Ucerasa, ulodesina, Ultiflam, Ultrafastina, Ultrafen, Ultralan, U-Nice-B, Uniplus, Unitrexato, Unizen, Ufaxicam, UR13870, UR5269, UR67767, Uremol-HC, Urigon, URitis, ustekinumab, V85546, Valcib, Valcox, valdecoxib, 5 Valdez, Valdixx, Valdy, Valentac, Valoxib, Valtune, Valus AT,

Valz, Valzer, Vamid, Vantal, Vantelin, VAP-1 SSAO inhibitor, vapaliximab, varespladib methyl, Varicosin, Varidase, vascular adhesion protein-1 antibody, VB110, VB120, VB201, VBY285, Vectra-P, vedoliztunab, Vefren,

VEGFR-1 antibody, Veldona, veltuzumab, Vendexina, Veninunun

N, Venoforte, Venoglobulin-1H, Venozel, Veral, Verax, vercirnon, vero-Dexamethasone, Vero-Kiadribine, Vetazone,

VGX1027, VGX750, Vibex MTX, vidofludimus, Vifenac, Vimovo, Vimultisa, Vincort, Vingraf, Vtoform-HC, Vioxl, Vioxx,

Virobron, visilizu ab, Vivaglobina, Vivalde Plus, Vivian-A,

VLST002, VLST003, VLST004, VLST005, VLST007, Voalla, voclosporin, Vokam, Vokmor, Volmax, Volna-K, Voltadol, Voliagesie, Voltanase, Voltanec, Voltaren, Voltaril, Voltic, Voren, vorsetuzumab, Votan-SR, VR909, VRA002, VRP1008,

VRS826, VRS826, VT111, VT214, VT224, VT310, VT346, VT362,

VTX763, Vurdon, VX30 antibody, VX467, VX5, VX509, VX702, VX740, VX745, VX745, VX850, W54011, Walacort, Walix, WC3027, Wilgraf, Winilam, Winmol, Winpred, Winsolve, Wintogen, W1P901, Woncox, WSB711 antibody, WSB712 antibody, WSB735, WSB961, X071NAB, X083NAB, Xanthomicin Forte, Xedenol, Xeto,

<img file="MX372859B_D0296.tif" />

309

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Xefocam, Xenar, Xepol, X-Flam, Xibra, Xicam, Xicotil, Xifaxan, XL499, XmAb5483, YHB14112, YM974, Youfelina,

Youfenac, Yuma, Yumeroi, Yuroben, YY piroxicam, Z104657A, Zacy, Zaltokin, zaltoprofen, Zap70 inhibitor, Zeepain, Zeloxim Forte, Zema-Pak, Zempack, Zempred, Zenapax, Zenas, Zenol, Zenos, Zenoxone, Zerax, Zerocam, Zeroespasm, ZFNs, zinc oxide, Zipsor, ziralimumab, Zitis, Zix-S, Zocort, 10 Zodixam, Zoftadex, zoledronic acid, Zolfina, Zolterol,

Zopyrin, Zoralone, ZORprin, Zortress, ZP1848, Zucapsaicin, Zunovate, Zwitterionic Polysaccharides, ZY1400, Zybodies,

Zycel, Zyrofen, Zyrogen inhibitors, Zyser, Zytrim, and Zywin-Forte. In addition, anti-inflammatory drugs, as listed above, may be combined with one or more agents listed above or herein or with other agents known in the art.

In one embodiment, a drug that reduces, inhibits, prevents, and/or alleviates inflammation, for example, one of the 20 drugs provided above, is delivered to the suprachoroidal space of the eye using the microneedle devices and methods described herein, and is used to treat, prevent, and/or alleviate a disease or disorder selected from arthritis, degenerative arthritis, psoriatic arthritis, arthritic disorders, arthritic pain,

<img file="MX372859B_D0297.tif" />

310

IMPI

Mexican Institute of Industrial Property osteoarthritis, autoimmune arthritis, autoimmune diseases, autoimmune disorders, axial spondyloarthritis, chronic prosthetic joint infection, collagen-induced arthritis, osteoarthritis, rheumatoid arthritis, senile arthritis, 5 seronegative oligoarthritis of the knee, autoimmune and allergic inflammatory diseases, inflammatory diseases, inflammatory disorders, collagen diseases, Discoid Lupus Erythematosus, Immune deficiencies, Immune diseases, Immune disorders, Immunodeficiency diseases, Immunodeficiency disorders, Immunoglobulin (IgG2) deficiency, Immunoglobulin deficiency, Inflammation, Lambert-Eaton myasthenia syndrome, Polymyositis, Dermatomyositis, Polyneuritis, Postoperative ocular inflammation, Polychondritis, Sporadic inclusion body myositis, Systemic Lupus Erythematosus, T cell deficiency, TNF receptor-associated periodic syndrome, Tropical spastic paraparesis, Wegener's granulomatosis, X-linked severe combined immunodeficiency disease, Behcet's disease, Crohn's disease, Crohn's fistula, Cutaneous lupus erythematosus, acute inflammation, acute inflammatory edema, adrenocortical insufficiency, brain inflammation, chronic lung inflammation, corticosteroid-responsive inflammatory skin disorders, skin inflammation, dermal inflammation, 25 dry skin inflammatory disease, ear edema,

<img file="MX372859B_D0298.tif" />

311

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ear inflammation, glossitis, inflammatory bowel disease, inflammatory degenerative disease, inflammatory diseases of the eye and/or ear, inflammatory lesions in fungal infections, inflammatory lesions, inflammatory pain, inflammatory diseases or disorders of the skin, inflammation of the mouth and gums, inflammation of the mouth and throat, musculoskeletal disorders, otitis, pelvic inflammatory disease, perianal inflammation, Postoperative inflammation, pulmonary inflammation, rectal inflammation, refractory idiopathic inflammatory myopathies, seborrheic dermatitis, swelling, aphthous ulcerations, chronic polyarthritis, juvenile rheumatoid arthritis, rheumatic diseases, Sjogren's syndrome, Sjogren's ophthalmic syndrome, transplant rejection, acute allograft rejection, chronic graft rejection, graft-versus-host disease, humoral rejection in heart transplantation, Humoral rejection in kidney transplantation, organ rejection in kidney transplantation, solid organ transplant rejection, bronchiolitis obliterans after lung transplantation, bone marrow transplant rejection, chronic lung transplant rejection, corneal graft rejection, delayed graft function in kidney transplantation, heart transplant rejection, homograft rejection, immune rejection of hESC-derived therapeutic grafts, rejection of

<img file="MX372859B_D0299.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

312 Kidney transplant, liver transplant rejection, lung transplant rejection, organ rejection, pancreatic islet transplant rejection in type 1 diabetes, kidney transplant rejection, and xenograft rejection.

In one embodiment, the drug delivered to the suprachoroidal space using the microneedle devices and methods described herein prevents, and/or alleviates macular degeneration (e.g., age-related macular degeneration, macular degeneration). Dry age-related macular degeneration, exudative age-related macular degeneration, geographic atrophy age-related macular degeneration, neovascular (wet) age-related macular degeneration, neovascular maculopathy and age-related macular degeneration, occult without classic choroidal neovascularization (CNV) in age-related macular degeneration, Stargardt disease, wet subfoveal age-related macular degeneration, and Vitromacular Adhesion (VMA) associated with neovascular age-related macular degeneration).

Examples of drugs that treat, prevent, and/or alleviate macular degeneration that may be used in conjunction with the devices and methods described herein include, but are not limited to: A0003, peptide Ά36, AAV2-SFLT01, ACE041, ACU02, ACÜ3223, ACU4429, AdPEDF, aflibereept,

AG13958, aganirsen, AGN150998, AGN745, AL39324, AL78898A,

<img file="MX372859B_D0300.tif" />

313

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

AL8309B, ALN-VEG01, alprostadil, AM1101, amyloid beta antibody, anecortave acetate, Alterase Anti-VEGFR-2, Aptocin, APX003, ARC1905, ARC1905 with Lucentis, ATG3, ATP binding cassette, subfamily A, gene member 4, ATXS10, 5 Avastin with Visudin, AVT101, AVT2, bertilimumab, bevacizumab with verteporfin, bevasiranib sodium, bevasiranib sodium with ramizumab, brimonidine tartrate, BVA301, canacinumab, Cand5, Cand5 with Lucentis, CERE 140, ciliary neurotrophic factor, CLT009, CNT02476, collagen monoclonal antibody 10, complement component aptamer 5 (pegylated), complement component aptamer 5 (pegylated) with rambizumab, complement component C3, complement factor B antibody, complement factor D antibody, copper oxide with lutein, vitamin C, vitamin E, and zinc oxide, dalantercept, DE109, dexamethasone with ranibizumab and verteporfin, disitertide, DNA damage-inducible transcript 4 oligonucleotide, E10030, E10030 with Lucentis, EC400, eculizumab, EGP, EHT204, embryonic stem cells, human stem cells, endoglin 20 monoclonal antibody, EphB4RT inhibitor, Receptor

Soluble EphB4, ESBA1008, ETX6991, Evizon, Eyebar, EyePromise Five, Eyevi, Eylea, F200, FCFD4514S, fenretinide, fluocinolone acetonide, fluocinolone acetonide with ranibizumab, fms-related tyrosine kinase 1 oligonucleotide 25, fms-related tyrosine kinase 1 oligonucleotide

<img file="MX372859B_D0301.tif" />

314

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Mexican Institute of Industrial Property fms with receptor 169 kinase insert domain, fosbretabulin tromethamine, Gamunex, GEM220, GS101,

GSK933776, HC31496, n-CoDeR Human, HYB676, IBI-20089 with

Lucentis, iCo-008, icón 1, T-Oro, llaris, lluvien, lluvien 5 with Lucentis, immunoglobulins, integrin immunoglobulin fragments alpha5betal, integrin inhibitors, IRIS Lutein, I-Sense Ocushield, Isonep, isopropyl unoprostone, JPE1375, JSM6427, KH902, LentiVue, LFG316, LP590, LPO1010AM, Lucentis, Lucentis with Visudin, Lutein ekstra, Lutein with bilberry extract 10, Lutein with zeaxanthin, M200, M200 with

Lucentis, Macugen, MC1101, MCT355, mecamylamine,

Microplasmin, Motexafin lutetium, MP0112, NADPH oxidase inhibitors, Neoretna, Neurotrophin 4 gene 4, Nova21012, Nova21013, NT501, NT503, Nutri-Stulln, Ocriplasmin, OcuXan, Oftan Macula, Optrin, ORA102 with

Avastin, P144, P17, Palomid 529, PAN90806, Panzem, Panzem, PARP inhibitors, pazopanib hydrochloride, pegaptanib sodium, PF4523655, PG11047, piribedil, platelet-derived growth factor beta polypeptide beta aptamer (PEGylated), beta polypeptide aptamer platelet-derived growth factor (pegylated) with ranibizumab, PLG101, PMX20005, PMX53, P0T4, PRS055, PTK787, ranibizumab, ranibizumab with triamcinolone acetonide, ranibizumab with verteporim, Ranibizumab with volociximab, 25 RD27, Rescuia, Retaan, pigment epithelial cells

<img file="MX372859B_D0302.tif" />

315

IMPI

Mexican Institute of Industrial Property epithelial, RetinoStat, RG7417, RN6G, RTI01, RTU007, SB267268, serpin peptidase inhibitor, cade F, gene member 1, shark cartilage extract, Shefl, SIR1046, SIR1076, SirnaG27, sirolimo, SMTD004, Snelvit, SOD Mimetics,

Soliris, sonepcizumab, squalamine lactate, ST602, StarGen, T2TrpRS, TA106, talaporfin sodium, acid

Tauroursodeoxycholic acid, TG100801, TKI, TLCx99, TRC093, TRC105, triamcinolone acetonide with verteporim, Trivastal Retard, TT30, Ursa, ursodiol, Vangiolux, VAR10200, vascular endothelial growth factor antibody, vascular endothelial growth factor B, vascular endothelial growth factor kinoid, vascular endothelial growth factor oligonucleotide, VAST Compounds, vatalanib, VEGF inhibitor, verteporin, Visudin, Visudin with Lucentis and dexamethasone, Visudin with triamcinolone acetonide, Vivis, volociximab, Votrient, XV615, zeaxanthin, ZFP TF, zinc monocysteine, and Zibrestat. In one embodiment, one or more drugs that treat macular degeneration described above are combined with one or more agents listed above or herein or with other agents known in the art.

In one embodiment, the methods and devices provided herein are used to deliver triamcinolone or triamcinolone acetonide to the suprachoroidal space of an eye of a patient in need thereof.

<img file="MX372859B_D0303.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

316 same. In a further embodiment, triamcinolone or triamcinolone acetonide is delivered for the treatment of sympathetic ophthalmia, temporal arteritis, uveitis, and/or ocular inflammatory conditions. In one embodiment, triamcinolone or triamcinolone acetonide is delivered to the suprachoroidal space of the eye in a patient in need of treatment of sympathetic ophthalmia with the methods and devices described herein. In another embodiment, triamcinolone or triamcinolone acetonide is delivered to the suprachoroidal space of the eye in a patient in need of treatment of temporal arteritis with the methods and devices described herein. In yet another embodiment, triamcinolone or triamcinolone acetonide is delivered to the suprachoroidal space of the eye in a patient in need of treatment of uveitis, with the methods and devices described herein. In another embodiment, triamcinolone or triamcinolone acetonide is delivered to the suprachoroidal space of the eye in a patient in need of treatment of one or more ocular inflammatory conditions, 20 with the methods and devices described herein.

The triamcinolone composition provided herein, in one embodiment, is a suspension comprising microparticles or nanoparticles of triamcinolone or Friamcinolone acetonide. The microparticles, in one embodiment, have a D₅₀ from about 3 pm or less. In

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY an additional modality, the D₅₀ It is approximately 2 pm. In another modality, the D₅₀ is approximately 2 pm or less. In yet another modality, the D₅₀ is about 1000 m or less. The microparticles, in one embodiment, have a Dgg of about 10 pm or less. In another embodiment, the D99 is about 10 pm. In another embodiment, the D99 is less than about 10 pm or less than about 9 pm or less.

In one embodiment, the triamcinolone composition comprises triamcinolone microparticles. In a further embodiment, the composition comprises polysorbate 80. In another embodiment, the triamcinolone composition comprises one or more CaCl₂, MgCl₂, sodium acetate and sodium citrate. In one embodiment, the composition comprises polysorbate 80 at a % w/v of 0.02% or about 0.02%, 0.015% or about 0.015%.

In certain embodiments, the drug delivered to ocular tissues using the microneedle devices and methods described herein prevents, and/or alleviates fibrosis (e.g., myelofibrosis, fibrosis in diabetic nephropathy, cystic fibrosis, scarring, and skin fibrosis).

In one embodiment, a drug that treats, prevents, and/or alleviates fibrosis is used in conjunction with the devices and methods described herein, and is

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318

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY supplied to the suprachoroidal space of the eye. In a further embodiment, the drug is Actimmune with Pirfenidone, ACUHTR028, Alpha VBetaS, potassium aminobenzoate, P amyloid, ANG1122, ANG1170, ANG3062, ANG3281, ANG3298, ANG4011, Anti5 CTGF RNAi, Aplidine, Astragalus membranous extract with sage and Chinese Magnolia, atherosclerotic plaque blocker, Azol, AZXIOO, BB3, connective tissue growth factor antibody, CT140, danazol, Esbriet, EXC001, EXC002, EXC003, EXC004, EXC005, F647, FG319,

Fibrocorin, Follistalin, FT011, Galectin-3 inhibitors,

GKT137831, GMCT01, GMCT02, GRMD01, GRMD02, GRN510, Heberon Alfa R, interferon alpha-2b, interferon gamma-lb with pirfenidone, ITMN520, JKB119, JKB121, JKB122, KRX168, LPA1 receptor antagonist, MGN4220, MIA2, oligonucleotide 15 microRNA 29a, MMI0100, noscapine, PBI4050, PBI4419, PDGFR inhibitor, PF-06473871, PGN0052, Pirespa, Pirfenex, pirfenidone, plitidepsin, PRM151, Pxl02, PYN17, PYN22 with PYN17, Relivergen, rhPTX2 Fusion proteins, RXI109, secretin, STX100, TGF-beta inhibitor, transforming growth factor 20 receptor beta oligonucleotide 2,

VA999260 or XV615. In one embodiment, one or more of the fibrosis-treating drugs described above is combined with one or more agents listed above or herein or with other agents known in the art.

In one embodiment, a drug that treats, prevents

<img file="MX372859B_D0306.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

319 and/or relieves diabetic macular edema is used in conjunction with the devices and methods described herein, and is delivered to the suprachoroidal space of the eye. In a further embodiment, the drug is AKB9778, bevasiranib sodium, Cand5, choline fenophyrate, Cortiject, choline oligonucleotide^—raf 2-methoxyethyl phosphorothioate, DE109, dexamethasone, DNA damage-inducible transcript oligonucleotide 4, FOV2304, iCoOOT, KH902, MP0112, NCX434, Optina, Ozurdex, PF4523655, SAR1118, sirolimus, SK0503, or TriLipix. In one embodiment, one or more of the drugs that treat diabetic macular edema described above are combined with one or more agents listed above or herein or with other agents known in the art.

In one embodiment, a drug that treats, prevents, and/or relieves macular edema is used in conjunction with the devices and methods described herein and is delivered to the suprachoroidal space of the eye. In a further embodiment, the drug is denufosol tetrasodium, dexamethasone, ecalantide, pegaptanib sodium, ranihizumab, or triamcinolone. In addition, drugs delivered to ocular tissues using the microneedle devices and methods described herein which treat, prevent, and/or alleviate macular edema, as listed above, may be combined with one or more agents listed above or herein or with other agents known in the art.

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

In one embodiment, a drug that treats, prevents, and/or alleviates ocular hypertension is used in conjunction with the devices and methods described herein and is delivered to the suprachoroidal space of the eye. In a further embodiment, the drug is 2-MeS-beta gamma-CC12ATP, Aceta Diazol, acetazolamide, Aristomol, Arteoptic, AZD4017, Betálmico, betaxolol hydrochloride, Betimol, Betoptic S, Brimodm, Brimonal, brimonidine, brimonidine tartrate, Brinidine, Caite, carteolol hydrochloride,

Cosopt, CS088, DE092, DE104, DE111, Dorzolamide, Dorzolamide Hydrochloride, Dorzolamide Hydrochloride with Timolol Maleate, Dropthymol, Fortinol, Glaumol, Hiypadil, Ismotic, Isopropyl Unoprostone, Isosorbide, Latalux, Latanoprost, Latanoprost with Maleate Timolol, levobunolol hydrochloride, Lotensin, Manigen, mannitol, metipranolol, mifepristone, Mikelan, Minims Metipranolol, Mirol, nipradilol, Ñor Tenz, Ocupress, olmesartan, Oftalol, pilocarpine nitrate, Piobaj, Rescula, RU486, Rysmon TG, SAD448, Saflutan, Shemol, Taflotan, tafluprost, tailuprost with timolol, Thiaboot, Timocomod, timolol, Timolol Actavis, timolol hemihydrate, timolol maleate, Travast, travoprost, Unilat, Xalacom, Xalatan, or Zomilol. In addition, drugs delivered to ocular tissues using the microneedle devices and methods described herein which treat, prevent, and/or alleviate

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321

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ocular hypertension, as listed above, may be combined with one or more agents listed above or herein or with other agents known in the art.

In certain embodiments, one or more drugs can be delivered to ocular tissues and/or the suprachoroidal space using the systems and devices described herein. Delivery of one or more drugs into the suprachoroidal space using the microneedle device described herein can be achieved using one or more microneedles. Furthermore, combinations of one or more drugs can be delivered to the suprachoroidal space using the microneedle device described herein in combination with delivery of one or more drugs by intravitreal (IVT) administration (e.g., intravitreal injection, intravitreal implant, or eye drops). Methods of IVT administration are well known in the art. Examples of drugs that can be administered via IVT include, but are not limited to: A0003, A0006, Acedolone, AdPEDF, aflibercept, AG13958, aganirsen, AGN208397, AKB9778, AL78898A, P amyloid, Angiogenesis Inhibitor Gene Therapy, ARC1905, Auroeort, bevasiranib sodium, brimonidine, Brimonidine, tartrate brimonidine, bromfenac sodium, Cand5, CERE140, Ciganclor, CLT001, CLT003, CLT004, CLT005, complement component 5 aptamer (pegylated), factor D antibody

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322

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY supplement, Cortiject, c-raf 2-methoxy ethyl phosphorothioate oligonucleotide, cyclosporine, triamcinolone, DE109, denufosol tetrasodium, dexamethasone, dexamethasone phosphate, disitertide, DNA damage-inducible transcript 4 oligonucleotide, E10030, ecalantide, EG3306, Eos013, ESBA1008,

ESBA105, Eylea, FCFD4514S, fluocinolone acetonide, fms-related tyrosine kinase 1 oligonucleotide, fomivirsen sodium, fosbretabulin tromethamine, FOV2301, FOV2501, ganciclovir, ganciclovir sodium, GS101, GS156, hyaluronidase, IBI20089, iCo007, Iluvien, INS37217, Iso.nep,

JSM6427, Kalbitor, KH902, lerdelimumab, LFG316, Luceritis, M200, Macugen, Makyueido, Microplasmin, MK0140, MP0112,

NCX434, neurotrophin gene 4, OC10X, ocriplasmin, QRA102, Ozurdex, P144, P17, Palomid 529, pazopanib hydrochloride, pegaptanib sodium, Plasma Kallikrein Inhibitors, platelet-derived growth factor beta polypeptide aptamer (pegylated), POT4, PRM167, PRS055,

QPI1007, ranibizumab, resveratrol, Retilone, retinal pigment epithelium-specific protein 65 kDa gene, 20 Retisert, rod-derived cone viability factor. RPE65 Gene Therapy, RPGR Gene Therapy, RTP801, Sd-rxRNA, serpin peptidase inhibitor F member 1 gene, Sirna027, sirolimo, sonepcizumab, SRT501, STP601,

TG100948, Trabio, triamcinolone, triamcinolone acetonide, 25 Trivaris, tumor necrosis factor antibody,

<img file="MX372859B_D0310.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

VEGF/rGel-Op, verteporfin, Visudin, Vitrase, Vitrasert, Vitraveno, Vitreals, volociximab, Votrient, XG102, Xibrom, XV615, and Zybrestat. Accordingly, the methods of the present invention include administering via IVT one or more of the drugs listed above in combination with one or more drugs described herein delivered into the suprachoroidal space using the microneedle device described herein.

In one embodiment, the drug is formulated for storage and delivery by the microneedle device described herein. The drug formulation is a formulation of a drug, which typically includes one or more pharmaceutically acceptable excipient materials known in the art. The term "excipient" refers to any non-active ingredient in the formulation intended to facilitate handling, stability, dispersibility, wettability, release kinetics, and/or injection of the drug. In one embodiment, the excipient may include or consist of water or saline.

In one embodiment, the fluid drug formulation includes microparticles or nanoparticles, each of which may include at least one drug. Desirably, the microparticles or nanoparticles provide controlled release of the drug within the ocular tissue. As used herein, the term

<img file="MX372859B_D0311.tif" />

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Mexican Institute of Industrial Property "microparticle" includes microspheres, microcapsules, microparticles, and beads, which have a number average diameter of 1 to 100 nm, most preferably 1 to 25 nm. The term "nanoparticle" refers to particles that have a number average diameter of 1 to 1000 nm. Microparticles may or may not be spherical in shape. Microcapsules are defined as microparticles that have an outer shell surrounding a core of another material. The core can be liquid, gel, solid, gas, or a combination thereof. In one embodiment, the microcapsule may be a microbubble having an outer shell surrounding a gas core, when the present drug is disposed on the surface of the outer shell, on the outer shell itself, or in the core, the microbubbles may respond to acoustic vibrations as is known in the art for diagnostics and/or may be used to burst the microbubble to release its payload at/within a selected ocular tissue site. Microspheres can be solid spheres, can be porous, and can include a honeycomb or sponge-like structure formed by pores or voids in a matrix or shell material, or can include multiple discrete voids in a matrix material or shell. Microparticles or nanoparticles can further include a matrix material. The shell or matrix material can be a polymer, amino acid, saccharide, or other material.

<img file="MX372859B_D0312.tif" />

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325 known in the technique of microencapsulation.

The drug-containing microparticles or nanoparticles can be suspended in an aqueous or non-aqueous liquid vehicle. The liquid vehicle can be a pharmaceutically acceptable aqueous solution and can optionally also include a surfactant. The drug microparticles or nanoparticles themselves may include an excipient material, such as a polymer, a polysaccharide, a surfactant, etc., which are known in the art to control the kinetics of drug release from the particles.

In one embodiment, the fluid drug formulation further includes an agent effective to degrade collagen or GAG fibers in the sclera, which may enhance penetration/release of the drug into the ocular tissues. This agent may be, for example, an enzyme, such as hyaluronidase, a collagenase, or a combination thereof. In a variation of this method, the enzyme is administered to the ocular tissue in a separate step from the recoil or after the drug infusion. The enzyme and the drug are administered to the same site.

In another embodiment, the drug formulation is one that undergoes a phase change after administration. For example, a liquid drug formulation can be injected through the hollow microneedles into the space

<img file="MX372859B_D0313.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY suprachoroidal, where it then gels and the drug diffuses out of the gel for controlled release.

While the embodiments and methods herein describe delivering a medicament to a target tissue, the embodiments described herein may be configured to facilitate a biopsy procedure and/or removal of a substance from a target location.

While the modalities have been described above for use in ocular tissue, in some cases, the modalities and methods described herein may be used in any other suitable body tissue. For example, in some cases, the use of an adjustable-length needle may be beneficial in conjunction with standard phlebotomy techniques during drug infusion and/or blood draw from a vein. Thus, while modalities and methods are specifically described above for use in ocular tissue, it should be understood that the modalities and methods have been presented by way of example only, and without limitation.

While various embodiments have been described above, it should be understood that they have been presented by way of example only and without limitation. Where the methods described above indicate certain events occurring in a certain order, the order of certain events may be modified. Additionally, certain events may be

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY carried out concurrently in a parallel process when possible, as well as carried out sequentially as described above.

Although the systems and methods shown and described herein already provide drug delivery into the suprachoroidal space, in other embodiments, the systems and methods described herein may be applicable to the delivery of any suitable therapeutic substance to any portion of the eye, such as the cornea, retinal area, or vitreous humor. In other embodiments, any of the systems, methods and devices described herein can be used to deliver any suitable therapeutic substance to any desired target tissue (including non-ocular tissue).

Where the schemes and/or embodiments described above indicate certain components arranged in certain orientations or positions, the arrangement of components may be modified. Similarly, where the methods and/or events described above indicate certain events and/or procedures occurring in a certain order, the order of certain events and/or procedures may be modified. While the modalities have been particularly shown and described, it will be understood that various changes in forms and details may be made.

<img file="MX372859B_D0315.tif" />

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For example, although the injector assembly 2100 is shown and described as including a biasing member 2146 configured to exert a force to move the actuator 2320 to assist in delivering a medicament, in other embodiments, the injector assembly 2100 (and any other injector assemblies shown and described herein) may include any suitable mechanism for producing a force to move the actuator 2320. For example, in some embodiments, an injector assembly 10 may include a stored energy member, such as a propellant canister, a compressed gas container, a magnetic energy storage member, an electronic energy storage member (e.g., a battery or a capacitor), or the like.

Although several modalities have been described as having particular characteristics and/or combinations of components, other modalities are possible, which have a combination of any of the characteristics and/or components from any of the modalities as discussed above. For example, while the extraction member 21280 is described as being included in the system 21000 and configured to be coupled to the medication container 21310, in some embodiments, the device 2000, 3000, or any other device described herein may be used with and/or include the extraction member.

<img file="MX372859B_D0316.tif" />

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

329 extraction 21280, or any other extraction member described herein. Furthermore, while the needle assembly 3200 is shown to be included in the system 3000, in some embodiments, the system 2000, 21000, or any other medical injector described herein may also include the needle assembly 3200 or any other needle assembly described herein. However, while the injection assembly 2100 is described as being included with the system 2000, in some embodiments, the injection assembly 2100 may also be included in the system 3000, 21000, or any other system described herein. Similarly, any of the systems described herein (e.g., system 2000, 3000, or 21000) may include or be configured to be coupled to a hub that includes a convex distal end surface such as, for example, hub 7270, 8270, or 9270.

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NOVELTY OF THE INVENTION

Having described the present invention, it is considered as a novelty and, therefore, the content of the following is claimed as property: