Stabilized formulations containing anti-pcsk9 antibodies

1 35355Β1, 201 AOUT 1 I 0 excelled bulb containing the bodies of d-pad PCSK9) full description of the technical field: .jk Alatir 1 to 4 p spanking Mtadh therapeutic antibodies formats. And more specifically, the other on 1 GS 1 to a current 0 spanking a pharmaceutical pump Tttml on gm anti human Ertbad Nhdido Beruti Avbimkl; Fattaz Abroc 1 n Tiei human Sashleysin a Kiksin Q type 9 (PCSK9). List Almtuwaliadt 10 deposited Half 25.ST compatible script to the list of sequences simultaneously with the current specification. Wei 0 Odrq Mho.at one of the text file references within this document. The Dint paper copy of the list of 10 Alhoagliat, Mtma; 0 z saluting him Mai Ha half 25.ST 1 to 1 Zaa Buaq; Khze not y * Ci \ 0 n the current standard. Background Rhyming must Stah 1 molecules 1 for therapeutic big (ZZ 1 for example 0.1 to Agam 1 delegation) are b 4 & lt ;; with 1 to Dzbiat what 0 of Fv to give 7 patients 0.0 p Ahtvaa Ha'ha lighted Oe x, Suha, 15 and Achkd 1 Maha to Ahvo. And the cell 1 to Example 0.0 the fact that one of Agam a 1 Mlajah Lhasa 1 couched in specific-for Sal Erd 4-degradable, or M 6 km or chemical modifications is Mtaloh 0 of not 0 Besg 1 Iol trustee) I correct. .ptoagaf 0 Pat body Mdhann prevailed in B I t the height of Alo 1 Altkhaddmh languages ​​in the formula, but also a 0 on the quantities wannabe excipients Zbh to some of the land. Elaoh & lt ;, 4 Deleting it must take into account other considerations is steadiness when Z Megh PM 0 Gadd SA, d. And "waging 0 20 examples of these additional considerations for wife Anhlol and Rtmz Jem Olmmjah 1 to 0 Memklo Thouddhirh to what,

MA 35355Β1 and Aloiv aortic or ration b. Consciousness, when Viz 0 0 b m Advantaged been 's Alaie I: Akj; p ut blacks presented are published 0 Sgz his mount, and has been erased; Father 0 n completed one of the Med, and be reminded wife was not doing as well as 0 Ihod father ZZ any trauma Besooh occasion. 5 P now Algadh not! Zimkuliriz protein Tabas wells bad a Z g Aa and (PCSK5)! Omiah fleecing% 1 V 'end to large' to bundle Elaha snitch Ahlap b 0 No father 'Dutt 0 d 0 to Oouam Asdh's »PCSK helm Ekboukha Yale 0 treatment plant or. Aloyah g land was 'Ri 4 0 Koaarol in 1 cm and! Crowned S. free formation Aadhun my mother Aryan' slips Ozzy 'rather Amgt Ohle for anti-radiation to Odhadh for PCSK9, p between parents see' in the completed Adola was 10 057457/2008, international Aahllb RTM 057 458 / 2008. 1 of the first medicine RTM 057459/2008, 063382/2008 international Alhllb RTM. Completed Adola RTM 125623/2008, and APRA, its only 0 hip rice 7,572,61.8. Completed Adola RTM 077854/2010, and APRA, Aloaaa of rice 0166768/2010. The Alera, of the nation RTM 0065902/2011. 1.5 Although Alosam Alamadanh g PCSK9 known, but there are pilgrims in the field of pharmaceutical new small c Olney, bless antibodies for PC.SK9 and 1 Lenny be fixed Ot semi-Z enough to give to patients. 20 3

3 MA 35355Β1 Alkmhv for only 0 Hhraa Levy 1 current Akharaa need Allchorh above and Levi is the 0 Dhufter pumping Sdlaah Sa 7 t g Anti 0 Shi associated Lu 0 a protein enzyme Kongrnaz protein vanguard of mortal expressed R. Klkaaan type 9 (PCSK9). 5 in the aspects I find, is to provide pharmaceutical Hblh liquid, include: (1) body »Khad human Zatbt particular protein enzyme protein Kongraz vanguard Shri R. Adt Kiksin Q widely 9 (9.PCSK); (2) Mahlo, for structured; ( 3) Munib Htherk Swe; (4) Chet; and choose) (a) p viscosity. In a Alnmang, the Presentation antibody Atd ~ Z and Keys ranges 6 to 50 g 7.5 Bh 0 AAA * 10 1 Li Ho Lee 1 200 ± 30 mg a ml. In Nmong path others are Presentation antibody Eia 0 Rkats. 1 m of 50 g me a 0 to ± 7.5 Bhm of 0's. In Nmong Akhra are served antibody when Wa is about 100 mg a ml ± 15 Bhm a ml 0, y 6 Zj ace is Tahedbm 1 rein in one of the anti-I -kels of about 150 mg a ml ± 22.5 Bhm a ml 0 in Nmong least are Presentation recycled bridles when Kels a ho me one of 175 mg ml ± 20.25 Mjmaml 0 0 in the latest model of the blood of one meat counter at 15. Kels is about 200 mg ml t g Heq Bhmmerml. In a 1 Bzj, bridles anti include any one or more of the amino acid sequence Ahamven Volh km identity: 1-8. In a Alnmazje Jem daad includes S) variable region of Coffee trick (HCVR) include areas determine cosine heavy chain 1.2 and 3 1 each of which include a succession of succession identity: 2 number, Mtwaah number 20 Hoiv: 3 sequence identity: 4 No. , respectively; and (b) Mngnoh area for a series Khgegh (LCVR) Stml to identify areas cosine middle Alkhvagh 1.2 and 3 (LŒ & gt; R20LCDR3-LCDR1) 35355Β1 of Ai'hab 3 Vdrdiote »a, respectively. FIA-Elyd 1 Nardabdsbyd 6 ;; Dablass 60 E 05 "00 0. 0 6 ± 4 0, modulate pH 6.0 ± 0.3, ± 6.0, and threatened me t; 0; Yale: 0; Iim_, 6 ± Q0.h ,, Q ^ GG 0.2, pH

0 C at a specified Nmong, the land of one Brouhmna b Alaouah 0 Kun 6.0 for +3 0. In a Alnmang, includes Anhlol organizer pharmaceutical ho 1 I 1 rack 1 Vdroajabi 6.0 S 10 E 1 Ilal Zmh, and 1 the one who characterized Ptzm effective in over Draouh g Alsailevyo one end Ooolas 1 Z a Sloja 5.5 Afmalaa; Illama 7.4, or St-Hsc 0.0 ppg not about 6.0. 1.5

MA in one 0 Yz .bikun sooo Hzm p 0 Elan · In Ed Aladj 'Ecot I-Q I 0; / d 5 Rlolar ± 0.75 d .olar to 50 t a land. ± 5-7 0.0 and Ar- in I Abzj 0 universe who I j x 10.0 and lar p 5'a t .ulad or 6 to her 0.0 and Lahr. In spilled 0 d be a less-Z Q 9 x 20 * ë R. Allard G 3.0 to Wheeler or 6 to 20 mesh 0 and Lahr. In] fairly Alang, Dan Afban I-Ar income 40 p .olar ± 6 million Mola t or about 40 nano Molar. In any Anj, -kod Ibb | Ka Lacock well 8. Z Unni as 0 j {· incision or guardian. Dd. D 0 in the food-Azha .kon a 4 b Ocoee Aczk any Wade A AAA 0 n Crown to that point 20 i 35355Β1 20 & lt; Blksamer 1.88 and poly Asli Jykol 50 (0.3. In Nmong Mahdn, be Munib spontaneous Almchehrk polysorbate 20. In a Alnmang, organic Munib polytheist be when Trtheis ranges from about 0.005½ ± 0.00075½. 4 Li-ho 1 Lee 1½) ± 0.15½) & quot ; Warren to size & quot; Or Özen / Hhm & quot ;, where, s presented a Alnmazh., Be, ../.1 a & lt ;,: 0 gm and 01.a PL -10. /. 0 g '5 For example, 1. Iaz ho 1 Li 0.2½) ± when and as have the 0.20 J 1 Mchk polysorbate organic 1 Mzbb as trumpet Sorzt 20, _, allof 0 Aledouh Alzlb 010 x 0 H converts in Nmong last 6 Heh 9 a. 0.03% Osv / ho 10:01 1 Li Li) w / w of Heh 6 A 'or a .0% 015 ± ./.0.01 be when Tkz which Hhm. Termination of sugar Akhhmoah Pettm the Nth Alnmazh, C A Oltthst a sugar worker. A, be Alnmang 10 in one consisting of sucrose, mannitol and Hbhwazz, Z Gonh Mahddo Likud years, Altthbymth Q 10 Dhiroz 0 007 000 t 0 a 10 in a Alnmang, be Gaml installation when R'Kiz ranging from 1½) ± 0.15½) w / v to 20½ ± 3½ weight / volume. Set in Nmong, the installation factor when sucrose Wikeez a 5½ ±% 0.75 w / v or about 5½ weight and size. Set in Nmong another factor is 1.5 sucrose installation when Keys of 1.0½) ± 1.5% of the size or weight, about 1.0½) and Zn'r Hhm. In Gonh; another specific installation and sucrose when Tnkiz be a 12-year-old Aplum / ± 1.8 (/ Warren of 00; a: a) 0 l & gt; Ee's 0 n Hhm or about 12% of the weight of Hhm. In a Alnmazje are selected to reduce the viscosity of the Atjmugh Olney consisting of arginine Helrllaurel factor, Theo Banat sodium, Iao Banat Alomoiaom, ammonium Brittat 0.20 ammonium chloride, both Reid Alcaleom, zinc chloride and sodium acetate. In a Annmadj, be reducing the viscosity factor is a-Orivn Heder ^ for Orben. 6 35355Β1 in a Likud Avazj 0 0 Mltenbl Aldoi I; / 8 triple strands z 10-year Rlar 1.5 ± 0.0 and Zq lar lar 150.6 22.5 ± 0.0 and Lao. Ed Aladj, Iike 0 n 6:00 Allarrolo 00 A-; Rajabin # count j E 50 t .olar 4 5-7 t .ulad Ed 6 to 50.010. In Ahdaazj 0 Likud I 0 for r b r a-rays 0 I this ypg 40.0 and Lahr ± 06 R. 0 and Alao 6 to 040 in 6 the- T! Extent Abdj 0 be Dhue 1b Alhelab 0 NowNot OS b 0 b Dam O (j I 25 Me 0 Ioiv humiliated 0 n! F t 0 Levi Aq 6 5A x. because e Does 0 t 'in! extent Alang' Joel Asc 1 Ed 25 days 1 what 0 z 0 Labs * 0 a / 0 and 8 Labs ± 0 L / H 0.10 in; Haddalama'aallarroeay 25 Se, Tia 1.6 neighborhood * normal result% '7'akhma e 0 a% of dL; 0's, a. 3.5 My Boaz ± 10%, 4.8 06 * commencement 10% 0 6.0 Tq Bo 0 g ± 0% a, 7.0 m * ± 10% and a 7.1 pp as a d 0% '7.2 m 15

UK a ± 10./0. Tneaouz and 0.7 ± 0% AA 8.9 A 6 E parallel ± 10% '10.0 Salora 0 E. Barr% 10.6 0.0 a 0 /., 11.4 * 0 aaah worker know. H'aasi a 0% BTS Boaz 11.8 ± a 0% & lt; 12.4 meet lar * 010 / A'13.9br to a 0% *. 14.0 Tta * and ± 10./. ' 15.5 d * a 0%. Or SPA * E:; above 50 J », VM» PSC 5 00 '0 15 t! E Kames .460: 69 x. Continued t k 0 m. In Ed Alazj0'loe Father August barrage: T 0, DOCUMENTS-al ;; s 0 decide; -vyb E y Alsdlaa 0 Ala.z 195 29 t t! Pannier t mm 0 m Ed 6 to me; Er;, Em.daa 0 to Ale.haesalomssla, 2201.20 7 7 1 35355Β1 33 million Osmol a LMO, or about 220 million Osmol t Bjm. In a Alnmang, Olosmo-Mechanism 1 Sgh 1 divulge to Shehadlaveh liquid 330 ± 50 million Osmol t Bjm or ho 1 Lee 330 million Osmon did km 'in a Alnmazje divulge Osmolih liquid pharmaceutical formulation 435 ± 65 million Osmol no kg or 5 0 s 435 million Osmol a kg. In a Alnmang, hoarse Osmolih pharmaceutical formula Alaila 440 ± 66 million Osmol a LMO, or about 440 million Osmol a LMO. In one MUNG, Dh Osmolih liquid pharmaceutical sorry 458 ± 69 Z Osmol t LMO or about 458 t Osmol a LMO. In a 1 to Zmadj, is one Schas the persons of 96% or at least 97% are Asph is 10 dissolved Wenger from Jem counter A- Ρ.Κ9 of August Alfdlab agents d Elola z oo Tkhozbn liquid pharmaceutical formulation at -80 Dhar ^ 0 Ioah, Tqo what do determine the 0 and 1 Plan Kromatouhav exclusion of Alhhm 0 in one of the tastiest 0 paradigms, are Aschas at least 56% of the picture is the basal and non-acidic (ie, main image sorrow or shipment Aliasah) of the body, according to PCSK9 Z August as upper pharmaceutical liquid three months after Z Aceh Alfdlab a 7 questions at -80 ° C & lt; Tqo what Jade determined Boisthkromatogerav ion exchange. In a 1 to Zmazgel is extracted at least% 0 A, or at least (1) () / 0 n AAC 0 Subject to is a 0 Kkah and is dissolved from the antibody g PCSK9 from Albailh pharmaceutical formula after the 'Ilmz 0 lattes b 4 of storing pharmaceutical Aceh Aiailh Ezd -30 ° C, according to -5 are challenging valley (2) exclusion Kromatdav 1 1 Hhm. I would like to Alnmang, was Amtkhalas at least 56 Behold the image of the main charge of the Table 21:00 1 35355Β1 Alamada 1 and PCSK9 pharmaceutical Alailh the guest after three months of storage capacity, pharmaceutical oblique at -30 ° C, according to what is determined Boisthkromatogeravy ion exchange. In a Laghmanj, it is extracted at least 96% or at least 97% of the picture Pollack clustered and non Altlh of pregnancy daad y PCSK9 liquid pharmaceutical dye Ban three months A liquid pharmaceutical formulation stored at -20 Drahh Celsius, according to is determined by the Chroma & quot; and Graf exclusion size. In one of the models, the Amtkhalas at least 56% of the image of the main charge of Lean counter g PCSK9 liquid pharmaceutical formula after Refrigerator months of Tkhozar 0 liquid pharmaceutical formulation at _20 ° C (Tbakoh what is determined by the Chroma-Graff exchange Pokerschool 0.0 A in Ahab Alnmang, is extracted on Wallach 96½) of the image is clustered and non-dissolved from Jem anti-PCSK9 liquid pharmaceutical formulation for six months after the liquid pharmaceutical August Drahh stored at 5 ° C, according to the determined in Ath chromatograph exclude Alhhm. In a Alnmang, is extracted on the persons of 58% or 59½) from the image alum abdelhady From abdelhady Z antibody to PCSK9 of liquid pharmaceutical August after Olath months-Z Tkhoz; n 15 liquid pharmaceutical formulation at 5 degrees Celsius, according to be determined and Asithkromathurav exchange Pokerschool . In a Alnmang, it is extracted at least 94% of the picture is Almtnkilh and August H 3 T. antibody y PCSK9 Z Pharmaceutical Asamagh Anailh after six Thor from Tkhoz; n August Asamedlanah liquid at 25 ° C E According; to be determined Boath chromatograph exclude 20 Alhhm . In a Alnmang, Amtkhalas are at least 45% O'o 47½) of the genitalia is basal Gner. Acidic Y antibody to PCSK9 Family pharmaceutical formula after six Chheu-t r 9 9 1 35355Β1 August Asamadlanah liquid storage at 25 ° C, according to 6 cm determined Boisah chromatograph exchange Oladon. In a 0 extent Abzj 0 cm draw at least \ 9% or 92% of the image is clustered and Pollack Alhah of antibody and PCSK9 from Anailh pharmaceutical formula after 28 days we store 5 adjective 1 Blazd Anailh at 45 degrees Celsius, according to Yum determined Boisthkromatogerav Escaaz pilgrimage 0 m. In a Alnmang, CM draw on persons 35% -or- 37% of Almmorh Gtar Aidip acidic Od of PCSK9 antibody pharmaceutical dye Alailh Ban for 28 days of ashamed. Liquid pharmaceutical formula at 45 degrees Celsius, according to the CM determined Boisalh chromatograph exchange Pokerschool. 1.0 in one aspect, CM Presentation pharmaceutical liquid formula, Tttml on: (1) pp. 50 ± 7.5 Bhm a t 0 to 1.75 ± 26 mg ml of t body fluorescence pustular Aiehl legally set the body of the human PCSK9; (2) from 0 milli Molar to 40 ± 6 milli Molar e Sudainz 0 (3) Z 0½ to 0.2½ ± 0.03½) (Laura size) trumpet sorbate 20; (4) Z 0% to 12% ± 1.8½) (Rzr and size) sucrose ,; and (5 ) p 0 0 Melli and lar to 50 ± 7.5 t Mula'r Orpf 'E 0 15 Q 0:00 p 0 x 1 ho Lee 5:34 Li ho Lee 1 6.7. It includes lava counter a 0 PCSK9 from congratulated attractive Z Mtqh Htg one step 77 to Jeddah (HCVR) and the variable to the authority Khgegh (LCVR) to include Tolegh HCVR / LCVR a limit-added AAC zones 0 or LLU less protective (HCDRI-HCDR2-HCDR3 t LCDRl0L € DR20LCDR3 & gt; 0 any MSAS 6 Apt acid 1 for dad to Mtolgh figures identity: 2 - 3-4 a Mtwalt Parfam identity: 6 -7-8ad 20 respectively. in particular Nmong, antibody includes for PCSK9 t - variable HJ Tmilh 35355Β1 HCVR)) and the variable series Khgegh (LCVR) include succession Hmgy my son from succession, and identity: 1 and. Sequence identity: 5 number, for Akowala (raised to it later. (& Quot; mAb0316P nee a Alnmang of this GAP, pharmaceutical formula include (E) 50 ± 7.5 mg a ml of mAb-316P :; (2) 10 ± 1.5 Melli Molar Hatidin; (3) .0.1% ± 0.01.5½) (trace and size) Bobby Surat 20; and (4) 6½ ± 0.9½ (Lanza and size) sucrose, when Znm pH 0 Bagh 6.0 ± 0.3. in one of these Alnmang the guest designated viscosity of about 0.1 Snna 7. Port. Laghmanj in a specific formula of this topic, osmolarity of 220 ± 44 Collapse 'Osmol a kg. Nmong in another, pharmaceutical formula include (!) 1.00 ± 20 mg a ml mAb-316P; (2) 20 ± 4 million Molar Hishadan; (d) 0,2½ ± 0.04½ (and trace Hhm) Crown sorbate 20; and (4) 12% ± 2.4% (and a trace Hhm) sucrose, at pH repealed No. 6.0 ± 0.3. in one of the models of this particular version, of the viscosity of about 3.5 Snna Boaz 0 in a Alnmang of this particular formula, an osmolarity 440 ± 88 Collapse Osmol t kg. in Nmong another, pharmaceutical formula include (1) 150 ± 22.5 Bhm ml of a -mAb 31.Ρ; (2) 10 ± 1.5 and 0.0 Lahr Medellin; (3) 0.2% ± 0.03./ '!, 0.01./. ± 0.00-15 (% (and trace size) poly Soeriat 20; and (4) 0.a% ± 1.5% (and a trace size) Akron, at pH of 6.0 ± 0.3. My one Alnmang of this one formula Akhaanho Tbbg viscosity of about 6 Snna Aois. In a MUNG of this particular formula, an osmolarity 5 d 4 ± 65.25 million Osmol t LMO. In a Alnmazh of this particular formula, after Nkhozbn formula at 45 degrees for 28 days, as 092% of the antibody is genuine and & gt; 35½ of the antibody is of an image charge 11 35355Β1 August. En Ainmang taken it in this topic specific formula, after Anasigh stored at 25 degrees for six months, & gt; 94% of the antibody be Osalioo; 5 45) / 0 0 n palpation., Can almost be 0 n pictures Ihnh Home. In one of these Annmang August August, after August Tkhoz 0 0 5 yen I der-Tt Study for two months, & gt; 96½) p antibody is rust and & gt; 58% of the 1 antibody Ecot image Alhih necktie. In a Olnmang of this particular formula after formula stored at 20 degrees for one tenth Thro bend, & gt; 97½) Z body 1 to be anti Osao and & gt; 56½) of the antibody is of an image charge in August. In a Alnmang 0 n this b F-0 storage prepare formula at -30 ° for a period of twelve affect Thro, as 97½ of El Jem 1 CKD art Obe and as 56% of El Jem anti be the main picture Ihnh. In a 1 Bzj it is this particular formula after formula stored at -80 degrees for Athy found Sha S. 1 97 0.0 n Adam counter is genuine and & gt; 56% of the antibody Ako.n of Ihnh image convergence. In some Alnmang of this particular trait, Ihtvgl% 85 ί of El Jem I barely as much as 9 A'soloanh after 28 days at 45 ° C,% 82 ί after 28 days at 37 ° Mia 0 Yeh, or War? 98% after 28 gesticulate at 25 ° C. Bagy Alnmang in August of this August, Ihgz 0 ί% 85 of the antibody biological Bakdzbeh after six months at -20 Celsius Dhirjh, Oct 70½ months after Mate when Dzhh -30 Celsius, or 79 S½ Wa after six months at 0.80 Drahh C. In some Alnmang of this particular character, retains as 81½ from Adam Acad biological ability after eight cycles of freezing and turn, Wa or 84½ retains its activity of antibody diversity after 1:20 minutes of flipping. In another Nmong from this side and Tttml pharmaceutical the guest on (1) 1.75 ± 26.25 mg t D of mAb-3! 6P; (2) 10 ± 1.5 Mesh 0 lar sedan; (3) 0.01½) ± 0.0015½) 12 12 i 35355Β1 (Lanza and size) Crown Surat 20; (4) 5½ ± 0.75 () /. (The trace size) bis; and (5) 50 ± 7.5 milli Molar Orjtn, counting Ram Herugiy repealed 6.0 ± 0.5. In one of these models is the specific formula, an Aldzojh 6 0.6.a Szna BL 0. In a Annmang of this particular formula, emerging Alosmoah 330 ± 50 million Osmol a LMO 0 in a Olnmang of this 0 specific formula, a 5-storing the guest at 45 d 1 of a 28 and Notices ick ο91 / of antibody nostalgic Osaa and & gt; 38% of the antibody be En Hora shipment abdelhady From abdelhady. In a Alnmazh of this topic Adeinh formula after formula stored at 25 Dzjh for six months, it is% 94 ί of the body and be parented Alamadan% 47 ί of the antibody of an image charge Alriaah. In a Alnmang of this particular formula, after the storage capacity at 5 e for a period of six months, 10 have 1 s 96½) Z body Alamadan be parented and 59 ί½) of Lean counter the image of the main charge. In a Alnmadhu of this particular formula, yet responsible storage of formula when Mdz 0.20 for three months, and have 96 ί½ of El Jem counter-parented and be 56 ί½ of the antibody of an image charge abdelhady From abdelhady. In a Alnmang of this particular character, after the formula stored at ~ 30 for three months, it will be% 96 ί of the antibody as an original and be 56 percent are bridles 15 counter-image of the consignment Rabasah. In a Alnmang of this dye gastrulation? After Tkhoz; n August at -80. Lydda three months, a & gt; 96% of the body 1 of the anti-parented and .kon & gt; 56 p huh Lean counter the image of the main charge. In one aspect, in one aspect, Yum Presentation pharmaceutical formulation according to any slashes are attractive Alabakh in a container. In a Alnmang. -nkon 1 to Hawi Leroux, Rh 0 Crown n / t and 7. Form Z 20 be 'container Garorz Rjajah. In a Alnmang, Varurh be 1 g BJ type Viorm Ob.j a stopper and Rocelikat Nat Z butyl rubber coated Bgrukrbun. Nmong in another, be one of the container 13

13 IK 35355Β1 way Tserbb Nqiqh. Nmodj in another, be Olhao, in the form of its I- Ttmdd 1 _ihl Anhla t envelope Balgru carbon. Most viewed in a Agth '0 that any Ara Mhazt R & amp's; Bgol 1 μ contain less than ho 1 Lee 500 & lt; E to Apion within 1 Sht Asudh Awa 27-0 (dam; Dah Smtatabhotdtd Hru / Bonn & lt; and Gala & lt; p 0 Tat Z Yum not-a Leslie 0 n 5 Ollaaks 0 in a specific Nmong more, be 1 cannon Ara I p Zach within NUOVA ONIPI del 1 d Mzodn Bahh y 1 t grandfather; t Rs 0-27, and Daddah Rubber 4023/50 Mglgh d FLUROTEC,

The rubber tip cap 27 FM. In a specific RSS Nmong; you have no Blaspk or Mzo.dh. 3 ml double needle 0-27. Set in O'kther Nmong, are & quot; Ong any plastic margarine Tell 0 BECTON DICKINSON. 1. In one aspect, the Presentation Pharmaceutical Saah Titkl Z (: a) 75 p for a 0 to ± 26.25 Bhm a 0 for gm's anti PCSK9, (b) 0.l. 0.0 and Lahr ± 1.5 t Rlar bad Ram Sdroumni 6 ± 0.3, (c) 0.01½) and influenza Hhm ± 0.0015½) poly Surat 20, (S% 5 Warren / cm ± 0.75% Skeror, and (e) 50 0 any Molar ± 7.5 0 any Molar Wasit E where (a) SHTML antibody at 70 solution Joab and sleep identity: 1 and 070 of around Wareham identity: 15 5, (b) 0 A.zad & lt ;, 90% z Olodzm 1 Kadh in the formula have a molecular YAG 155 weight 0 kg d 1 to Tun ± A. whole Daqun, (c) and 0 a more than 50 percent are only 0 Tm 1 Kadh in August 0 fact N. activities Tszewa 1 effort 1 electric Ttg ho one I 8.5, and (d) Smone 75½) to 90 puss are one of Agam Adnadh in his father and be a processor array Buz. In a 1 Vazj, made ​​up 'to Sagh'laidlanah of (, a) 75 A.. Bhm a year ± 26.25 Mjmamlmn 20 antibody for PCS.K9 of paragraph Afabqh directly, (b) 10 R. Moar d 1.5 t Molar Biden, number is 0 Drhgiy 6 ± 0.3, (c) a 0.0% and influenza 0.0015 ± r½) Crown 14

14 MA 35355Β1 0 housewives and 20 (d) 5% and influenza cm ± 0.75% Skeror. And (p) 50 t t .olar ± 7.5 Molar arginine, in the water. In one answer, the Presentation Shehadlanah'nstml formula (a) 150 mg. A del 0 a t ± 22.5 mg a ml of antibody and PCSK9, (b) 1.0- million Molar ± 1.5 milli Molar j 0 h was 5 pH 6 ± 0.3, pushing) 0.2% and trace Hhm ± 0.03½ international) o 0 s 20, and ( d) t b (1) incorporates Lean I barely on the WVD of succession number identity: 0.1 and LCVD of succession identity: 5 number, (2) more than Z 90% m 0 v Alosam 1 delegation in the formula have Osv mow; u a 155 kDa ± 1 Klvi D 6 n, (a) and 0 of more than & lt ;;% 50 antibodies in the guest have a Nqalh T. 0 Levi effort Am_baia deny ho 1 I 10 8.5, and (4) 0 n 75 (where Al 90½) Z Alojmsam counterrevolution in the guest be the processor array Anihuiz . In a Alnmang, the guest pharmaceutical consisting of (a) 1.50 Bhm t ml ± 22.5 mg 0 m t & lt; 0 n antibody d PCSK9 from previous its impact paragraph, (b) a 10-year Molar ± 1.5 t Molar Hstidin, number, Hidogeni 6 ± 0.3, pushing) 0.2% and influenza 0 Hhm ± XJ0003 Crown in 1520, and Z) 1.0% and influenza Hhm ± 1.5 ½) Skeroze in the water. In a 1 to attractors, the Presentation pharmaceutical formula bless (!) 1.50 mg / Hlhrles ± 22.5 mg a ml of an antibody to PCSK9, ZB) 10. milli Molar ± 1.5 t Smalar Hustad 0 n, and No. hydrogen 6 ± 0.3, (c) 0.01 % and trace Hhm ± 0.001,5½) poly '..urat 120 and (d) of 0% and .znr size ± 1.5% sucrose, where Z.a) Wendell Adam Olamadat HCVD Jp 20 of prestidigitation Bertm identity: 1 r.CVDj Bawwabat number id: 5, 2 g) Behold, foaming at 90½) Z Olosam 1 1 delegation have Dzea weight of 155 Chloe Daqun ± 1 Kllo Dalton, (3) and 0 of Z & lt; ·; 15 15 1 35355Β1 50% of one of the antibodies in capacity have Nqalh Alkmana equal to the voltage of about 8.5, and (4) 75% 90% 4 Li Z antibodies in Olaevh 0 Amaa.lh the fact that I was 3 Algakoz. In one August paradigms 0 & lt; Ablazhh be b z (a) 1.50 m / 0 to 0 Rlz yolk 22.5 ± 0. 0.5 t of pregnancy of the reported (PCSK9 of the period Alapth Bairh, (b) 1.0 t & quot; lar ~ 1.5 t Molar Hayden, Rtm Adrugiy 6 ± 0.3, (c) 0.01% 0 for / Hem ± 0.0015./. Poly Soeriat 20, and (d) 10%, and trace cm ± 1.5 / sec,; not in 'to mAh in a absorptions 0 is provided Bah Bd'zlaz Chesd & lt ;, (!) 1.00 Til 6 d Hai Bjm / t from gm Meh 0 Ed and PCSKS, (b) 20 t of $ 03 ± Yi Alao PM 0 condemns 'DTM I. Madrugiy 6 ± 0.3, (c) 0.2% and Raza m ± 0.03% and Crown Ruba 0.2' and (d)

12 A / e Osv ', m ± 1.8, /. 0 discriminate 0 B (1) Chet 0 for mm any z * ¥ IICVD Brtm Auah: .1, LCVD de; At number identity: 5, 2 and 0 of Erbd 0.0 Loza p Aloim abused; in b be for 0 Warren Jezzini ypg 155 CKD Aoun ± 1 Kiio Dadon '(3) Wei Ezhd 0.50% of any one Algadh Jam in b be 4 Nith Levi' Bhd Aldha'na Yum Y'ala 15, 8.5, and (4) 0 n 75% to 90 a /. Age Alosam ESL; in Μ 1 rack ^ committees b-cent Alghoz 0 in a Alnmazh., Pharmaceutical The guest is composed of (a) 100 mg a ml 0 First: 00 '1 & lt ;; 0 n 1 rein stubbornness for PCSK9 paragraph Alopth directly, (b) 20 Mia and '0.0 me' t Z and then righteousness, Ena 6 p 0.3, and (c) 0.2% by weight * cm ^ 3 .- Yum 0 Amq 20, and Z) 12½) and Zubair size of ± 108 ha? Sucrose, in water 0 20 16 16 1 35355Β1 in one answer, is the destruction of pharmaceutical formula include (a) 50 mg did not over Lear g 7.5 mg did not ml of body Alamadade (b) 10 mM Molar ± 5. A passed Molar Hstidine No. Haidarugeni 6 ± 0.3, (c) 0.1% and influenza Hhm ± 0.0,15½) Buffy Q 9 reat 20, and Z) 6½ colored no size ± 0.9½ sucrose, where (1) the antibody includes HCVD for succession 5 identity: 1 icWj number of consecutive number id: 5, (2) and more than 90½. They are antibodies in the formula have a molecular Ebag 55-weight A- kilo, Dalton ± 1 kDa, (0.3) and 0 of more than 50% of the antibodies in the formula Ihon a point equal to the voltage of about 8.5, and (4) from 75% to 90% of the antibodies in the dye be set Agheirz processor. 10 in a Alnmang, pharmaceutical formulation consisting of (a) a 50 mg ml Melli layer ± 7.5 mg ml of a body. Daad for PCSK9 of paragraph 1 of Abgh Mbatrh, (b) 1.0 over Molar ± 1.5 mM Molarhtidin, pH 6 ± 0.3, pushing), 0.1½ and trace size ± 0.015./ Crown Morbac 20, and (d) 6½ and Zzlam size ± 0.9½ 0 sucrose «in the water. In one aspect, the method of preparing fjjj and Kébé Mamedh drying include body Amshad g 5 for PCSK9 and less than 0.3% water. Method comprises the following steps (a) process ° 0 C at Iarora glass of water, and an antibody y PCSK9, and Hishides, and glucose, and .bola Surat 20 '(b) after 0 so yum & quot; dill Alobh at around 5 degrees Celsius births about 60 minutes, (c) count is then reduced temperature at a rate of about 0.5 degrees Celsius per minute, and (d) after Ndk including my 6 by Ezl 0 approximately -45 ° c births of about 1.20 minutes, (d) after accustomed · Bam 20 'Qeft 1B ( Li about 100 mTorr, (and) then be Zadeh Dhirjh heat I canceled Z 0 1 Lee 0.5 ° C per minute, gg) after it is installed Akuligh at 6 or 25 Drahh 17

17 MA 35355Β1 little 0 births ho; Lee 78 efficiency 0 (h) Z deletion was g; birth uniformed A & lt; a ball I Hall x 0.2 Dre ¥ in Allqqhl & lt; i) After that directs install Altolegh at about 35 ° C for about 6 Ain 0 Zq d temperature at a rate of 6 to 0.5 Drlob, (do not) and then Dlkatmtet Altolhhh count 6 of 25 Drjhv 0 of ho 1 Lee 60 Dikh 0.6 abused in the limit) Take 0 as Taatar 1 to baste Eva Z steps (l) 1 to fill Washi 1 Tarurh 1 BP 1 I have a nest 1 Toagh 1 g of step (k) gas Aleriujzn 'and (m) Ong Dam 1 1 Harorh de z n 0 1 uh ho me 80./Ο are 1 Kt 1 to Joy. In a Alnmang, it is connected Doje Valley to 2-8 der ^ .ioah after step (1), (j) or (k) and Qktohsd 1 Study stopper 0 in some one Bzje I step (a) the body of the reported for 9.PCSK be counted 50 were a ml ± 7.5 mg a ml 0 and be Adthdan d 10-year Holar ± 5 aa 0 is unknown; lar (Ram Hedrojtna 6.0), and is one of the poly-sur-0 s 20 count 0.1% ± 5-0.01%, Wick 0 rang Az I 6 () / 0 ±% 0.9) . In Oha 0 Alnmang, the body includes the reported g 9.PCSK on HCDRJ Bdalih been identity: 2, HCDR2 Dwih identity: 3, HCDRjj number of sequence identity: 4 number, and LCDRl beasts' was identity: 6, LCDR2 de 1 Maly was V; 7 and LCDR3 to MTW 1 Maly been is-a: 8.0mAb-3l6P in a Alnmang, antibody includes t PCSK9 on HCVD Temara was identity: 1 IXZVDj Twalah been identity: 5. in a Alnmazje (1) includes antibody Erh 7 was not one it was identity : 1 and 1 LCVD been Mechanism was identity: 5, (2) what .bzad 90% of the objects in the Alamadanh Altolegh be 0 for Jria weight of 1.55. KDa ± 1 kilo Daqun, (3) and more than 6 Li 50% of the objects Almanadh my Akuligh his point Tawi voltage of about 8.5, and (4) from 75 to 90 to pass the antibodies in Altolegh be a wizard centuries. 20 1 35355Β1 to find Jawatb and are providing pharmaceutical Habh frozen drying include PCSK9 antibody g and less than 0.3% water, and Olney Yum Anajha according to the method of Ansabq side. In a Jawaib, the trim Pharmaceutical Habh, include pharmaceutical drying Habh frozen En one former Jaib hostile suspended my water. In a Alnmang, Ttkod Alakibh Alaidlanah of 50 mg of 5 ml ± 7.5 mg ml of a 1 body Adad for PCSK9, and 0 of Hai Olar ± 1.5 dollars Hai Kdn (number Hedros 6.0), 0.1./. G. 015. Buffy EX 20, and 6% ±% 009 Skeroze in the water. In a Alnmang, 'we are comprised of pharmaceutical Alakibh 1.00. A mg ml J 5A mg did mL of antibody for 20, PCSK9 Rlar ± 3 milli milli Molar Hustides (HD number 0 and Gyi 6.0), 0.2./) ± 0.03 /. Buffy Soloa 0 20, and 12./. ± 8..1 (/ Skeror, 10, one of the water. In Nmong another, pharmaceutical Alehibh of 150 mg consisting of ml ± 22.5 mg a ml of Table 13:00 Anad g 30, PCSK9 milli Molar ± 4.5 milli Molar Hstidin (pH 6.0), 0.3 /) ± 0.045 /) poly sur; s 20 and 18 / ± 1-2 () / sucrose, in a performance · in Nmong Akhrkzlk 0.1 pharmaceutical Zhabh x 175 mg consists not ml ± 26.25 mg of & lt ;, Den Lean 1 FD for 35, PCSK9 t Molar ± 5.25 mM Molar Hsudain (number 5.o pH 6.0), 0.35 /) ± 0.0525 /) Buffy Sohrbat 20, and .21 / ± 3.15 / sucrose & lt; In the water. In some Apmanj, Attml Jem counter for PCSK9 t HCVD to Walh Brnm identity: 1 LCVDj for succession identity: 5A and number. (B) and foaming 90% 0 n 1 objects Anadh in one me .bikun his weight Jezzini canceled 155 kilometers, d 1 to Tun ± SAL Lahlou . Dadn, (c) the light of replies z 50% g (& gt; 2 antibodies in Alakibh have Nqalh equal Adad Adana number Delly 805 a. Weight) Z 75 /) to 90% of the objects of 0 delegation in 1 Aakibh Dalj Bmah 0 Uh 1 Kakoz. 19 19 1 35355Β1 me one aspect, the Tq-Diem y 2 Kébé pharmaceutically according to any of the preceding aspects, where Zkibh Allchorh be contained in the container. In a Alnmang, the container is a bottle, and Olney in some Alnmang be Garola glass. Nmong in another, the container is a syringe. In some Alnmang, hide him be Mhakth glass Altvhsy low. In a Alnmang, 'we Anhaknh syringe NUOVA (..) MPI length E. 5 ml glass with Babern 0-27 Companion wall, plug Maiat 4023/50 Malvh d FLUROTEC, cover both ends of the rubber FM27. In one aspect, the Tq 0 Lim crew includes a pharmaceutically composition according to any of the above aspects, and container, and instructions. In a Alnmang, the container is pre-filling syringe. In Nmong Mann and 'be less syringe Rjajah NUOVAOMPI 1 length ml with a needle Nat thin wall 4) -27, and Daddah 10 0 Tat 4023/50 0 Glgh d FLUROTEC, both ends of the cover of Almanat 27 FM · Su 0 P become Avang only-Z from the current Alakhqaa clear revision of the description Wassily Intalla. Description Altsali for Achterba Say describe the current Alatizh, it is understood that it is not limited to the ways and situations Tgeraah company of refund and Sgha, Ed and that these cases may 'Ntbas. It is understood that Almassallhat used in this document, p 15 for the purpose of description Nmang Aaivh I; do not be amazed U Tkl.n & lt ;, Bill in August because Ntay extima g current expansion is only appended claims. What did not solve d otherwise, have all Heh terminology used in WAP Is e 0 1 Lud Zs meanings Olney understood by a person skilled in Laval 1 Vveh A'da Ivtha Ibb this one the other 1 GS. WAC 0 of 6 used in this document, the term ho, Wali, d Ashaddamh administration to b digital 'or. 20 the scope of certain numerical values ​​Cited: Behold, z to 1 Ge Z 0 0 Z 0 n A'himh A-: Here U is not 20 35355Β1 Athaus a 0% z i edit your, jj blood in 0 de Adzgl Lal Z Dali 100 & quot; -99.4 0.1 b) y 99 1.1 mm Ashha Ive 1A (against TB 0 99.1 '99.2' Doo-Z despite XY can A'dam J Q cent and 1 Dad b Ad Secret; Q in Haiqlviihalaaislaola -4 but Ed Bakolawadadgla 0 x 0 Vvega Abe.oiloaoa Akrtalshfessalliqlalagalakalovehl 0 Azguet. Mig pharmaceutical Wei 6 nebulae in the OT humiliation 0; a 0 Ake w V p TLS 0 z 0 T. Il and | fairly presented Alozl (z o 0 1 Il rewarded Z Hmikh, or j, etc.. -m Ahd't loyalty 8 Aoossaa 8 j) E 9 An 6 Yloatchalofairsd

When merging. H 0 p 0 for Kan's confirmed to Ed AAA g Aallat Lalai Z Q 0 E U for the purpose of Ailat 0 0 0 you do not tan PM 0 Dhold ever. Q Invite with 00 Z m 0 Fill the Welcome 0 & quot; Si echo the mystery of the presentation, however Elahm 0 0 0 e z ash. 7 light of Zj to the oasis Idli '

Be the end of me p & lt ;; R uu, Ao h r, n s Aat rad 0 0 W Birotin Z Abe 4 9 0 G Keck I to Azzim / Sil 4.0 Shaws Valley (, PCSK). Bumpy about) / Select !, Nur 0 n Lahraa 1 Ouaili Salga 10 Dlaal Q 0 for Z: (1 to 3) 0 Gaz *? », 2), nWVj) to Oammahrlo 0 Baetbinto (3) i-Bazavi trap is Ba for Y Sur y z Oena; (4) CE Rrari Hecln Z p. 21 00355Β1 I and 0 good, (5) Emz 0:00 b Haakon no 'up Rds e kunas and small c a-to Ash Olney Atnmha Aladzba me Glades Mufaadh to Tertbt- walked 0, but Sogahsmkhadda (k, Aloldil | o; 0 d Ilah 0 insisted 0 lost, of 0 d ^ Rtm; and .ozdavalofmavdh 9 to A0.sat 0 to Baloua.; exponential 0 Aa 0166768/2010, Alaua; Q modulate 0065902/2011. Oib first sang 077 854 / 20.10 'have meant Z expression & quot; body Advantaged & quot ;, provide him Ouah 0 H, according to not-groan in automatic; that j 0 refers to globulin immune molecules include Rest international hμι BPA 0; f, Shkin (H) and two series combi (L) connected with shares pioneers of the second / Ted, Hilo En 1 units Aztma-Dah them (for example, IgM); however, Ndlj Gniiat Alajafi.aorn one of my loyalty to 0 be Hyman only heavy chains (ie, Olney 'lack Mlasl Khgegh) as well as within the scope of an antibody expression definition 0, each composed of heavy God of variable region heavy God (is mentioned abbreviated herein as HCVR or Vh) and the Study constant heavy. consisting of fixed area for a series of three Akqilh 22 35355Β1 Zaloqat, 0CH3, CH2. , CHI Khgegh each comprising a series of variable-area chain Khgegh (Bla are abbreviated herein as LCVR or a 7) (f) of the instrument Ouabh Khgegh. And Iek Almtha fixed Alkhvagh for a series of one domain (CL1). And Imkz & gt; Matq Vh wa 7 E 1 'u 0 m 0 is fed sub excessive Altagawt areas, SPA j 2 the s Elmah-A 0 areas Thd.la 0 of 1 Tamim (CDRs), and Uwe At 1 a distributed with Olney areas are more conservative, SPS Yeh; Lq Altha Mnac frame (FR) - Iellvkl Vh wa 7 of the three regions CDRs and four FRs frames; 0 ppm and-placed Q heal one for my son to Tr.v 1 Krbuque in any next: CDR3, FR3, CDR2, FR2, CDR1, FR1 FR44 0 unless the peel to the other, the Almattny & quot ; g Mdild & quot ;, as e -m 0 in this one Los me that it includes Dzliat cm Amadarka 0 Amzllt his part Maha Rush Mull't antibody 0 0 Yesh seen the term & quot; part 0.1 ducks to Mull 0 1 antibody & quot; Or & quot; part 0.1 Duck Los F-1 for a special Adam counter (or. J 0 Ath Dze body Amadad'a or & quot; fragment antibody & quot;), Z is, -m in this Adhu: Iaah, to one or AA from Hzaio g Anti reserves Bakdry meant Alarabat Nov 1 b PCSK9 Obhari or I to him. Be Almqa 1 and d of the term & quot; Cm mg 9 Ed isolated & quot ;, according to Atkhadd; Meh in aa 0 request one for free to c 30 Anti be free t far from 0 limit to Agam 1 Massadh Aryan two thousand I Thddeddat Ez 0 of 6 births antibody (Presentation Master 1 for example, cm Anti isolated associated identification; in one rein CSK9 a Lalai Aknoun free 'far from Alosam anti Ashe Erbt specifically Mall 0 0 s also fairly see Z human PCSK9). Almhtalh & quot; Enbt to Uo, 'or U Amos 0. Reminded, aware that Table 0 m S or 0k ο s Joel's part 4 against Slade I) does not p 0 E in conditions j 0 and 0 for access. And Ekn F mm Alarabat balances Aa'b Adthal Ί undermines p. 10 X 1 J1f-, 0 and Lahr larger or. Wharf sets U; Dakat Vac% 23 23 1 35355Β1 linked qualitatively well known in Egal and include, for Anthal, Algsal Algshana Pantadl; Rzzn Albulasmon surfactants, and the like. In spite of that, the antibody Almrol who Brat qualitatively b PCSK9 has been characterized by an inverse reactivity toward generators against I see; Shell PCSK9 molecules of the annual I (originally united genes). In the context of the current Olaraa, the bodies of five Olamadanh multiple brands are (for example, a flood, a double quality) which is associated with PCSK9 Okz 7 and one or w. More than one additional antibody generators '' linked to qualitatively PCSK9 & quot ;. In addition to the Zlat, Fa 1 T. antibody Olmrol may be free to Hdkber of cellular material Ooekemaiah see. Examples of antibody has been reported y PCSK9 in the pharmaceutical pumping governors Balakharaa a ^ me in your post Tgb 1 patent A'lomrakih No. 0166768/2010 0.1 to patent Alorlonh Rum 10 0065902/2011, and bristles AA 0 international No. 077854/2010, it has been included 0 of 0 Detective Vihakamilo under References This document . According to certain Nmang of the current ERG, the bridles Alamadan d PCSK9 mAb-3l6P Uri R. IgGl human includes a variable region heavy bunch Olney be a special type granite 0 E -IGHV3 23 and the variable series Khgegh Olney be of subtype 1-IGKV4 (;; Λ 15 partie and Lefranc, The Human immunoglobulin Kappa Variable (IGKV) Genes and 15: 1,71-183; 1,998 .Joining (IGKJ) Segments, Exp. Clin. Immunogenet; and Scaviner, D. et., Protein Displays of the Human immunoglobulin Heavy, Kappa and Lambda Variable. (and Joining Regions, Exp. Clin. Immunogenet., 1999240-16: 234; in some Alnmang, the body includes PCSK9 mAb-3l6P to replace acid and illiterates. One & lt ;, 20 for less, leading to Tver in the shipment from us, Msvy antibody surface proportions to MTW 1 j -IGKV4 24 24 Ma 35355Β1 1 to Lalh germ or succession 1-ÎGKV4 strain Jerbomih. allocations numbers correspond to positions MTW 1 a 1-IGKV4 strain germ, and the amino acid contained commission document with antibody generators Information system global immunohistochemistry (IMGT), as, described in, .Lefranc, Μ.-Ρ., et al 37, IMGT®, the international ImMunoGeneTics information system®, Nucl. Acids Res (2009) D1006-D1012. In some Altmang, the exposed surface includes a specific area 5 7 1 completed Dz (CGR). In some Alnmang, be selected to replace or replace the amino acid groups of the amino acid N 0 Haaa a substituted amino acid polar z y charged vinegar 1 CDR2 & lt; Ely Sunni example, when (the subject of 32) of 1-GKV4 !. Mmoha that Zqoy Akaadelat Alilldh to distribute Tan 0 s 1 S counterattack, Khaso at the surface of an environmental Benny (and Leach, the sales example, my CDR) cases not 0 Tdkin 10 predicted for firming cm Mkhad in 0 solution in Seche AAC 0 paradigms, provokes insisted three mulch for PCSK9mAb-31, p & lt ;, Atal a; 160 Las t Aloll, kills gone -fou in August Daschle Atare area ambassador area M Asad Ilhak p repented 23-1GHV3's 0 Addhu 0 a or Tala! -IGKV4 to Lal 0 No Aviv 'in b 0 z Ayzj 0 Whitney Spdal' and substitutions Alectorobius 7 security 0 n M AAC 0 him Z (a), p. 15; Rodlab 0 of 0 instead Dd! Pfikotaiv 0 d; Chapter 3 (loyalty) (z a S I to Olha 77) Z GQHV3.23 and (b) a security acid Katti Haddou my age Mai y 1 Fold Atarhh 2 (FR2 ) (z 0 El Do; p Ads 51) Q 1GKV4-I- will prevailed -ada-instruments scarcity Daaabollietdash s 'I tuck d Lh-, Li' Z Joel; I surfaces .CDR lowest p 0 0 Alz.b to units of Rove does not Bmcn followed by a 00 to 20 m is in the anti solution 0 25

25 MA 35355Β1 according to certain Nmazh current Ackhea, antibody includes for PCSK9 pustular, or part of the link to the antigen, the specific Mnalqh the integrity of heavy chain (HCDR) E of the sequence number: 2, HCDR2 of succession number: 3, Wa ^ Za 2b 4 of succession number: 4. In certain Nmang, Amstml y PCSK9 antibody, or part SSH link to antigen, the HCVD succession of No. 1-according to certain Nmazh 0 Khhraa fled empty, incorporates fluorescence for human PCSK9, or, part of the link. The antigen, specific Mttqh any I Khhagh (1 (LCDR) (kappa born 0 his machine No. 0 was 6, LCDR2 s; my employer 7, LCDR3J for Mtwab number: 8. In Mmang .chtnh, the body contains. Alamadan g PCSK9, or SSH part Link generator antibody, the LCVD of succession number: 5. been 1 for a reference to one of the body I can almost unrestricted model used in the examples given in the current demand 10, the name & quot; mAb-316P & quot ;. are referred to as this one Adam 1 FD led Arraz Allard RIP 7,608,693 S 0) Η4Η098Ρ. Attml Η4Η098Ρ) mAb-.31.6P) on Mtloah acid pair HCVR / LCVR xj on succession Bogam identity: 5/1, and Naiaqat -HC0R1-HCDR2 S HCDR3 / LCDR1-L6 ': DR2-LCDR3 Ashe blood Yalh 1:00 Veh 1 of 4 Ram 6.bh : 2 -3-4 I author a identity: 6 "7" 0815 can Kgaot 1 Meh from Jem counter, or the frame of him Association generator Andd, Amehtoaz in pumping Chidlaveh Z 1 Akhhrl current building & lt numbers; 0 Alejo 1:00 1 specified Almtalo; of 0 n 1 Ck , Hila En 1 Nrov served for it. J-il and Alodadaliqsd 0 Yalmkh that, and IM 0 x 0 bad can a 0 Nmtoa Z was 50 ± 7.5 a year; 3 250 ± 37.5 p 0.0 p's Table 0 em! '- ·); 60 ± 9 are a g to 240 ± 36 completed a 0 for 0 n August 3 newcomer; 70 4 .ha mg of t d 230 ± 34.5 was /.l 0 n completed newcomer 80 ± 12 were 20 26 35355Β1 a ml to 220 ± 33 p. a 0.0 n Jem newcomer; 90 ± 13.5 mg g t d 210 i 31.5 ml Mahm not of the body I barely; 100 ± 15 Mahm / of; Li 200 ± 30 mg t ml of Jem 1 to Z; 110 ± 16.5 mg no ml to 190 J 28.5 mg no 0 for 1 or I barely; 120 ± 18 mg of 0 for u 1.80 ± 27 mg have not passed from one curb 1 FD; 130 ± 1.9.5 is a ml; Li 170 ± 25.5 mm t Mmermn Ed S 2 140 ± 21 ml of Bjm! Li 160 p Bjm 24 g of a curb A.vd: 150 ± 22.5 Bjm / Mlmanaljm newcomer; Ao 175 ± 26.25 Bhm not ml. On sales of Oial, can 'brain cells Alakhma 4 on the current H1-to his 5 mg did not; Ho; Lee 60 Bhm. A year; About 65 mg / 0's; 6 to 70 m no 0's; 6 to 75 p for boring; Auala 80 mg / 0's; Ho; Lee 85 Bhm a D; 6 to 90 p t t; M'la 5 and Y ml; 1 ho me 100 mg of 0's; Ho; 105 Bhm me for a 0; 6 to 110 mg / PVC; about 115 mg of 0 for: 6 to 120 mg a year; 6 to 125 was a & lt;,; 6 to 1:30 p t of; 6 to 135 was / D; 6 to 140 Mahm not Mulla 6 to 145 was a dL; 6 to 150 m of 0.0; 6 to 155 m / of; 6 to 160 ml of; About 165 have been a ml; 6 to 170 was a ml; Monsters were 175 / t; 6 to 180 was a year: 6 to 185 mg a ml; 6 190

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Mg / ml; Ho.ala 195 mg. / He Hlz 210 mg / t; ho me 1 215 mg / ho me 1 230 mg / Mullah ho me 1 235 w did not e ... A-1's ml; or about 250 ml of Mahm are one body through the mouth of specifically human PCSK9. Excipients and pH 27 35355Β1 include pharmaceutical formulations Allwarzh current Balackherba on one or more of the Ovogat 0 tuck the term &amp; quot; dilatable, as used in this document, any worker is a therapeutic afraid to 1 formula for Axayja coherent, or wife, or Ibata required. In certain Nmang, pharmaceutical formulation of the Akhaaa include organic Munib Hishark least one Z Aua hydrated .bodian, to the stability of Lean daad and PCSR in addressing Aasirih conditions; you 0, the Sia example, spin. And, in some Alnmang, Ndrn meant by 'Aaz.ban to 0-bit Be well ;; 0 of 00 &amp; gt; &amp; Quot; .. n 'a 0 0 a reply shower * With .ko_n more than 3 ½) are Aldjam 1 Anti meter 1 km from quantitative ball to the flesh of a lion (t LÎ Mohlria t throughout the preparatory treatment. In Z Alnmang, Aanaaljh a-not being Ptdoam along Contains the antibody aspects Akazavi 1 Msheemk birth ~ slugs 6 to 120 Dhqh 0 s ^ DJ Meith, .bikun one organic Mzb Aczk is fought for Torre vulnerable Z Avovi 0.0 such as Ikea 0 reimburse double (Aithelen) - includes Khoad tension Tahi year is Ovotiq Damokt - in pumping Alakhm; p automated 4 0 Ouay Q; Yale 1 fell; Crown Rrat 0 such as polysorbate 20 at 0 v 28, must Sorba 0 40, Buffy Sorzt 60, polysorbate 65, poly Q 1 t e 8, Wall 0 v ~;, Loud 0 It 81; in the HF 85, Bo (and Cassatt b and clothing Aha Polo E POV lobby Worley; l and 188, Boss 407; or-poly M Khkol (Μ (PEO Kzs d Adola 0 Hlat 20 20 tween, and Mono lattes -½ and 0 and has a cyanosis Q 1 is not international; Qya d.'s; d 0 Elyapouloys 181 DDD 8 »F. the Iaiti turn a blind healer Lacey Ge 1 Ionic V in Alhkh block! p 0, 0.0 automatic Ze Z Adhu's Aceh Ιβ in Ake; Class: Ba: 1 to Mqmod Z a-MI g: 'Y &amp; quot; 0: 00 00 0 'd 28

28 MA 35355Β1% 0.0015 to 0.2% ± 0.03% reduced surface tension. On ways 1 Ithal, can _i_ inject another 1 GS 1 to present the presentation ho me 1 0.0085%; 1 ho me 0.01%; Ho Lee 1 0.02%; ho 1 0.03 jabbing me}; 1 ho me 0.04%; ho; I 0.05%; 1 ho me a 0.06%; ho, to 0.07%; 6 to 0.08% y ho me 1 0.09%; 0 0.1./.Ϊ about 1 ho ho me 0.11./.Î 0.12./.Ϊ 5 1 Lee Ho Lee 1 0.13%; 1 ho me 0.14%; Ho Lee 1 0.15% y ho me 1 0.16% y ho me 1 00:17 huh; 1 ho me 0.18%; 1 ho me χ10.19 &amp; gt ;; ho me 00:20 1 / e; 1 ho ho me 0.21./.Î 1 Lee 12:22 () /); 1 ho me or 0.23% Bo.la Q 0 and 20 or roses. Boluxa 0 0 R. 88-1 can also include pharmaceutical Alakh of current Alakharaa on one or. 0 n more stabilizers of the type and quantity Olney prove antibody y PC-human SK9 under the influence of heat stress conditions. 10 In some Alnmang, is intended to express Chan Anhafezh greater than 6 to 91.) / G Table 0 m counter in the original consensus when it is being kept Anhlol Olney Foy on Aldjam Alamadan and 1 thermal Mzpt at about 45 degrees Celsius to YG 1's to about 28 Juha. In D Alnmang, we Assod of expression &amp; quot; proof &amp; quot; He. Hat.bm bloc less than about 6 () / 0 from one body to that point daad 0 blood Aa Alaqa presented Anhlol containing the antibody thermal installer at ho me 1 4515 ° C for Mdh'nsal to 6 to 28 days. Of course to be used in the current 1 Altab O'guetae- Osalil 1 Korz Arye from Jem counter by size exclusion, and the fact that as an oldies 0 0 Ouahh and Dhumr handsome bridles counterattack. In certain Nmang, can vary fuser Carr or alcohol u 0 Bam Aiaah p sucrose, Raharz and Maillol, or any Tolte them, that "Zkn that Ttagawt any 0 z Amhawwah 20 Alassah Bia Z Alglerov Anhddh purposes Almqaudh Olney -stkhaddm for her b. In Manj the company of, Imrn that Qioa pumping about 3% to about 14½) m 0 cr Ookho.l Q 0 Cree;: 111 i 35355Β1 29 Zhh; Heq: '; Ze 08 for% a 3 Yo.a%: Amala 4A 0 ya. ^ Ouaodea 10 (Presentation torrent 1 for example, sucrose 1 u 0 geese or. Minsul) * Zdheldela ,, "bad '^; b; J; (Aad% families; Tmbakh, Tsb &amp; quot; &amp; quot;:' ^ :: for deletion 0 M0 - to A'0ee b, o .... . Sa-free 0, leaded, termination .000 Al 00; Ya's ;; 30 your responsibilities 0 Aaldsat 0, 0.0 »// Adam ,,,,: 0 E j 00 E 0 Hey, Msab 0 Steppe 00 ills; for, Ilal pal 0 of August 00, no., uncle 0 touched; Yahr, what«, no / .; Lara 01 500.92 for over &amp; quot; prevailed 03 Q No 0.0 E, a ,, E, E 0.0 A'ab'oua * 20 30 30 i 35355Β1 Z Aglul which contains Jem nest for both and be Aiol mouth Z about 45 bb i repel s 6 28 U-1. in Z Abzj 0 0 to the fact that Azad À j 0 is the z Be z 1 Wael 94%% 0.5 t or presented at least 95% ± 0.5 Iwo t μι 'not in Twas S Tbakalmapm sets. Boathoo 0 Aturav one must Lean I -tm applicat 0.5 Dam canceled Includes contracts father and; Jul 1 Mgdm I -.wala 37 indications of any 9 commencement '&amp; lt; any Delly 28 v. be Azhod 0 n S γ or satisfied with a &amp; lt; 0 h 0 pain equ Lalai not Iike 0 n 0 each;,. Tu. and betrays determine this; fast that his estimate Z μ1 Ashe late pain lion 0 0 as upper Sha 00 A.sagh to keep the pregnancy. kills Jem prevailed z. Azh Od 1 Ktl Acaa-m 3 S 0; Az resort Levi Jem Almnad Ahli 'and-Kdn Bmge Ed 0 Aze Aatmb 0.1! Zbaah Wash. Adiabmav 0 d μ to Alabt Alabej 0 Sal M. Z largest one body to one of the most fragile counter. Aceh Akabath occur - the reported 1 Like I jyk part to Hhm less than the original Jem counter 0 in some 1 Zmazj, it is one of the unintended to fatigue 9 for fixing is where Z persons 38 () / ± 0.5 () / or at least 29% ± 0.5½. P 1 rein in anti be in the picture Ava Aceh 1 for private B 0 15 according to 'what is determined by the chromatograph exchange Pokerschool I 1 Ath Z 1 Gfel the one with the antibody and have Amehlol; 16 at about 45 degrees Mtoah to Mdh'sal to ho one to me 28 days. In some Alnmang, it is intended to express fix it where it is at least 46 ° of 0.5% or 1 to less 39½) ± 0.5% of 1 meat of the reported on p. 6 Rh 1 Khzh Aaeashh 41 * him, according to is determined by the chromatograph exchange 1 Kadv when retaining Z Anhlol ever (: ) 2 contains anti bridles and Athlol be organized at about 37 ° C for up to 28 days Ho'la. Is intended to express shipment Deshaies or pictures termination 1 Vithiszh, * and Aljze Q 31 35355Β1 Ed 2 Amo 0 Ed CNN seeks Yap 0 as upper g Rj Tdo Ionic in termination ΉΛ Lalai 0 with Bhgh as upper 0 of Bgm Walker &amp; quot; Iaadih &amp; quot; Z A Spin Walker, and "b &amp; quot; Z destroyed, but / * can be a pain to Lsg 0 Dlab of only six current Z RTM Hades ranges 0 n 0 to 2 • 5 to 6 to 6.4. R. sales fell 0 can be pumped p Wallace E. Wadley replies 0 -0 and to 5.5; -0 And 5.6; And 0 to 5.7; 6 to 5.8; 6 to 5.9; 6 to 6.0; 4 to 6.1; Basin 6.2; 6 to 6.3; Hur 6.4; Or 6 to 6.5. Z in Alang 0.8 n Sunni Adtm 6.0 ± 0.4; 6.0 ± 0.3; 6.0 ± 0.2; 6.0 ±, 0.1; 6 to 6.0; Or 6.0. In Bafn Akazja Att 0 for A'glul Facilities or Zz; m iPod Banquet z μ and 0 U 1 a D'hd Z persons characterizes the extent of Tbm Atdakhlkp or Jrvi with the extent of juniper Hdros 5.5 - 7.4- in a 1 Anaadj, it is one of the solution 1 Bzm Ma'at ionization Add canceled 6 to 6.0 to 0.5. In propolis by 0 0 0 Iat Paul Zmouaymaholim Guens's. In grown; JP 'Hecdt S Mukhodo when shaking the bag 5 0 0 0 Zlar 0.75 ± 0.6 lar to 15.6 ± 25-2 Lal 0.0 and Lal; 6 Ramoular Ramoular ± 0.9 to 14 ± 2.1 Molar t R.olar; 7 .olar t over 1.05 m ± 0, lar d 13 mesh Moo 7 t ± 1.95 Ralal; 8 0 in Rlar D2'e 0.0 and babysit 12 milli Molar ± 1.8 Mhmolar; 9 t Mzlar ± 35 ..! R.olarnla A; 0.0 ± 1.65 and Lal 0.6 Lahr; Over 10 Molar ± 5..1 Mramoular: Aouhwala Ha t Olal 'in certain Nmang, Aglul Banquet presented Htnn system includes at Ha 0 t Rlad &amp; quot; &amp; quot; "AVI Molar, when Hedrugiy number of ..6 ± 0.3. As well as Ekn that p 0 1 SG 1 to Shehadlaveh of current Alakharaa Yuj one or 'AAA Ahaaz E 4 Z wife low or 0 Akkh Ashe Dawi Z wife paralysis Wa &amp; lt ;, p Mahe Egar 1 meat 1 for anti-g 32 35355Β1 PCSK9 (on Spbl example, generally &amp; gt; 150 mg ml t n 0 1 Mkhad body). In some Alnmang, August astray on arginine sufficient quantity of the portfolio on the viscosity of the liquid when Ash Aisagh of 20 ± 3 years of Boaz 0 Ashe of 15 ± 2.25 whoosh Z, or Z Isaiah 11 ± 1.65 years of Boaz. In some Laghmanj, the formula include laid the amount Kavth to maintain brjj viscosity counting or lower than the 10.6 ± Sunni 1.59 Boaz 0 in the models B, Nur 0 of pharmaceutical August of Alakharba 1 for current teeth, preferably in the forms of "Orjiven Helrokhlolel &amp; lt; I canceled 10, Melli Molar ± 5..1. Molar million to 90 million t Mola ± 13.5 milli Molar 0.20 May Molar Matti Holar ± 3 to 80 ± 12 Molar Hai Haley Rlar 0.30 t Holar ± 4.5 milli Molar 70 mesh Molar ± 1,0.5, 40 mM Falr ± 6 t .olar to 60 ± 9 0 me Rlar or 50 useful Mehrlar ± 7.5 t Molar 0 small c Aquemeah Okh 0 Qa to one aspect of the current Alakhari, the pharmaceutical the guest Nat low viscosity, generally p 0 Gh liquid equal Antotr Viologia, which include: (1) antibody human Art b kind PÇSK9 (the torrent example, mAb-316P), counting Wikeez of 50 mg of 7.5 g ml mg / 'do, including DBS / t ± 1.5 Bjm / RL Mjmrell 1.50 ± 22.5 Bhm of 0's, Ao 175 Mahm. 0.0 for

+2526 Mg a ml; (2) buffer solution system leads to an adequate regulation at around A'0rh my God 0 and 00 lows 6.0 ± 0.3; (3) sugar or sugar alcohol works, among other things bit 1 J; (4) an organic solvent Mtherk, protects the structural cohesion of the resolution of the counter; and (5) are the salt of Î 0, works to maintain viscosity at temperatures can be processed to give the character ~ cJ Omda acid E Yum 0 for z 't 0. Skin. 33

33 MA 35355Β1 and Fa for a Alnmazh, include pharmaceutical The guest Ai: (1) g 1 IgG fluorescence human associated qualitatively b 9.PCSK includes substituted Mngarz area heavy Anssalh-type 23-IGHV3 and is replaced Khgegh variable region sequence of the type 1-1GLV4 for For Lovell; rn.Ab-31.6P) shook seen 0 and h 0 n 50 ± 7.5 Bhm / t! to Yauala 175 ± 26.25 mm a ml; (2) Zzam of lotion regulator includes Hustadezo which regulates effectively at about pH 6.0 g 0.3; (3 ) sucrose; (4) Mnglv nonionic, such as poly Ishet; and optionally (5) arginine salt. According to a Alnmang, pharmaceutical formula to include (E!) Body lg6.ll Mtan human associated qualitatively to PCSK9, and includes HCDRl WAP number: 2.12 (: 116.1 for Mtwaqah number: 3, HCDR3 of succession number: 4, LCDRl of succession number: 6, LCDR2 of succession No. 7, 113, '6 of 10 for Mtwaiah number: 8, Berkaz of 1.75 mg a ml ± 26.25 Bhm a ml; (2) Hatidin at 10. milli Molar ± 1.5 mM Rlar, Olney when rum e; Drocala 6.0 ± 0.3; (3) Mcros at 5 (/ and Nana size ± 0.75½ weight Hhm; (4) poly 0 sorbate 20 when 0.01½) w / v ± 0.0015½) and Raza Hhm; and (5) a-Orjiven Hedraklorbd at 50 Molar ± 7.5 milli milli Molar. 1.5 According to a Alnmang, Tttml pharmaceutical formula: (0.1) antibody specifically Erbbt igGl human body. Human PCSK9, which includes the presentation .HCDRl for succession identity: 2 No. 0.12 (111 consecutive number identity: 3, HCDR3 to Mtwaah identity: 4, 1.LCDR number of Mattel intention number identity: 6, LCDR2 for succession number identity: 7, 13) 1 Bualeh identity: number eight, counting Yakir of about 150 mg t ml ± 22.5 mg a ml; (2) Hishadan at 10 .rrlar j 5. .1- Mramoular 0.1 the one who regulates the bridge at 20 Hpedrogeni 6.0 ± 0.3; (3) jjjL I 0 10½ influenza and the size of ± 1.5% and Zzahhm; i 35355Β1 and (4) poly Surat 20 at 0.2% and influenza size ± 0.03½) and influenza Hhm or 0.01%, and influenza size ± 5-01 (.). 0½ weight / Hhm. According to a Alnmang, pharmaceutical characteristics include: (!) Body fluorescence IgGl human Irenbt specifically the human body PCSK9, which includes HCDRl janitor number identity: 2, HCDR2 5 to sequence identity: 3, HCDR3 to round about number number identity: 4, LCDRl to succession No. ID: 6, LCDR2 for succession identity number: 7, the LCD for succession identity number: 8, when wa canceled about 100 mg of Mae j Bhm a 15 ml; (2) Hstidin at about 20 mM Molar ± 3 million Mola T, which regulates when RFM Hivrugeni 6.0 ± 0.3; (3) Mcros at 12½ and influenza size ± 1.8½ Ronse a size; and (4) polysorbate 20 when 0.2½ and influenza ± 0.03½ size and weight Hhm or 10 0.01½) and influenza Ham ± 5-0.001 ()? Raza and size. According to a Alnmang, pharmaceutical formula include: (-1) antibody IgGl pustular Asenbt Thanido body human PCSK9, which includes a nest HCDRl Bualeh identity: 2, HCDR2 number Bualeh number identity: 3, HCDR3 of succession spraying is 0 G: 4, LCDRl Joab, and flammable: 6, LCDR2 for succession BPM identity: 7, 3 Hhhd 1 mounts number is; E: 8, I hand of 6 to 50 mg t ml ± 15 7.5 mg a ml; (2) and Peden at 10 mM Molar ± 1.5 mM Mollard, who Adject when pH 6.0 ± 0.3; (3) Skerozaand 6% and influenza Hhm ± 0.9½) and trace size; and (4) In Murat 0 20 when 0.1½) and influenza size of ± 0.015% and Raza Hhm or 0.01½) and influenza size ± 5-0.001½) and trace m according to O.hd to Azjh Pray pharmaceutical dye on: (1) an antibody human Irenbt IgGl 20 Thanido human body PCSK9 1, which Licht 0 &amp; lt's ;, Ntay MTG 1 and LED 0 him Edeiah Man MTW; b identity: for 0 and scope Mtver for Dalla - 0 n August 6 Drnm number id: 5, Ezd 0 d 175 35 35355Β1 mg a ml ± 26.25 mg ml t; (2) Hsmahd 4 n Get me 10 Mulau j 1.5 million Aolal &amp; lt; Which regulates the pH at 6.0 ± 0.3; (3) I sucrose 0% and 5 g trace Hhm 00.75% and trace cm; (4) Poly passed, it became 20 when .0.01% (and influenza Hhm ± 0.0015½) and trace Hhm; And (5) A.-Orjiven Hedrozawrad at 50 mM Molar ± 7.5 »any Mola and 5, according to a Alnmang, pharmaceutical dye include: (1) an antibody IgGl pustular Ergt specifically Balhm human PCSK9, which Attml wide Mtver series heavy 0 n Mtwab Drdm identity: 0.1:, and the scope for Mtejer 0 Dallah Khgegh succession of identity: 5, where; / canceled number about 15 010 t Mahm ml ± 22.5 mg ml t; (2) 0 Q I Hsail 01:00 any Holar ± 1.5. 4 m j Molar, which regulates at pH 6.0 ± 0.3; (3) Skeror at 0 for% and trace Q 0 a 1.5½) and trace cm; and (4) Buffy 0 and Oat 20 at 0.2% and influenza size, ± 0.03½) and trace Tt one size or .0.01% and Nzerhjm ± 0.001.5% and trace size. According to a Alnmang, 'Nstml dye Chidlash on: (1) c 0 mm anti IgGl Shi Di specifically Balhm human PCSK9, which includes a range of Mtver and a basket heavy Z Mtoala shelf 0's identity: 1, and the scope of .tver series Khgegh Z sequence identity: 5, when the number insult is about a 00 mg ml ± 15 mg ml t; (2) Hstidin at ho me 1 20 mM Molar d s 1 Molar me to organize at pH 6.0 ± 0.3; (3) Mcros Eta 0 12½ and trace Heh 0 to 1.8% m Wanda; And (4) 0 Leslie Sat 20 P 0.2% w / m ± 0.03% Wonder Hhm or 0.01% (and trace the size of ± 0.0015 A% and trace size. According to a Alnmang, Nstml pharmaceutical dye on: (1 :) g Z. A 0 Je neighborhood's : Thanido Balhm human 9.PCSK, which includes a range of Mtver heavy father, his 3 Z Mto'b Shuqom identity: termination and scope Mtver Khgegh of a series of successive identity: 5 number, at 0, shook built 6 0 20 36 36 i 35355Β1 mg t ml ± 7.5 mg R. ml; (2) Hsudain at 10 mM Molar ± 1.5 mM Mollard, who Inglm at pH 6.0 ± 0.3, (3) sucrose at 6 (/ and trace size ± (· 0 () / and trace size; and (4) poly Ishet 20 when 0.1½. the influenza size ± 0.015½) and trace size or 0.01%, and trace the size of ± 0.0015% and influenza size 0.5 received in other Omalin of this document additional examples of non-exclusive Lsg pharmaceutical Olney covered by the present invention, including the operating examples contained below. Wyatt and wife pharmaceutical small c pharmaceutical pumping show Alwarneh Bala current dislocation typical levels &amp; lt; Tmah stability. aware of one of the Mstale 6 fixed, as used in this Aloiiqh reference to one pharmaceutical Ck, that 10 Alosam caught inside Tanvgz pharmaceutical formulations degree Mahboula Z August constructivism Alkimyabh or biological Alokhnegh after storage in specific circumstances. Cuba has fixed August and, if the existing anti bridles were not kept inside to 100½) of Sgtha Abek Sak up biological or after storage for specific Fihrh time. In certain cases, perhaps 0, away term has Bhouc 90 e / No 0.6 to 95% 0.6 to 96%, about 97% of 0.6 to 98%, or 15, 6 to 99% of the Formula 1 rein in anti structural or function after health sa ZB specific. 0 Bmcn Vyas fortitude, of Ban'oxiae see, select the percentage of anti-μ 1 pray Dd in August after dedicate to Fihrh Rmenah specific at a specified temperature. Himkn cheek: Dr. August Achuih μ Anti insisted by, among other things, the analysis chromatography insisted 0 Ham (z For 1 for example 0.1 to analyze one of the chromatography 1 Wael high the pot bass 0 Td 1 to Hhm [SE-HPLC]). J 0 Apr 20 &amp; quot; an acceptable degree of Akpat &amp; quot ;, and Faqae to Astkhadd; m this one scales in this topic Abe Mar 0 0 x 1 Il Behold not 37 37 1 35355Β1 least 0 En 190 A of the original image to the resolution of the counter in the formula after storage for Ghabra g 0 marginalized specific counting the number 0 JH free 1 Rh company of. In certain Nmang, it can be detected at least about 90%, 91%, 92%, (93%, 94./) 0.095 /} 0.96) / .097 / E, 98 (/ 99½ l) or 100% of the original image to the resolution of the counter in the formula after storage for a specific time by surprise when temperatures Dhirjh 0 tha Dah. 0 Mamad 5 to Ichaeln Aq 1 t Anhdd of time which can be beyond measure consistency on persons 14 days 1 z 1 to less than 28 days / Presentation least 1 month, presented one of the least 2 months, presented one of the least 3 Shahura &amp; lt ;, persons 4 months. E at least 5 months, at least six months, the parents 7 months, pardoned Alokd 8 Z at least 9 months, presented one of the least 1.0 months, presented land 11 Throe presented exponent 12 is, on Aloqoy 18 months, presented at least 24 1 or more a month . It can be 1 degree heat Rh S. Ashe 10 can Tkhozs pharmaceutical Chiah then when assessing the reliability of any temperature Ouaouh are approximately ™ 80 degrees Celsius to about 45 degrees Celsius, for example, storage at -80 Hawwaa Dljh Celsius, about -30 ° C, about -20 ° C, 1 ho me 0 ° 0 Ioat «Drjh_8 about 4 ° C, about 5 ° C, about 25 C Dhirjh 0.6 to 35 ^ 0 der Ioal 'about 37 degrees Celsius, or about 45 degrees Celsius. For a 0 to Thal 0.0 Ekn B. 1 t Alsit 15 'fixed to the Pharmaceutical as one united after six months of one of the storage at 5 ° Mbrih, it was Oct 0 Thae AAA ho 1 Lee 95./., 96./. 0.97% or 98½) from 1 to Djam 1 Sources of 1 original and 1 Plan SE .HPLC · .bmczknlk considered. The formula Chidlaah fixed as 1 happened after 6 Shahuz of AAC 1 Sad I 25 Drjq Celsius, that was one spotted largest ho 1 Lee 94 (/., 95 /., 96 (/., 97½) or. 98./) p 1 antibody families by SE- HPLC. Amkinkzlk considered. Anasigh Chidlab Dalla Ida 0 hubby happened 02,028 days of one of the storage at 45 ° C, 1 O'n been spotted larger than about 0.91 / (0.92 (/,

% 93.94 /) 0.95 (/),% 96.97 (/. Or 98 (/) of one of the body 1 to Mgad persons Bo 1 Sz -SE i 35355Β1 for 3 HPLC. Amczkds Atar b 1 Sdlab all Ada united d .lolo DePaul Q Aksen counting -20 Drschewh.! n then Aktt 0 F Aklr p. 6 and 6% &amp; lt; 97. * '• or 98% Sm'd 3 1 FD Asesla 1 &amp; lt; a Ihcglkeir b no-S'a Mae 0 d Zlaz 1 rivers of p I -30 Ddt not been Ammi-F ; / d 6 e 9% '97 a% or 98./. of the most pressing 3 0 FD Ahli SE.HPLC Η -tnmzs August August Alhbdlabh 0 termination; a united after 0 lah Ihor Saksny -80 per ¥' ed then plug the larger 0 n 6 to 96./., 97./. 0.98 a / AN s 1 x s-Wiwa 0 Tal SE-WLC. 10 can Bs a chat 1, q) j. Tami, Dub Adudas 0 Halmqlvi afforded 0.1 I Ps b after: stocks, seen for a count I each Rara hands; E b of coded j 0 g Ha.a to August ¥ of birth paralleled Muftmla '* x Thd'd August b was Zd Mzatm iPod, x to B. A / Z, s to 0 Atomavae: s kl (t 0 for August dam, o m b 0 for 0 JU ^ me-performance M s [fSE-HPLC). &amp; Quot; degree disadvantaged of the baht, "I lion 13:00 weakness paternity my Az 0 abused p _tm termination 0 6% g ​​was: Get the presentation, the more my Horh Mbri in bb 0 d p each; 15 Idrmurarhb.yyd 5%, 4%, 3%, 2%, a 0/0 E 0.5%, or a -0% 0 n August 31 FD t eating ^ da si in b after S Agren specific Rey Z each &amp; lt ;; b 'shower not all yield Wales 0 Tia 1 Khadddh BBC after me Aakec hav g surplus' z land 28 Kl'l all eating and Ada b &amp; lt; Dr. Wael p 0 to 0.1 to 3 Thod humiliated. Z b 4 persons each meal and e 0 m 't least six Ihor 0, t 0 No 7 Iho. Z 1 Lash 8 z 'z land grate 9 0 Z persons 10 months, t least Aathro, a Ic, Lash every 12 0 R. persons 18 b: Z 2039

39 MA 35355Β1 least 24 months or more. Can Olney ranged degree heat can then store the formula J .; Taaa consistency of about -80 degrees Celsius to about 45 degrees Celsius, for Almthado 0 Altak ever at about -80 ° C, about -30 Celsius Dhirjh, about -20 ° C, 1 ho me 0 ° C, about 4 ° -8 ° C, about 5 percentage Dzjh, Ho'la 25 Dhirjh 5 about 35 degrees Celsius, about 37 Dhirjh Celsius or about 45 degrees Celsius. On ways example '0 Bmcn stable pharmaceutical formulation consideration if happened after six months, from Akiprin at 5 degrees 0 Ahl a percentage that has been Ktzv Waaqid r ho me 3.// 2. 1 /.,.!%, 0.5 (// or 0.1./ 0.0 n Adam 1 FD in the conglomerate picture. as well as can be regarded as formula pharmaceutical 0 Apth if broadcast Baal 0 No 0 months 0 n Akeabr 0 n at 25 ° C, have been spotted Ash Z about 4%, 3%, 2.// for% E 10 0.5 (/., or 0.1 (/) of El Jem counter in the conglomerate picture. walked so Spar August in August "fixed for mischief if occurred 28 days after the Altbern at 45 Drlo intestinal« that was Akiav Ash 0 n 6 to 6.) / 0.5 (// 4 (// (3/0, 2./0 0.1 (// 0.5 (/), or 0.1% of 1 rein counter in the conglomerate picture. Amczknlk considered Chidlab formula birth if Ahdt Baal 0 Lala w 0 Hor g 1 Takzen I -20 Drzin Study 0-30 degrees Hioah or ~ 80 ° C to then discover Oqan of about 15% 3.2 (/ 0, l 0 of 0, 0.5./., or 0.1% of the antibody in the conglomerate picture. can measure the stability, among Othiae see; Thdel 0 August 1 Shih blood Anti dL in the acidic part O'kpr Otia 1 to exchange Aloona (MSI; acidic &amp; quot;) 0 Gh in Neutral Adde blood mg 1 Ed (0 Mtadl'a form), where 1 Kpat Htmaa Exa Ha part r brain 0 Ed in the picture in August. without one Argbh in Alaltaz 13:00 -bnzerah the company of, the father Naa Z 1 meat Vdqr μ 1 1 1 FD curb a 20 Thnh Zlbh Aker and Bakali be a burden to the ACSH Z pressed 0 to 1 m Mgad Lalai not discriminate 4 ο Alobe (1 Zh, Ouae 0,. ..and Almthaa 0,, 2002, 16 Robinson, N &amp; quot; Protein Deamidation, PNAS, April 40 35355Β1 5283-5288: (8) 99). Aceh Almioibh not identify the poison daad to authorize an acidic or apocalyptic

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'' Degrees chat acceptable &amp; quot ;, according not 0.0 using i cullet in this deposit, and 6 d 49½) Q 1 antibody at most acidic larger image do Akeshavi in ​​Isla d 1 for storing League 6 H Rhishh wiped 0 Ende at a specified temperature. In Nmang bb 0 Aa Drlo 0-bit 0.0 Ekn Achshaph 6 to 49 / E 0.45% 0.040 / H 0.35% 0.30% E 25% 0.20% 0.15% 0.0 a% 0.5% 0.4% A% 3% 2 , a 0 of 0, 0.5%, or 001 e / e of the antibody in the form of the most enthused in the formula after aka 0 Zain surprise specific time when Drlo certain temperatures. Oih not p oversized Adzv 1 Gddh 1 Lenny B 0 generated cheat Azthbat for Osusan, eBay least 28 days 'E 4 Z land-month performance on one of the least two months, presented at least 3:00, R. land 4 Vhor' R. Wallach A Z 0.1 to less than 6 Thor, Alonl Nest 7 months, Z 8 persons and persons Shahur1.d months &amp; lt; 0.0 0.1 Thor 0 land at least 11 months, presented one of the least 12 persons Sha 0 z z r 18 land 24 months or eat. Can be varied temperature can then Tkhozs August when deaf SECOND r ho me 1 -80 ° C to about 45 degrees Aioah. Z b example, in August about Ed 0 0 -80 ward off Mbrih, Drt about -30 Celsius, about -20 ° C, about

<img img-format="tif" img-content="drawing" file="MA-35355-B1D00422.tif" id="idf0003" />

22./), 21./. 0.20 (/), 19./., 18./., 17./., 16% of 15./., 14./. 0.3% of the 41 41 i 35355Β1% 12 &amp; lt; 10./., 9, /., 8. /), 7. /., 6 (/), 5. /., 4 »/ ', 3. /., 2. /.,!%, 0.5½ (or 0.1./. daad of the body in Sourhki acidity. Amczknlk considered pharmaceutical Alaevh fixed if after six Ihor event of storage at 5 Dzhh Celsius, that was Aqa of about 32, / 'a 0% 31% 30 a 29% 0 28% a 27, /. 0.26% 0.25 /), 24./. 0.23 / ?, 22./. 0.5 21./., 20./., 19./., 18./. 0.17. /., 16./., 15./., 14./., 13./., 12%, 10%, 9%. 8%, 7%. 6% &amp; lt; 5. /. 0.0% 4% 3.02 / 'A!%, 0.5% or 0.1 »/' bridles of the counter in the form of Okir acidity. Amczknlk tenths Alaidlanah formula Iapth If, after six Ihor Akkhozan Atd of 25 ° C, that was less than about 43%, 42%, 41%, 40%, 39%, 38./., 37%, 36% of 35%, 34, /), 33./., 32./., 0.1 31./.,30./.,29./.,28./.,27./.,26./.,25./ . 0.24 ./., 23./),22./., 21./. 0.20, /), 19%, 18./., 17./) 0.16 / '0.15 (/' 0.14 ./, 13./. 0.2% a. 10./., 9%, 8%,% 7.6) / (0.5, /) 0.4, /. 0.3, /), 2. /., 1, /), 0.5, /) or. 0.1% of El Jem Almenbad in more acidic image, Amczknlk considered Alaevh Assadlazah Eatth if Ra-W-0 count 28 days 0 n a 1 stored at 45 ° C, that was one Is Ho'la 49 /) 0.48; '?, 47 /) 0.15 46 /.,% 45.44) / 0.43) / 0.42) / (0.41) / 0.0% 4039 (/. 0.38 /), 37%. 36, /. 0.35 (/., 34% of 33% &amp; lt; 32./., 31% &amp; lt; 30% 0 29% of 28./) 0.27 /) 0.0% 26% 25 a 24% 0 23% . 22, /). 21) / 0.20) / 0.19) / 0.18 /) 0.7% A, 16%, 15./. 0.14 /., 13./. 0.0% 12 10./., 9. /. 0.8 , /), 7%, 6% of 5) / 0.4 /),% 3.0% 2 1 /., 0.5 /) or .0.1, /) of El Jem one of Gadd Okinki 0 p; ie, / no. 20 Adam can other ways to test is 0 penetrates the current Alakhozaa g i 1 to 4 Mazle / heat Balh Altagazai to determine one thermal Tbaat and volatility Walt then 1 km maximum b-d A'lthat 42

42 MA 35355Β1 1 to Mekaveki and 1 to absorb counting ho me 1 350 pp Mehr counting or 6 to 405 Z is over the limit, "Dr. Ecale Amehlol. The torrent 1 for example, can one Etbar formula Z Wallace current Boath, as one Kazt not 0 d six O.chehr or more of Oltkhoz; n when ho 1 Lee 5 degrees 0 Ioah to 25 der 0 Hee Celsius, was one as a non-in .405 1 for a special mg Ashe ho 1 Lee 00:05 (nest torrent 1 fell; Khum . i s; 0:04; 5 .03, .02, .01, or Ash) p Q 00 Zabtazsd can one serve measured; for Z.hat biological or Aakar Alarkat of 0 to Ash additional 1 FD 0 p Touch 0 P 1 of its own to tell one to prove. Nest for 1 example, can one Ebar Valley, one of the private Bala 0 current Tirba Aualo Ed 1 Kazt after the Gaza stored at 5 degrees Xue 0.25 Dhirjh C and 45 Hljh Celsius, hate ZB Ta Mahdnh (for example, from 1 to 2.1 Thro) with the body F y y PCSK9 Almujahud inside one of the formula roaring presented one to link to a very Ashe PCSK9 0 n 6 to 90% or 95% or Okl- Z Z armpits of the antibody storage straw 1 Zzkor. J sets Please choose a Alaratat YMCA and 1 T. Z as 0 1 Arct Bo; middle for money, ELISA or spray Albulzern 0 shower selected. 1 Kat Albiodhuja by measuring the experience of whipped PCSK9, such as my nest fell 1; l 0 0 J nation Zabbar Laura; p. 15 of PCSK9 with God Agh 1 1 Laney include one curb 1 FD y PCSK9 counterattack. Shower Hhas 1 antibody dilemmas such cell directly, such as the torrent example, via the R FACS. Buckets Q, the 1 Tt Abaadi to Zam PCSK9 can be measured in the presence of the antibody and helped PCSK9, and Mqarkh actively 9.PCSK system in the absence of g r Advantaged In Aozmaz.j; shower to be PCS-K9 internally for the cell. Looney other Nmang, can 'to express PCSK9 expression and Rush' Mitbma 20 in the cell. 43 35355Β1 been clarified additional ways to assess the stability of anti-g in the formula in the examples below. Ngihr liquid pharmaceutical formulations in Bala 0 current Hhraa, in certain Nmang, low to medium levels of viscosity. And walked to the viscosity be as used in this document to Glz wife, divorced wife of a. The military viscosity Mkiesoe flow-resistant fluid influence of gravity 5 qualitative. When you put Maiaan sheep in the same Alhhm standards for wife poetic Mtmathamh allowing Ptdvgahma specific gravity, the Almaj meat takes longer than the abundance of the fluid at least for my wife Addvy 0 0 yen through capillary action. For example, if the fluid Amtafrq 200 second D does not pay and it took another 400 seconds, the viscosity Almaj Acani reached twice Dzojh Almaj first nest 0 Bass Doje Gl. And &amp; quot; absolute viscosity &amp; quot ;, Olney sometimes called dynamic viscosity or Albesatq, p behold as upper-c wife Gl of intensity Almaj (divorced wife live viscosity = X Alkthalo). YAG &amp; gt; B Azub 1a e I} ΓΪ b hyper L to Alahloul Wa Zly time. Bumpy Nhe Ia'e, Ed Alandlo Ed x 4 [μ Stoke (St,). The unit reached, wife of S 1 neighborhood Zrlab, ie a Ae- for x-Ilu 0 g Alhsh Houhdat 1 Lenny Oguz (&amp; lt;!,). And &amp; lt reached; Dah SI for Zdlo I t Ha 0 Elllabl (s-mPâ), where 1 1 = cP t-Pascal Thaveh. 15 2 (1 was 1 Ihaddamh P, Move displays one of Mtoa 1 Mzkhgd of Allzo.t 4 excited Ely PS Another 1 GS 1 to present, Wife absolute less than ho; Lee 15 '6 And as (0 j Port) Baby 0, formula 0 Akhalakharaa will be Atar that her 00 Lzo ^ shares AVI Bmqa 6 a Ba.shaddam stands T. Gazzs Szojh 1 to measure it Fa August 1 ho 1 Lee 15 Mznab 0 parallel 0.0 financial 4A Sphippois 4 about 3 e p rice ~ 09 aa 21 1 1 0Λ, .150! .. 9 six, Boao, Boaz 0.6 to a 1:00 Kansai

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44 1 Ayagd; Bala'tharh into formats 0 Aaa and Ytms 0 No Vamad 60 miles "as; Li about 5 a Idh. Ss p 0 Blhs 6 :: I Aliqt. Blloba 0, p; the Lord is; E-Tia *. 6 to 32 Salar, to Aas x 34! 6'lad, if 2 mg 0.6 to 28: W: T: T:; Ataat: T E 0 «E *, for Aa4'aaez'► 1017, Auala 16 6 1'5a b 1 and ... Z, Z .. * 0 SSH» E, a 10 Q No, Lay JJU Z, μ dam d? hPcsK wells (i sales z, g 6 to 55 a Bhamad 15 light of the; for Ymalatley 200 mg / ml) Bhouagh one blood newcomer 0 p Aoajaf your 0 Yeh Hdaouh 0 n 6 to 25 t jiy p 6 to 100.0 and lar - to Olalooly Zq 'r ed Roger W 1 Sagq can - Z 0 1 Li di any I 0 for the elderly I do not Zz t Hpalm 0.10%. Containers and roads can own Balaatta P and 0 -0 Dsbg Akplai continent agents, some S in any Yu, Father Hayes led Hat Ela 0 for irrigation. War Dam Lyle 0.9 n Aud etc. 1 Amudallaah d pw 5 Iv 20 45 35355Β1 Blaspk 00 et glass or sealed and sterile Nat Hhm Mahdz like Harunah of or ampoule, or survived a 9 0 cartridge, or a bottle. It can Aammthaddam lament Mokhtlgh of bottles to put Formulate area and a 00 to 1 current Akharba inside, including, for example, glass bottles or plastic Chgavh and non Chgavh (z Jf, Wael Nehrmaph 4). Similarly, a Odash-or any goods 0 yen Alanecat drizzled 1 GS or give pharmaceutical pumping contained Balakhh current 1 p. Walked exist pharmaceutical small c contained in the current Balakhhi Alloy Wheels titer Alttjhan or Altnjsan ''. As is clear is full, my ordinary skill in the doubtful, 'modus operandi involves Zmsh generally use hot rod Tnhstin his job puncture the bottle and therefore button Li can be loving him the bracelet and remove them from the syringe. This process will lead E0 for .rb trace amounts of Altnhstin internal Anh Nlmranjh- can be made Emlat Gore and address Okhrtma subsequent to Tqublkamih Oltnhasin in the syringe. Lima used in this document, the term Njstin Ayari means that syringe containing a / n or 0. Tawi 500 parts per billion (ppb) of Oltnhstin. Means the term Tnhsdn Mnkhvkhos irrigation containing a 1 m no more than R 500 Dze each Paddon 0 n Akossen 0 u 0 example 4 walked contain low herring Antinjstin, according to the current Akharaa, the U r not more than ho 1 Lee 490 E 480 470 460, 450 440 430 0.420, 41.0, 390 350 '300 250 200, 150, 100.90, 80.70, 60.50, 40.30, 20; 10 of tungsten or less. Olmkab visited the coating 13:00 to 1 in Olrnecat Almatkhaddmh rubber, rubber Oldadat not used 0 Ilaq bottles slots, to prevent contamination of medical Angtoyat Almjrnh inside Asranjh or vial, or to maintain the Thbatma. Accordingly, the small c pharmaceutical contained current Balakharl, according to Tmazh certain 35355Β1, it may exist in the syringe piston Tttml on an envelope, or d 1 vinegar bottle 0 Ikn Μ} \ Baga blocked 10 1 de rubber coated. For 1 for instance, you can Ashe or coating 0.1 of Daddah I Shu carbon. Examples of earplugs or one has Nbert for presses B. and Olney 0 Masp 1 Karorat and Alanecat Anhtoah pharmaceutical pumping contained Balakhari a 0 to a, de i Athaal, in Bara; T1 to Omkhh Karim 4,997,423 (4,997,423); 5,908,686 (5,908,686); 6,286,699 (6,286,699); 6,645,635 (6,645,635); and 7,226,554 (7.226,554); AVI Odri containing Tama full within 4 Mk 1 sell this document. And Mamo 1 fled examples Ende Adnadat amplitude; Maly Wa 0 for CAPS) for the painted one for in can Askhadd 1 Maha in full swing, but the current 6 Declaration F1 for Alaa "FliTecD &amp; quot ;, and one to an oasis of (West Phiwmaceutical Services, Ine. (Lionville, PA., And be ®FIuroTec Ara for example to encapsulate Florwabon then 'Sthaddamh to Olhl or let 0 Tj a 0 t z 1 Akyq surface rubber. according to certain Nmang current out, -d to toe 0 grandfather pharmaceutical SV Sartj 0 T. -altndjemtin Tttml the piston Malli Bachlo-Ro / Pui 0 can give pharmaceutical pumping into acceded across departments Z digestive Hthel additional (t Spao_, Wael 4 ci skin, or intravenous, or, intramuscularly, or within the membrane Albrunona, ect.) or. administration through the skin, or through the mucus, or 6, equ; or lung or the nations. and 0 Tdkin Adam Edh means of delivery with Bagafi or burden 0 marginalized 0 Ekn Addh a-frames &amp; quot; VUL to A.dhal one of formulas 1 to 1 Shehadlab Villardh Bala 6 current Declaration under the skin. cripple examples, the torrent but not limited to,

Z ™ Owen, Mumford, Inc., Woodstock-, UK) AUTOPEN), Pen ™ DISETRONIC Disetionic Medical Systems, Bergdort ', Switzerland)), pen IIUMALOG MIX 75 / 25ΤΜ, Pen ™ HUMALOG, pen Eli Lilly and Co.,) HUMALIN 70 / 3QTM 47

47 MA 35355Β1 II, ΝΟΧΌΡΕΝ ™ I, (Indianapolis, IN, and 111 (sk, C: openhagen, Denmark; NovoNord),

NovoNordisk, Copenhagen, Denmark) NOVOPEN RJNIOR ™), Pen ™ Becton) BD ΟΡΤ.ΙΡΕΝ, OPTIPEN PRO ™, OPTIPEN ™, (Dickinson, Franklin Lakes, NJ ™ sanofi-aventis, Frankfijrt, Germany) OPTICLIKTMj, STARIET). Examples 5 and means of delivery providers include by or syringe automatically once used and has applications in the delivery of a pharmaceutical Rabibat contained current Balakharl skin carving, categorize but not limited to, Qlml ™ Novo Nordisk) FLEXPEN ™ ^, (sanotkventis) SOLOSTAR),

Eli Lilly) KWIKPEN ^), Mqahn ™ automatic SURECLICK (.Amgen, Thousand Haselmeier, Stuttgart, Germany) PENLET ™ ^, (Oaks, CA), and, (. Dey, LP) EPIPEN 10 and Pen ™. (Abbott Labs, Abbott Park, IL) HUMIRA was contained in this document also use means Terpb Nqiqh to deliver pharmaceutical Olmsg contained Alatitra current 6. Akma is a user j This Alutah, the xùa ..... a..d way to doubt two minutes aware of the way the delivery of subcutaneous Msammmh to give large amounts slowly (for 1 fell; Ta 1 to about 2.5 ml or more) of the therapeutic formula round abundance Zmaah long 5A &amp; lt; Ely E 0 1 Bill for example, Ho'la 10, 1.5, 20, 25, 30 minutes or more). ? Zer ,, nest Speed ​​1 for example 0.1 to Arah Emiri No. 6629949 (6,629,949 .US); US Patent No. 6659982 (6,659,982 US); and 116-46: 167 Controlled Release SAL, .Meehan et ai (1996) and is Satml 0 minute Altserbb EZE ; especially for the delivery of doses Kberz of proteins for therapeutic 1 1 Hjodh. Φ / jb '&amp; lt; Ely Sphl 1 for example; 6 to 1.00; 125; 150; 1.75; 200 Bjm / Rao acres) of Ajail Allargh. 20 48 35355Β1 in a Alnmang, liquid pharmaceutical formulation include about 1.75 mg / mL ± 26.25 mg / mil Z PCSK9 antibody that is administered subcutaneously in a volume of about 1.14 ml ± 0.17 ml syringe filled in advance for. In a Alnmang, be Anhaknh Abaro syringe Zjacquih for what length of 1, filled with Buffy one measuring 2.7 and Rabia Sdazh rubber 0 sa 00 Z a 5 Mufty CFC and needle cover of rubber. In a Alnmang, Anhach righteous p 1 OMPI ml in length from Akhaguen glass ave been t 0 and -27 Mas her hand needle cover of the intifada Almhmat g ΡΜ27 and 0 Daddah kind of Olhlat 4023.50 fodder b ®flurotec 0 10 15

MA in a first Bmazj, Tesht 0 for b Chidlada 2 pardoned about 150 mg / mL ± 22.5 mg 10 hoping z 1 body 1 for anti t PCSK9, which is administered subcutaneously in m z ho 1 I 1 g ± 0.15 t Vimahvhmmfairshbkbak 0 in one of seven Zj, the fact that the S Libra p Mhah Shake; Wagih 1 Mlmnagvh 1: 4 high-scales one wall 27 and stopper p 1 Rubber g of Jru.phippon cover Arz Mhlat 0 in one Pearls 0 as it will be 1 AP, ah Z OMPI Amlessay 1 Study Almrodh needle end -27 aa m; 0 n Adla 0 y FM27 and Dr. Tai 50 / 4.23 dpa flurotec® Alamehkhaddamat Alalajh Im 2 x Ala 0 Edlaveh be one Ck Chidlaveh 1 for private Balakhvaj Wadley Moghaidh, S. Yi Obe see the 0 '; me 11 d be stimulated! j RIP! and Aybab Att Biat .U' PCSK in Zlash 0 RIP 0 and me-Z 0 Aaftlat A.ilal F 0 Om s blood 0 Il , Shatt / Asdl As.a's; Atk 4 Al 't 49 35355Β1 and Ovrt fat in the blood and excess grease in the blood family and Snaz Albrocnn Aschbi Albbta in slander and Tza; Albrobbe Alchkmi 1 Lta Alaildja in growth tri hyper Gelsered blood and hyper Thelash blood Gelesrad in the family. Examples -izm examples Alabh to provide! WABC Achrisv in Laval 'stepped up and qualify you; Piech 6 0 Ekh me and use Alakhara ways and-oh-la, and sat Pei limit Q father Z crosses 0 0 Adlole will not run correctly Alakhozj melted 4 m. Lund conducted attempts to Mann della Alorlam Lalla (t j, 0 coated waffle, degree Hrar 5, n.) Are on and some are set to equ Oladalat Aalriet · Pei did Dd to Z so 0 1 Oh parts of the mall. And Zen Aldzbna p. 6 i Wazzt Aljvena, and affixed Arara be in degrees parental and be Aaft counting or; b are Cgt Valley 'Sow Akosher; T. special ops age in the age of Walnut AAC ?; Ocoee 1 t o Lahi Aralo; and Yale I am in Aalatl and brain Alhvi Z door E0's (Alooua 0 of 1 delegation of current and PCSK9 Walles) to determine Allowagat Atuagh p 0 g Abro.d Valley, spraying Otherwise, tactful keeps Al 'Agh father of SSH regret the enactment of the P 1 Ljk Lawson in the 0-Dade. The Aye 0:00 buttock Ag'l Banquet d Al'd ABS asset for increased; Althat special one for Thal RFM I: develop a formula of 0 Idhah PCSKl ΜΑΒ-316Ρ Crescent organization and Almnibat 1 Mczkh and wanted Althabh free one confidential Syed Sioux 1 It was - by a 0 0 n 'Take _sldthin Alp 0 Special T. El Jem I barely wa . Then we do not tease Ss Amehlol 50

50 MA 35355Β1 regulator to determine the No. 1 Hydrogen your ideal Haat antibody to a minimum for him. Olney was used Altah then get Elaho Z b dramas Ktoar fixed liquid formula and also formula Dehydrated fixed freeze 1 to urgently Athaddam Alacletaki any given through intravenous IV)) or. Administration of subcutaneous (SC). Door Ltj property Alajafv Balthamid, was' to develop a formula 5 Use geminate and Olney can be re-Dhubanha with your sterile water (WFI) to (jf special in any of 50 mg / ml IVJ or 100 mg / ml of administration SC · The Bmah 9 re-decomposition own 0 50 mg '/ ml, the Menth property can be diluted in the IV bag insulted 0's' £ 0.9 (l) / sodium chloride to connect through 7 for for formula aa 0 accountability, are jewelers 6Ρ A3- mAb at 175 ± 27 mg / D and 150 ± 23 mg / ml. in a 1 to Zmazjz Pettm to 175 ± 27 10 mg / ml of mAb-316P at 10 ± 1.5 0.6 Lahr hull (RIP hydrogen 6.0 ± 0.3) e 0.01 e% ± 0.001.5% of poly 0 Rhrb 20.5% ± 0.75% Aur. in a 1 Bzj, the 150 ± 23 mg, / ml of mAb-316P are the characteristics. 10 d 1.5 to 0 me r not Stidin (HD 6.0 ± 0.3) 0.2 a% ± 0.03% or 01-0 number. /. ±% 0.0015) poly 6 housewives 20, 10% ± 5.a% Skdz. 15 1 Example No. 1: 2 Nhlol 1 Mzglm of anti PCSKI ΜΑΒ-316Ρ and land Ahvdloajabi 0 fact Tat 1 t Aard Madros and 1 malignant organized on 'Ibat objects Atagadh g PCSK9 FD 0 then b in Ala 1 x 1 cent. Has Hvanh 2 Mahm / ml of stubbornness PCSK.9 mAb-316Ρ to that point d 0 45 0 Dloua your responsibilities 1 in 10.6 Lal each of acetate (Bertm repel 5.0-5-5) and means (does Hidlod 5.5-6.0) L-T (RTM Adrojnn e ' e), l '&amp; quot; Otdhn &amp; lt; mastered a) 2 6.0 &amp; gt; And 4 d (A D 6.0-7.5) Ao.zs (RTM 8.0) p Ajellol Nrsolaly Tarn 8 1 Zm Ward Alhz 1 Dos Z Av't Arara 51. 35355Β1 protein (Table 0.1). For all your Alserbh been Ahamaz Ti 0 of 0 Saai all b s counting 0.35 ml in a bottle Bo ^, Celikan Type 1 de 2 0 Padam's loyalty to 0 Tatab Z Allosl 4432/50 and then packaging the ®FLUROTEC. J any one of the College 0 n mAb-316P G was her conversion to Islam was determined using chromatographic reverse Algsal 0? JL, August 1 Kllo of trusts in the original part of the mAb-316P may then be determined Kha z ^ 1 TB Alkrohatogerava Bastavaz cm. Be 1 g cake parental Alodhuoa nation p mAb-316P Ad been a challenge; generated using one for washing chromatography Alkatioti interchangeably. Has NOTE firming Astzn I Alogahy his limit and then fixing it Z during one of washing Alkroma 0 and B 'equ any (SE) SPS Alkromatoger 1 in Aakod Elka &amp; quot; Leonie (CEX), Andmh are 1 and drafting PCSK9 mAb-316P in the real regulator of Alhe 0 Tidin 10 mM Molar when Hidzojia No. 6.0 b 0 d a 0 w Z land one of the hydrogen 1 to special b mAb-316P through Magdalene 1.0 mg-m / ml 0 n mAb 316Ρ I 45 ° C of 1 Nhlol systems to meet the Q Ben figure any 0 Ross 05 a and Artem 1 Hedrojta 5 6 has Note 1 for the stability of Balbrutink 0 of then determine reminded 0 N.lal and SE. CEX as upper · I 0 I 0 m drafting mAb-316P in Anhlol organizer that its number Stidin hydrogen 6.0 (Adul RIP 2). 'Intensify Tech also Nhalilat' from Mar 1 T. hydrolyzed protein basically no Z M or Tnmhtr Sat, se 1 Mokhtlgh of Ed and Balat 0 Ed 0 Zy Ts 0 Akaij, the sixth of 10 mM Mollard was d 1 Iol Olmzzm when Hedros No. 6.0 b 0 of 0 d Btoula Akail formula Athvgh Bakjmad of 0mAb-316P E - 1 for Ztak of der; Sat Akelor one of alopecia Palm 0 Weihe that .lzerov A'loash to Taku-n No 1 No p (1 to No. 'to pH? 6.5) of the Anti PCSK mAb-316P in me and my ears one Kghae 0-for Nze 1 forever. On the contrary, when the number Alheidrod; - 0 Han

That; the resolution of I 52 ΜΑ 35355Β1 there is an increasing rate of changing images from Aljiia weight g mAb-3l6P NL Dutt Mlahzaa 0 Based on these data, the Aglul Aniz Almmtkhaddm Ans father mAb-31.6Ρ are preserved in Hidona number between 5.7 and 6.3. Be widely stability for mAb-316Ρ Mhaha to the extent of 1 to RTM pH Almnkur. 5 Example 3: Selection of protective substances in the counter pressure Alacaj been individual test Mnibat Almhakh Almokhtlgh Regarding Nrtma explain Tkows Aljsmat in the mixture completed the mAb-316Ρ result of pressure Alakj 0 explained decomposition Arh Your private material property Olney then stirred increase in optical density (00 &amp; gt ; Az 405 Natm, mbar. when Anhlol includes 0.35) mAb-316Ρ mL of 25 mg / ml 0 yen, 1.0, rn.Ab-31.6P Melli 0 E. Mollard histidine and RTM pH 6.0 ± 0.2 in the glass bottle from the Borough Dam 1 DAT from widely 1 capacity 2 ml p 0 having stopper z butyl rubber 4432/56 Mvkh b ®FLUROTEC) then Tanfe of swirling for 120 minutes (ga-wall No. 3). Of any solvents Ngher August Mushir Tm'takiimha Bonha enjoy the resulting urged flipping in turbidity increase. In spite of that, there 20½) p 300 10, PEG½) from 300 PEG and 20% p Run iPod spoken in 15 large thermal Anthbat private b mAb-31.6Ρ were also identified reminded through SE (Aljdo.l No. 4; and the same Alakiz m.Ab-316P, and Athlol Organizer Khalrov container as in the previous study tornadoes). Do not be drafted Olney O Polly Morbac 20 and poly Morbac 80 Brunak F68 and 3350 PEG no significant effect on the thermal stability b mAb-316P ^ was determined that p through SE and CEX making Almnaat Marshal Almnkurh suitable for formulation with anti-PCSK9 20 0mAb-316Ρ was selected poly Morbac 20 when the universe Munib private organic polytheist Baittaiwir in each of the formula Atjggh Bakhamid liquid formula of mAb-316Ρ because Agha Be 1 of 53 53 1 35355Β1 _khasaia .. alone in both private tumble thermal study own and -mAb .316Ρ study firming panting 1 Rev 0's a 4: choosing the protective material in the anti-thermal be tapped R. Alakhc 0 R Algrd | j for many of the excipients of containing sugars list acids 5 1 touched and inorganic salts in order to work on the ideal increase free firming 1 Ri's mAb-316P. A thermal destruction of Hdhes been installed for some materials and Olney examined in Table 5. Baltbh all Akjarb 0 K, the excipients thermal stability, has been included in the Mahlo. 20 mg / ml of mAb-316P in 10 mM Molar of Alheihidan (0.32 ml in a bottle of Boro Blakat of awareness for its 2 mL her g butyl rubber cover 0.4432 / 5 envelope b ®FLUROTEC). 10 have completed the cruise and Alorbatol and mannitol and Riwazz less amount of mAb-3l6P S then identified through testing SE. In spite of that, that I model Amstmlh Su 0 Messenger describes the amazing increase in turbidity compared formats Almttmlh on sucrose and .terpacz, Maillol (Table 5). Although it Mlahvlh have grown that sucrose and Riyaior and Mannitol! Y have any impact on wheezing in terms of Altarat in the shipment of Akhaddad PCSK9 mAb03I6P; 15 Had ci note that mannitol works to remove Altthbat run correctly protein during Nurat father "melting Mufddh. Thus, your mouth will be sturdier Combs mAb-316PJ when the 'do-or Spav a cruise or Alrwazz. The 0 Hull No. 5: Sailmajafih Majafdh then develop a formula to increase the chat anti PCSK9 mAb-316P, and in particular for 20 variables for shipment, and increased the maximum 'Nltaz Z m.Ab-3l6P. Paired Hmahh freeze-drying material - with 0.7 mL of 50 mg / ml of 10, mAb-316P milli Molar of -en; in a bottle sticky 3's share 54 35355Β1 1 to Borettat Capacity 0 n awareness Alao, for Bh 2 ml layer Mja ®FLROTEC Lanier must 1 de Vant 0 its butyl 50/4432, freeze drying, screening Kdrtma to install a, b-316P ^ - [Atjvv freeze when incubation at 50 ° C. And say analysis, has re-Ceccheo August Atjvl 0 to 100 mg / ml g of mAb0316P. It included Elsafts Atjgd greatest extent Z Cat 1 as determined by SE and CEX on: 1) 6% Z Az or 2) 2% 0 N Cruz to plus 2% of arginine. It has been selected 6% 20: sucrose for the formulation of the product

Aldoava mAb-3l6P. The eternal 'and E 1 Ij 0 Ztj Noana Mjhv Bakhamid 0 n 0's Daz .PCSK9 mAb 316Ρ by drying Panthamid in the form of seven protection of; ¥ named &amp; lt ;, 10 0 Ne 0 and Lahr Q Hitidin, and Ala juniper) to pH 6.0 ± 0.1; a 00% (and LZMA blood) from an international Rra 2 data 20.6% (and Lanza m) Z 1 Atamoz, and 50 mg / ml g of anti 0PCSK9 mAb-316P 15 wpm representation of age and Tat stress this August Asdh in a ¥'s RTM 7. then Taiwir freeze-drying anti pPCSKP mAb-3l6P R. cycle additional 'Tg calculated (drawer 3 and 1 Rh shift 1 for a glass one freezes) to the formula, and to the Qa ¥ B; m Mphas 0 price of 1 mussels 1 for the sinking of one of Ngadvi 1 for embedded 1 Grae 1 perimeter (mDSC). J not Athaoz Drlo Rh ¥ Lang seen 0 n Tg1 O'la 1 Tjgev Aloo.la, and 1 Lenny was Thdda Kkon -9 * 27 m '

Then Azz 1 c mÀb-316P Majafdh by 0 Fill the 5:30's der 0 n 50 Ed 0 AAA 0's seen 0 n mAb-316P, 10 mesh 0 lar from Peden (Alrzm Alheidbagiy Hlg 600 &amp; gt ;, A '. Z international 3 Rat 20, 6% of the 0 Cruz formula in rodents 0.0 Hajih Manala 1 T20 Mler and Tjg p 0 0 a Balthamid according to the following steps: 1. Hrzh 1 degree for storing 1 for a Mutalobh; termination 2-25 m loading 1 35355Β1

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2. 2. The initial detention at the low rate (time) Akjmad 4. Cthaz when: 5. Adjust Alngri point: ( e ) a lower rate (1) T1 Saiyn initial drying 7- storage temperature for the initial drying 8. initial Aiszewagy for 9- rate low (extend) the heating of secondary dilution: 10. storage temperature to mitigate one of the Tadi 1.1- duration of secondary Althviv 12. rate drop (time) antibody: 13. Cthaz when: 17:00 for 60 minutes 0.5 m of minutes (100 Dqqh) 0 of 45 Hmmadh 120 minutes 100 m Torre 0.5 m of minutes (40 Dqqh) 0.25 m 78 m t .saah 0.7 minutes (300 Dqqh) 0.35 m 6 Ssagat 0.5 m t Dqqh (20 minutes) e 25 ° C for 60 minutes * 4, l packing gas. Brod 15. Closing obesity carving Alngrig 80 shook from 1 to Datt 1 to Joey (608.000 t TOR) when the need for storage intensive after drying 1 Thaioa say , step closing Bessel 0 birth; been or 6's degree 0 free; Rh storage material Anhvdh for valid 2 '20:00. Then the production of lyophilized drug product Bachkdam predatory courses Olney described above to the well - characterized Bmgher paste, Ttoy Rto.bh (12:30 Er), and the time of re - formation of less than 4 minutes, and the absence of turbidity of a lengthy reconstituted. 5 56 56 1 35355Β1 the fact that the appearance of Anqurmhe Anajafv freeze Pollack unmoved Z 0 n u Lecco the Open Up t mAb-) niAb-316F0 316Ρ DP) hands CS incubation for Threinn at 50 ° C or. Name stored for a period of three months repel 5 d d C. There are no 'no Tater on the appearance of the number or hydrogen. Turbidity own had Ehar mAb-316P , which It re decompose and there Achtlafcber. Bnczykmah mAb-316: P 5 p . And then re - analyzed. There is no difference in all Z j mAb-316P 1 t been Oschasha. After Z of Alhvanh at 50 ° 0 Ioahkazt Menthat drug mAb-316P Agggh Balthamid p for 0 for 0% n 1 Okle eating and 0 of the challenge 0 hands reminded Q through 0 'SE-HPLC and 803% eat Thllokma then determined by CEXWPLC. We did not 'do notice any β when the drug product mAb-316P Atkhvv Ba Hamid has been stored Linda 3 0 a month I behold 5 degrees Celsius. There are no Vkdokbero at the event were also identified Nak use of bio - News for Advantaged PCSK9 any z Akat Olney has been compressed · Afflerd 6: mAb-316P liquid which name re decompose ate special re biodegradable product drug mAb race-316P Anajafv semolina late 0 d Presentation administration path. The sight of a given intravenously, is re - degradable SJ Iar -mAb 15 316Ρ using 5.0 mL of WFI sterilized Nah in 5.3 ml of Ihsanoglu, for Intml 50 each / ml of mAb-316P and 0 a milli Molar of Hesdin number hydrogen 6.0 SPA (and Rzahhm ) of poly Morbac 20 and 6% (and Zzahhm) of crore. And Balhbh to give through the SC, are re - biodegradable drug mAb-316P using 2.3 mL of WFI Ashm Olma'kh in 2.7 ml 0 n Anhlol completed on 00.a mg / ml /, REGN727 and 20 mM Molar Scdan 0.20 pH 6.0 and 0.2 number % (and Zzahjm) of poly Morbac 20 and 2A (and Zzahhm) of the cruise. Alhhm was available to withdraw is 4.8 ml with respect to the IV and 2.0 ml with attached 1 35355Β1 users in SC; p 0 Amrcelli up to 0.7 ml of Anhlol said decompose located in SC. Pfilh in b, p formulation Walsall mAb.3l6P the bereaved means Bedouin formula, n step intervention own Basaif tahmeed. Walsall be inAb formats-316P either when Bhmaml 150 (g 5 15½)) or. 175 mg / ml (d 5 a 0 a °) of the counter y PCSK9 mAb-316P- 10 d 1.5 ml of God 0 Tidin (number B 0 Ronnie 6.0 ± 0.3) of the poly - sur ^ T20 Ezd 00:01 hrs Dr. 0.0015½) or 0.2% ± 0.03% and 1 to sucrose at 5% ± 0.75½) 0.75½. or. A 0% ± 05% in the case of a formula Olney Ouija 175 mg / mil of character Ihon 1 Orajabn E d 0 ± 50 7.5 10 0 Bhmamulau been one Ktthav that anti PCSK.9 mAb-3l6P steady at Almtm filtrate. The use of filtration A Millipore MILLIPAK in the manufacture of clinical supplies while Arkh of Alakibh hed been Assadamh to Ogad Search (Millipore MILLEX DURAPORE). To Olmyrzh Balt 0 sad in vials of Adjaj, the stability of mAb-316P from Azh property Olney drafted (mAb &amp; quot; 316P FDS) No; Bam influence it significantly 0 Ezdma is stored in a polypropylene tube and Addo 15 to 0 liters or or any glass bottle Anbu Polycarbonate Pray to Harkerh of ASAP Gh Alqaa E Nkdo (Rom table 8) • Olmt's No. 1 0 a 7; Abailh capacity in Mahguetat filled in Msag been sin 1 E Turn 1 Sat development formula blasphemed development. The formula Nat higher Alakats formula liquid m 0 n mAb-316P can not be Ashaddamha 'in syringes filled in the Strait (PFS) to reach SC · 20 showed AAC 1 Ij z Balthamid special format REGN727 Atkhvvh development pipeline that Aglul Zm 1 to Osh and wheat hydrogen and organic comet Akirk material thermal installation are as any 35355Β1 b 1 Zbb Alheisidin, rum hydrogen 6.0 and polysorbate 20 crore. You can use the same Dick Almnaat 0 0 Khloar Formulate Tj relatives of the 150 mAb-316P mg / ml and 175 Mahm / ml. It has been added to version Alo- to Z : 175 mg / ml of the drug product mAb-316P in order to reduce the Yum Aldrojh Alopecia Babbbgh. 3J6P and 175 mg were examined chat be tapped for a product Ggar 150 mAb-/ ml in stretchers 1 ml glass is populated Azql prior-type Nuova OMPI (PFS) and are Mgartha private stable at 150 O75-A ml / gm of the drug product in the way one arbiter Alguetanat glass. There is no significant difference in your Mieh Oithll Aikmeatta or Agheiiaaia has been observed after incubation drug product 150 mAb-316P or 1.75 Mjm'rml Etl 0 45 ° C between OMPI PFS control glass and bottle. These data indicated that the drug m from the counter 150 PCSK-9 mAb-316P, and 175 g constant pumping manner, enough to Esckhadd 1 Meh in the PFS. Almt 1 of 8: Chat drug substance that has surprised by the ΜΑΒ-316Ρ been Eger 1 E stability studies to determine each Z chat private storage and pressure of 150 and 75 ml of a 10 YAG mAb-316P. Then use the test turbidity tests RP-HPLC to test the stability elves; loyalty of mAb-3l6P. Stability was determined Agheizayani Akablh extract images from Idhuban Aka 1 PC.SK9 mAb-3l6P in solution. It imkan be lost due to any protein leak

Abroc 1 to n or adsorb 1 g 0 Ely Alalh. The John parts of particulate matter in solution can be detected by 1. Ababaa or Khalal measurements of optical density (OD) at 405 Nano passed (measurements of 0 Karh), and one to test the latter, the Adriadh in OD shows an increase in Anekarh result 'Nkos Aldzeia 0, similar to 0 if Lahoud particles Aalagarh Olney been Thdnha through measurements (01 explains that one of the Aait may be too difficult to reach, to Akpat. blood or 0 Ttds mAb-3l6P Z Khalal -RP 59 ΜΑ 35355Β1 HPLC in RP-HPLC test, are citizen liquidation M counter A- PC'SK9mAb- 316P from column 1 of the process Aaeksa Ge Mzgrdh 0 a, n 0 Hzkl b 0 charged with insulting the specified g 0 d Ü 1 rein in one of the anti-mAb-3l6P that were 'filtered sequence comparison Bmkhalt Anairh that has been reported using measurements ix * mAb-316P Ohamaleneuvnttdidha 0 5 alter one for the entire ironing 0 Mabai 1 Li Alaptah own chemical integration antibody for mAb-) PCSK9 316Ρ) in Eivh 0 not take that most of instability Andja, to the formation of the modified Moors Almrbth on some Zs of Albroobn (the torrent example, conglomerates Altzhmh products fission. or, sodium .. changing of the shipment) and modified images 0 pesky Lalai Z PRO &amp; quot; because the (z St 1 for example Aelat z. Altahmah). Thus, the decomposition products are 0 Λώ ΙΏ.Α6-316Ρ Coordination 0 E. discovered Uv Ebarh p. 10 Onola differ in any o 1 0 E weighs mowing or a; Ahzh. Ako.n Adnn Aldz.mh or eternal. AZ 0 0 1 n T for baskets may then Hsalh Q m.Ab-316P by SE-HPLC original. The ratio is specific percentage to the original mAb-316P in the way Algaml chromatography excluding size may then be determined by the proportion of indigenous summit region to Almtah ALKYLATION each 0 anorexia Jem almost 1 y mAh-3l6P. 15 have been identified changing the image of the shipment for mAb-3l6P of mAb-316P basic chromatograph using ion exchange. Were identified peaks adhesive Olney grew filtered sequentially from Ammon CEX-HPLC using Ozonh detention Aabakh basic Summit Olney been renumbered Botha acidic peaks, while 'Nlk Olney filtered sequentially from CEX-HPLC column with the times of detention later Vtaleg them Oqmm Qadah'o . 'We own a percentage ratio b mA'b-316P dissolved in the way Algsal cationic exchange chromatography has been identified through Altver percentage own 20 35355Β1 b 1 Aqmm 1 Oash acid peaks and tops Alhaveh areas compared to the total of all the peaks Mounalqh

.mAb-316P been E0 light of Yat under Avarra conditions by exposing the body Alamadan Tjmuah of Aldat tests. Tmgl Tel 0 K Tests trading conditions are severe Olney exposing the drug, which was drafted during its manufacture the drug product. The fill material Olney has drafted mAb-316P my Polycarbonate bottles of 5 mL for the purposes of flipping and Daulat August / Alama; e Zoff Afsnn freeze. Olney has been filling the drug substance has dyeing mAb-316P in Matt glass to Yum Vham be tapped when the stability of Raja v high heat. Almt number for the: Dramat chat Tkhozs for Substance Drug has dyeing (FDS) and then spotted the 150 mg / mL of Substance Drug formulated by FDS) mAb-3J6P; 0.5 ml in 5 mL of 1 need Roofing; 150 mg / ml of Jem counter y 1.0, mAb-3l6P milli Molar of Alheistidin (No. pH 6.0) and 0.2 t of poly Morbac 20 and 0 is preached from) fixed in a chemical when it is stored at 20- t Dzeh percentage births 12 months. There is no Vkdokt for mAb-316P and there is no chemical decomposition great was discovered bartender Algsal Adkromatogerava Bamtavad Alhhm or Algsal chromatography ion exchange-and there are more than 91 () / 0 of mAb "316P his intention &amp; quot; original &amp; quot; As has been determined by excluding volume and more than 56 &amp; lt; / from niAb-316Ρ Ansttakb e n 0 main image Ihnh; Nak was also identified by cationic exchange. Results are summarized in Table 9. been spotted to 175 mg / ml of Substance Drug grown formulated FDS) mAb-3J6P; 0.75 mL per vial 5 ml of poly carbonate; 1.75 mg / ml of the body Almkhod 10, mAb-3l6P milli Molar Hesdin (pH 6.0), 0.01½) poly Morbac 20, 5% 61 35355Β1 sucrose, 50 Collapse Molar Orjiv 1 n) Ba 0 as jumpy 0 v 0 n a 7 Hhh 1 Vzaaiah and Ed Yap 0 0 No

; Takzbeh been counting &amp; lt; -20 ° C for 12 months. To A.bikunloa for mAb-316P not be Hmak Thllki 00 Lanier then Akchaffh 0 through n 1 1 Gml to Kromao.jrave Basavad 1 Hhm

\ 1 for washing Alkroma'dhujrave Mahel ion. Hack and more than 96 e / e Z mAb-316P Fill the August A'alolo as 0 A have been identified deletion through Esaad pain and? Kir z 56 over 0 n raAb-316P Call 0 concluded from the &amp; quot; image of 0 Ahzh the Chairperson 0 Ah'a and then selecting the deletion through 0 1 Saddle Aikatirna 0 results are summarized in the table, and 10 0 Alhthal No. 10: Dramat firming Alht slip Aar has p; Agha was Eger 1 E Turn 1 Sat firming 1 to pressure the 150 mg / mL »n article 1 for a drug Ashe was 0 T. Seach 0 a Z 0.35) (FDS) m.Ab-3l6P D - 0.5 t are 150 coke ml 10, mAb-316P R. Mollard histidine (No. pH '), 0.2% trumpet 0 sorbate 20, 0 \ ° a 0 Cruz) and m 1 de 1 for a drug one Lenny has 175 mg / ml 0.5) mAb-316P 0 for .- 1.7 0 for 0 n 175 mg / ml 10, mAb-316P milli Molar Hsaidan (Hedbahjaa number), 00:01 Abu first sorbate 20.5% sucrose, 50 mM 6 lar Orjiven) 0 Nmajraaadarattacialh varying high declivis in a bottle of; light of the Ross silicate No 2 t h Sladh 4 n Tu 4 ®FLUROTEC Mglgh rubber butyl 4432/50 was conducted Aabakah studies in g 1 Ott Z Crown Rboz 1 T. Study 5 mL 0 1 Scouts to 150 mg / ml and 175 Mgamalmml of Z 1 Iakar Olney has drafted mAb-316P was my beta is a physicist Akemiana when Alchleb ( or Cdubm) for two hours. Anhlol remaining remains Anha with no only in part and not 6 N. annual magnetic weight or variable images have been formed (RTM Table 1.1 and 1.2). Has also Mlahmvlh that the MAb-316P constant physical and chemical terms when Traeidah to eight cycles of 62 62 i 35355Β1, but ATA 0 0 level 80 d 1 JH Celsius and melt in the degree Hrarz room. Following the thanksgiving and cooling cycles 0 s mil yen born 1 T. Follow-up Agll Aglul Maria and pure noting the absence of any loss. Is not clubfoot E (Su 1 E to Kab titles soluble or products fissile) or Twinr in Accor A- any weight 0 Dha (t z x 0 Lal any of the tests SE or Z to 0.5 Dhars 0 n that Walsh 1.1 to Masagh d 150 and 175 mg 0 M / D 'for anti-PCSK9 I316PJ was Mato physical at 1 to incubate at 37 m or 45 Em for 28 days, but it H z 1 for the dissolution of ironing 0 I (tabular A..l and 0.2 a). The tests this Alajhaz that Marat 1 for the dissolution of one Ryikazt and Kodn 'blocks 4 and Hthat Savvy and the light scarves 0 Wei 6 Oof, - Z n number 1 for the dissolution of the flesh Alamadan's + slower at 37 m from him at 45. m- and somebody has a shower Hmak Tgtr- 10 Affi one thats or p 1 Ne g 150 or 0.175 -bhm '/ ml of Made Assar Almash 0.50 and or 75 and Mjma ml when incubation at 25 births 28 days-such as 11: Wit 0 Khiaih e the 0 Qar 150 mg / t mAb-3i6P consists of a 10-year Mzlar. Hespd.n; lightning 0 m Adruginy 6, and 0.01% poly 0 and DAT 0-2, and 0 a% Skeror , and. 0.15 Mjma &amp; lt ;, are \ μ 15 AAC 1 Ed PCSK9 mAb-316Pj. It consists Mttj property 1.75 mg / ml mAb-316P Z 10.0 and Lahr Mhdash, number pH 6, and 0.01 polysorbate, and 20.5% ( sucrose 4 and 50 j 0 and Lahr Aegean; and a 75 mg / ml g Anti PCSK9 mAb-316P- did lattes "z 1 so that one of Gesiah and 1 to any of the chemical stage of the property. 150 mg / Do or 75.a mg / t mAb-316P (DP) when one of the store at 17:00 births 6 months in the syringe Maljh Alle (PFS; I To'almot '1 Is 20 OMPI y 1 t thin needle 27 mm cover Nlabrh of Framework FM27 d h ZZ rubber 4023/50 envelope ®FLUROTEC) (Jdo.l 13 and 4A). And remained 0 1 0 Nhaoal J Bach every 63

63 MA 35355Β1 clearly not observed loss of protein, with no figure in Tver Agrugiy after this Alajhamat 0 In addition, there was no significant Tver in Onoi molecular weight or f 0 I Walsh b CEXj SE has not made it a chore. Alhthal 12: Stability stress. To Mgtj Afar (DP) 5 has been firming stress Mntij property 2 150 mg / ml mAb-316P test and a 75 mg / ml mAb-316P B1 Anadan previous refill syringes at 25 m and 45 m e. Both Alakarn physically stable when incubation at 45 ° C for 28 days or one to incubate at 25 ° C for 6 months (Aljadda'ol 13 and 4A) under Ayalol Raiqa clearly, did not observe any loss of protein did not happen Tver. At pH 5 after these stresses. However then monitor clusters and pictures of shipment when Ahtvay protein at 45 m 10 to 25 m. Waddell test Alajhaz This meant that this topic is Alaljellal confidentiality paths for transpiration of the property. And clothing for the drug product 50-1 mg / z, Zan 'Nkil mAb-3l6P 1.9 () / () and increased Alonoj 1 Hamoghaih 19.1 Z after incubation Atd 45. M. births 28 days. It has been monitoring the low level of chemical decay when embrace protein at 25 m. There was an increase in the quantity Alencih 4.0.8 of the bloc and increase 1.0.3½ in Alonoi acid after 6 months of incubation at 15, 25 m. And Bakph product Afor 1.75. Mg / ml, the more 'blocks mAb-316P Nph 4.1.8) Lang Alhamoghai and increased by 1.7% after incubation at 45 ° C for 28 days. It has been monitoring the low level of chemical decay when embrace a Tin 4 and at 25 m. There have been Zpadh 0.7½ in Altktay and increase 9.4½) in kind Alhamoghai after 6 months of incubation at 25 m 0 and each of Mitja property. 1.50. And 75.a.mjm / mL, did not Ihdt 'big horn in the stability 5fmAb-3l6P after Khhr 20 of incubation at 25 m. Alhthal No. 13: sizes filled 64

64 MA 35355Β1 The injection volume in Agshat filled in advance (PFS) containing the entire .1,5 / ml of Article Almenthh for the drug REGN727 is 1.0 ml. The Alhhm disposable injection of PFS eaters at 175 mg / ml of the drug product REGN727 is 1.14. Ml. Is not included 'any excess materials in the PFS reason that size is Achob in Avguenh not interest him (0.005 to 5 0.01 t). Example 14: Pat ΜΑΒ-316Ρ Hoad in storage have been spotted that anti PCSK.9 rn.Ab.316P 'Iapta when Toshiha sterile. Then use and &amp; lt; Dah Alin.chih MILLIPORE MILLIPAK Carr 1 s research and manufacture Waddle Oladad Alaklivekih 0 Luba, for Garzh storage in 1 Ivat one of the glass; the w 0 s 150 mAb-316P and 75 of 10 mg / ml of m.Ab-3l6P Olney has formulated not sinning ,, Epeshkkab 1 R. for i · Bam stored in the pop polypropylene or Poptaran or tube. Poly / Poyet Ao tube. In ¥ Zha 0 by 0 cell &amp; lt; a hard cover Gtho 1 for stainless steel (Table No. 15 and Adul Rzm 16) - &amp; lt ;; Land) 0 n Note the presence of decomposition when -kon the drug substance, to worded may ci custody Ed 0 40 Dred 0 Ioah for 14 crown, did not Taatmmlahzh any degradation between Rodeo 1 Mgarzh WAP glass Akr.d d 0 Oyat 15 plastic and stainless steel. 1 of Example No. 15: classified Khhais Table 3 of 0 Gadd's PCSK9 are ΜΑΒ-316Ρ then p 1 Tven Z 0 amounts mAb-316P (A value of 1 and 2) Z x 1 Lal Algsal Aldroytogerava dimensions Hoss and scattering ill seen | Q R, Yale (SEC-MALLS) W μ; 10 F Pass El 0 of what a (1 block to Olarh Z Aro.bn or Arwa proud. DD KU; 1 and 2 every 20 b r 1.54.5 and 154.6 Yu a-L * t j Acald hope 'to see the father; Rlalo .adh of 154.4 p 154.8 Yu T'kon (Bmtot 6 s August 5 D'vt) i 65 65 i 35355Β1 for Odhu 1 E 1 to prey Olney filtered in a sequential from a template SE. represent the main Angmh Almlkozh 6 to 96,7 -99.2½) Z area Imams total protein and be corresponding to the monomer painful mAb-316P (ie, &amp; quot; families &amp; quot; Almtkhaddm Fa). Imagine the mAb-3l6P through parity with the electric Alakiz on (cIEF) to determine the 5-point \ 0 to Tmaoa Aakhme my pictures asymmetric Olney its basic components. Been identified pi and the top one for Mtoth (% of Mnalqh Summit College) from Genat mAb-316P through cIEF that has been - in the internationalized No. 17. Todgl major lament mass (top 5) with pi has been calculated one the one who the universe at about 8.5 and 1 the one who then introduced at 66.4% and 68.0 ½) of the blocks at the 2 and Z 0 represents Almib Alonouh prevailing (top 5) antibody processor which Paljlaakoz Do Fd to Eban at the party C (ie, basic image Ihnh also was used here). Not allow for the analysis of Ankies Mehri mass spectrometry (MS.) Of mAb0316P of one of the schemes are Rebin block 1 and block 2 match in Paljlaicombl solo treatment position, and 298 efficiency 8 in the Fc domain in each of the blocks. Pose Photo Alglican A- B 0 LJ / form, Muli 1 h Algelaakosel Almlchor which is then summarized in Table 18. General (f), and then each of the 15 sets health b -hl z complex z uh) v Alglican 'dual antenna with many Mlibat 1. When 298.Asii. Although Z, the relative amount of &amp; lt; pronation Ojlambrosal processor Balbosel (GO) Almttml to lament Mellh E at A- 2 Cal Ozzy form fj &amp; gt; Of the amount in the image irony of the cluster 1. Lauder a 0 Ekly of Nelln, any relative Alkmat Bay Jlambrosal processor mainland (G2) and Hodhu Gela / torrent F mussels for 1 Godouxal 20 (.G1) 1 Klh Ai Hor del 2 Z in the cluster 2 has been reduced compared to the quantities own Bbuniat sugary chain in the cluster 1. Results from the analysis of LC / 'MS 1 Tven of samples ^ Da contract 1 t 66 35355Β1 (Take 0 of 16) to the then Thdidi Panama 209% and 8.4 Z are hand Ivilh'muftqrh series for 0 Tgl Alglican Ezl 0 SI1298 on the block A and 2-year chore. Glican schemes have been caused by HPLC analysis after the launch of the types Aloolijo screed from both quantitative mAb-316P. In each of the T scheme, then we get ops screed 1 T. derivative to Mjmoashn Risti: Alonouh bilateral century is Aanaaljh Balgacorell and Obaa Thaiah 1 Karen Haaljh Balgocovel 0 and within each group (treatment Balgakozhel and untreated Balghozhel) 4 was μ 1 to Olybiskrdat to images, d 1 j Jalaktozhel (G2), and Mono Jlambrozbil (Gl), and deadlines 0 Kozel (GO). Presentation was getting tasks done Ooleiho screed about deafness analysis in the MALDI-TOF. 0 YMCA Dh each CAC in 1 Khttin 1 Ovean that the level of 1 to address Aalgotozhel for providers 1 Ri niAb-316P was Rev particularly as upper 0 H, b Nouhz level 0 treatment plant tuck Zdr 0 80% and 9 to 86% in the 5 * (2, Ai Adhirzab 0 Presentation Although the B-1 for a total of 0 treatment plant Bolbual of 0 Kdarany 0 Htha: Hee , but less this 0 AAC Akhlaitk 00 Yeh in one of the abundance of one of Sabbieh pictures 1 to Glican in Cderadn ( 'not) Z 0 Mhdaa d then determine Sep percentage Overdrive 1 for peak Kdri 34.4 F and 39.6 d β Z 1 v 1 to Glican 1 processor Balhokozhel GO, and 1 H, and 02, on Waddell &amp; quot;' '' I shower humiliation 0 K; F-0 to 1 to C areas of nucleus He toured 0.1 45.8 hr, I 0 T.

Tat 0 1 Jbform Almt committees Balbozhel GO, well G, and 02, on &amp; lt; &amp; quot; 0 0; 'One of the differences in the extent of 1 to address Paljalakouz; for between 1 to Mekdain. The monitor we shall return (Dred.; Zman 45 &amp; gt; Bimaar 0 1.80 2.9% Sabala- PIL Hassys: Z: Ttkd ^ u 0 Overdrive 00% contract 0 for% in-Aka-belonged 67 67 1 35355Β1 Y is less than or sheltered 3% of the total areas see Alglican Olney then monitored in both Almkdaran. He has produced mixture Olmsheerk grills analysis molar of Mqnarin Alnengin absence see the bulk of his hand and linked Sep areas pinnacles Ikl Dorry j Ohalit Almchehrk well projected values ​​based on individual Althaliay each amount (see table 1.9). table 1: effect Anhlol organizer and pH on the stability mÀb-316P at 45 ° C for 28 days Alq'edy% loss ½) Alo.aa%-ed all my Alajala% (Bima &amp; lt ;,) Turbidity a carefree Alheid- / left-handed Alinvd 10.0 33.0 57.0 0.3 98.1 1.8 0:00 lack of incubation 2.4 ... 15.2 0.8 88.9 1.7 0.00 figure Ablah 6 to 8.0, 'Nurse u 3 ».,:; · 00 j Matta p H'z 0 Bio 1.3 89.4 2:00:01 Alrfm 1000 Rogel 0 s 8.0; for moonshine phosphate Q 0 0 Maj E 00 m code is» .tah 0.9 91.7 1.9 0.01 0.6 figure Ablajtq of a wrap. Phosphate 4.5 78.8 16.7 0.7 92.4 2:10:01 figure Alhedrouhana 7.0, winding phosphate 6.6 68.3 25.0 0.6 93.2 2 '. 0.00 figure Ablajany 6.5, for Gosvat 8.0 62-3 29.8 d 0 93.9 1.8 0.00 Perl 2 pH, for Gersvat 9.1 54.0 36.9 0.0 94.5, A. 00:00 Barr 0 m pH, Hscdln 8.3 59.8 31.9 0.4 93.1 1.9 0.00 'Stay 68 68 1 35355Β1 pH, Seksenat 9.9; .58 3,2.1 0.4 95.1 19 0.00 compaction b 0 Dugea 'Nlm data 99 62.0 28.0 0.4 94.6 2:10:00 Arqam Alheiarohani 5.5' 0 Dtadt 8.5 56.9 34.5 0.2 92.4 2:00:00 infant Alhdruginy 5.5, acetate 11.4 57.5 31.1 0.2 93.0 1.8 0.00 compaction Hedrojajny, 5.0 - .U (, Mei, 00 larg Aekar "Altver in the OD at 405 nano Molar for material to start. d average values ​​of Article Pollack Anandhanh each 12 table 2 formula: the effect of pH on the 10 mg / mL of 10, mAb-3l6P Melli Molar histidine at 45 Drhh C 0 births 28 days grassroots% insisted 0 move% underlying 1% to Tktlho original% gross turbidity 1 ID Alhedrugenir / Anhalh's sieve a. a! 31.1 57.8 0.2 98.1 '' 9:50:00 absence custody 0 p 69 35355Β1

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1 table and sleep 3: Toie Almz-Pat Akey {25 Yum / 0's ï &amp; gt; Ab-3i5p been 0 d de 1 Matlmayor 120 minutes __ grassroots% of 0 to acidic 0/0 basic% lumpy% only 0 no% gross Mahmaml) Aekard 0.1 Almnibat gait organic 1,0.3 s 0 T. 50.6 0.5 97.3 25.6 0.00 absence of Matt de 1 2 9.9 39.0 51.1 0.5 97.3 25.6 0.10 absence ever since LIBAT Mchanh 10.1 38.9 51.1 0.5 97.2 24.7 0.01 ./.0.2

70MA 35355Β1 Crown and housewives 20 10.2 38.9 50.9 97.3 24.7 0.01 O.h. Crown Surat 0.2% 96.9 25.2 0.01 00% v Bruad 1. - 10.3 39.2 50.5 39.0 50.7 0.5 1.0.2 0.5 97.1 25.3 0.01 I / e peg 3350 10.1 39.1 50.8 0.5 97.1 24.9 0.01 ./.1.5 PEG 3350 1.0.7 40.5 48.8 0.6 97.0 26.7 0.00% 20 PEG '300 1.0.3 39.8 49.9 0.5 97.2 1.e. 2 0.01 ./(10 PEG 300 10.3 38.6. 51.1 0.5 96.9 25.8 0.01 20 your responsibilities Bruyav Zhnikol a 0 for turbidity - Altdvi 00 Ed 405 Anu Molar Ha.shalb two clouds Almtoth article is eddy per nine pumping Aljdolno. 4: effect Almveataklad 25 Mjma 0's mAb-316P, which has an incubation Ahamngm Ntektl% Z ί Dhirjh C for 28 yo when ο machine 1 Edia% 0 Alo.aa Γ1 da; for Osaa ... for. rack 0.2 1 1 Ekarg Almnibat total pH 1 to Mtih 71 71 1 35355Β1%%% Mahmaml a brachial 10.3 39.2 50.6 0.5 97.3 25.6 6.:1. 0.00 absence 1.0.5 54.7 34.8 0.7 94.5 24.9 6.2 0.02 custody of absence ever since LIBAT w 9 Ke .10.5 54.3 35.2 0.5 94.6 24.3 6.2 0.03% polysorbate 20 0.2 10.4 54.5 35.1 0.6 94.8 24.3 0.2% 6:20:02 Poly Surat 10.6 55.6 33.8 0.6 94.7 24.6 6.1 0.03 0.2 g 'Brunak F68 10.6 53.5 35.9 0.7 95.0 24.8 6.2 0.03 PEG (½3 3350: 1.0.5 53.5 36.0 0.6 94.8 24.4 6.2 0.02% 1.5 PEG 350 y is Available harm 0 Bio is Tamam 4.2 88.8 25.4 4.8 0.12 PEG% 20 300 8.9 67.0 24.1 0.9 93.7 25.0 5.4 0.09 PEG (½10 300 11. .2 54.2 34.6 5.6 89.9 24.6 6.1 0.03 20½) propylene Gelmikd Li turbidity = Altver in the OD at 405 nano Holar for the starting material. 72 72 1 35355Β1 average values ​​of the article is Aldo 1 Mieh each 9 Formulate Table 5: Taiar material installed on 20 mAb-3] .6P mg / ml 0.10 milli Molar histidine at 45 ° C for 28 days S- Annagaady ½) (basic ½ % Almtktay% 'to pray% total Mjma.ml a; s 0 for Alheidro- turbidity I visual excipient examination 9.6 39.3 51.1 0.5 91.1 20.2 6:00:00 unacceptable absence 10.1 56.5 33.5 2.0 93.6 19.8 6.1 incubation 0.02 unacceptable lack of Mazh heterosexual 1.3.6 51. 0.0 35.3 4.6 91.0 20.0 6.0 0.03 11'.6 failed 150 over anything Molar 10.9 57.0 32.1 1.0 94.4 22.6 6:00:04 acceptable 20./. Cruz's 0 9.1 67.4 23.5 1.0 94.3 21.8 5.8 0..16 acceptable Swoptull 20% 11.1 54.5 34.4 0.9 94.8 21.2 6:00:02 Mqrl 10% of what Ntol 10.2 56.6 33.2 0.5 94.7 22.1 6.0 - 5.9 10:05 acceptable 20 (/ 'Trialun is. non. non 5.4 90.2 20.8 0.10 unacceptable% 5 73 73 1 35355Β1 rb available Matta 3 a Gelesarol 13.3 49.2 37.5 3.0 92.9 2-1.1 6:10:02 acceptable arginine 3% 10.9 58.0 31.0 1.7 93.7 19.8 6.1 0.03 3% acceptable Gela lysine turbidity - Altver in the OD at 405 nano Molar for the starting material. values ​​Achtusanh article is Anandhanh each and Sage .... \ and 0 '... 0 m 00' y table 6: Impact protection materials lipomas on mAb-316P oxide dryer, which has an incubation at 50 ° C for 28 days grassroots% 1% for basic Aictl ½) 1 Osay% gross Mahm / ml Alrim Alhsdrouhny turbidity visual examination soul 10.7 38.3 51.0 1..2 9'7.1 00 -6.0 0.00 for unacceptable absence 0 Houdazh 7-hee 35.1. 24.2 28.5 70.0 100 6:10:09 failed the lack of quality material to protect Ahsi 0 23.6 39.1 37.4 68 90.7 104 6:10:02 acceptable 2% sucrose 14.1. 39.2 46.8 1..8 96.1 -1.05 6.1 0.00 flash for 6% Skeron 1.6.8 42.4 40.9 3.4 94.5 114 6:00:02 Mqbo.l 2% sucrose., 74 74 1 35355Β1% 2 glycol 14:44 s AA 0 47.2 95.9 109 5.9 T. .. .. acceptable 2. /. Sucrose, arginine turbidity - Altver in the OD at 405 nano Molar Balbh start of a substance. 2 drug product dryer Balthamid been decompose to 100 mg / ml REGN727 before analysis. Almtusalh values ​​from the start of the four pumping material. 5 Table 7: Persistence run correctly Bmenth drug lyophilized been decompose to 100 mg / ml 50 ° C Mi 0 Ayla 25 ° C 5 ° C absence; 0 temperature. mo2. mo3. mo,). mo4 Mkhoziv &amp; gt; Storage 0.02 0.02 0.01 0.01 0.00 Turbidity 6.2 6.2 6.2 A 6 6.2 figure Olhad Rojmny 105 98,100,104,100% Total Almstkhalm 3 94.9 95.7 96.2 96.5 96.0 original% 2.9 2.4 1.7 1..4 1-.7 1 conglomerate% 43.5 46.2 49.2 51.5 50.6% only 'Massey 40.1 39.5 38.2 37.9 38.0 acid 75 75 1 35355Β1% 16.2 14.3 1.2.7 10.5 .11-.4 grassroots 152 NP NP NP 1.46 bio-test (reference 2% benchmark.) Aekard - Altver in the OD at 405 nano Molar for a substance start. D Amaaiv 0 R'lqubol: 50-200% of one of the Reference 1 to measure Table 8: Special compatibility with 50 mg / ml mAb-316P for 14 days at 40 ° C and 75% of Alrhaobh steel rust poly &amp; quot; To Rbunat poly &amp; quot; C-1 Rennes poly-propylene I lack of storage 0.01 0.01 0.00 0.01 0.00 0.00 turbidity of 98 .1.03 1.04 9998 1.00% total of 0.6 and 96.2 96.2 96.3 96.3 97.0 Ahli% 2.0 2.0 2.0 1.9 1.9 2.0% lumpy 45.5 45.6 45.2 44.9 45.7 50.8% 1 for a basic 76

76 MA 35355Β1 43.2 42.5 43.0 43.6 42.8 38.1% .11.2 acid Qoa 11.9 11.6 11.5 11.2 grassroots Ik 1% Rh 0 1 Cgther on 05 at 405 nano Molar for material to start. 1 Table 9: Furnishing 1 1 1 50 bear Mjmaml mulch mAb-316P PCSK9 as 2a months -20 ° Mthwaih &amp; quot; 30 ° C -80 ° C _ \\ 1 sample Alqaouh temperature Altkhozbn 0.0.1, 0.01. 0.00 0.00 Aekreet 405 OD) of Bannu. Molar) esthetic 11.1 108 104 100 l6P? M \ b (½ 97.2 97.2 97.3 97.5 1 of the original 1 Buzz) Mstkhalas 1.9 1.8 1.8 7-A: extracts 1 to Lumpy% 56.3 56.4 56.5 56.2 Almtkhalay 1 basis% 25.4 25.7 25.7 2.6.5 -11 Almatkhalas acid 0 / 35355Β1 - 0 for 0 g 1 Ed mAb-316P PCSK9 for a period Alhdolrfm 10: Special Baht j 175 mg 0 MAS 20. 30. 80. Dhirjh degree eye Celsius Celsius Celsius 1 Mgarzh 0.01 0.0.1 0.01 of 0.0 101 1.04 .1.00 100 96.3 96.4 96.5 96.2 2.7 2.6 2.5 2.7 a.% 56.6 56.2 58.5 29.4 29.4 29.4 29.4 13.9 14.0 14.5 12.2 months counted 80 degrees 6 Yeh ._........ .. .. 1 0 0 1 storage temperature for turbidity (405 OD Na Nu Molar) '% of the total will be saved RP-HPLC) REGN727) Stkhalay PG 0% of the SE.) REGN727 HPLC) 0χ0 REGN727 Mukalla extract (. (SE-HPLC disposer Alosa.ma percent are CEX-) REGN727 HPLC) CEX-) REGN727 6 Stkhk 0 despair 0

(HPLC extract 1 0 Qeda Uh CEX-) REGN727 H.PLC) Post 405 nano Molar OD turbidity A1 change in Erreur! Source du renvoi, introuvable. For Azh Alibde.aljdol RFM 1 1: Your Baht to 150 mg / ml 4mAb-316PFDS under Algguet Althamd / thaw conditions of 25 ° C Ed 'A: Its 37 ° C incubation 45 ° C incubation flipping the lack of pressure 2 test Acft 8 28 142 814 28.14 12 060 small g 0 n 78

78 MA 35355Β1 days Yu cycles »of days days days days minutes his bear minutes Algguet» to accept the unacceptable acceptable acceptable acceptable acceptable acceptable Fair Fair Fair food-1 Ts visual Aizar 0.0 () 0.00 0.00 0.0.1 0.00 0.03 0.02 0.00 0.00 0.00 Gao 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 a; Im Il &amp; quot; Yzja .1.00 10 199 989 998 98 102 10.1 100 0.0% total S 1 Hals 97.1 96.2 96.7 95..1. 06 is their 92.4 94.2 97.2 97.5 97.4 Alosaa% Mstts 1.7 2.2 2.0 2.6 2.4 4.1 3.4 2.1 1..7 1.6 x 10 Ts | 'Canutl% 53.9 49.1 51.5 39.5 46.3 29.0 38.7 54.7 53.7 53.6 Altahedls only one C% 26.5 28.9 27.8 36.9 31.9 48.6 39.5 25.9 26.1 27.2 P 1 0 Ra DDS acid. 19.6 22.0 20.7 23.7 21.8 22.5 21.8 20.2 19.3 1.9.5 baseband Almstkhadd% 81 98 NP 82. NP 85 NP 84 NP 84 dynamic test (0 / relative bio) Ammurbast 10 mM histidine Mhlar number Hidzojina, 0.2 (/ poly

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(½10 sucrose 0.150 mg / ml anti-mAb-316P PC.SK9, the lack of pressure 1 value is a medium of Nrasat stability &amp; quot; 7935355Β1 1 3 was a report one of Akkar B 'to change one Casey in OD counted 405 Madhu Molar compared textured Abe 4 1 Kubba parental vitality relative; together DNR say: 50-200% p 3 Z refer 1 ^ r, Aadolno. 2A: Mmh m 0 of 175 mg / 0 for jj &amp; gt; l'i ^ iePFDS '7 Althmydr prematurely 0 de Celsius NH me 1 7 3 ° C incubation 45 ° C Olhoudath Altqlst .adm having pressure test Aat..zt 8 Daulat .3,1 always 14 days 28 days 14 days 28 days 1.4. 1.20 days. minutes 60 minutes smallness minutes Zd be tapped pissed off is an acceptable vaccine Aqubol Fair Fair Fair Fair Fair Fair examination Bary Appearance 0.01 0.00 * non-came up .01 .00 .03 0.0.1. 0.01 0.00 0.00 6.0 6.0 d Turbidity is Qq. 6.0 6.0 6.1 6..Ι. 6.0 6.0 6.0 figure Alhedrugiy 9899 'is. Available 96 10 098 101.98 96 1.00% Mtkhalay total 96.1 2.h? is. vaccine 94..7 95.7 9.1.7 94.5 96.4 96.3 96.5 Low of 2.3% Msenkhalas 2.6 is journeyed 3.0 2.8 5.2 3.6 2.5 2.5 2.5 Schas A'lmtktl% 59.3 58.2 il ;; '46.9 56.3 38.4 47.1 59.0 58.3 59.5 Abstract Adde% 29.5 30.9 Ir. Vaccine 39.8 32.3 47.6 39.5 29.4 29.3 30.1% 11.1 Almstkhalas acid is 11.0. 13.4 11..4 14..1 vaccine. 13.4! 16 12.4 10.3 Almtakias grassroots 0.01% 0.00 is. Journeyed 0.01 0.00 0.03 0.01 0.00 0.00 0.0.1 Dynamic test (% bio Alash)% 5 80% 5 80 1 35355Β1 10 million Mola R. histidine, pH number, 0.01./ Morbac poly (sucrose, 50 mM Molar. Arginine 175 mg / ml anti 0mAb-316P PCSK9 Â lack of pressure 1 be a medium value of studies fortitude 0.3 turbidity = Altejer in (01 at 405 nano Molar for material to start. Alnmbh percentage vital relativity; standards 1 to Qubhn: 50-200 / m 04, 01 I encouraged one of Kebaimaa

Table 1 modulate 3: Special Baht; 150 m / 0 for PFS ^ niAb-315P5P ° C at 28 days. Thergda C at 6 .mo 5 percentage Dzhh us. 6 .mo torticollis Z acceptable acceptable acceptable appearance Mukul 0.02 0.00 0.00 0.00 turbidity of 6.1 6.1 6.1 6.1 Arqam a 4 Pedrojd 97,102,102,100% gross Mstkhalay 92.4 4.2 96.1 and 96.6% original Mstkhalas 4.3 3.2 2.6 2.4 Masmakhlmbo 1 35355Β1

PFS 1 to Lumpy ½) 35.8 45.7 Almstkhzqs List Domains% 50.9 42.1 31.3 31.8% 12.2 Almsthkhalsn Ahamany -1.0.2 9.8% Olmstkhalhs grassroots turbidity = Oltaar in the OD at 405 Bannu Molar ratio of material to start Table 14: Special stability d 175 mg / ml mAb- 316P DP in y 1 posts on C at day 0 25 stairs, C at 6 .mo 5 degrees Celsius trouble 6 0mo 0 shameful 0 yen acceptable to for Mqrl unacceptable acceptable appearance 0.04 0.02 0.00 0.00 Turbidity 1 6.1 6.1 6.1 6.1 Artem pH 100 101 103 100 (Barr 0 35355Β1 1 for Total lAkiJ 91..6 96.7 1% to drink ».stkhals 3.0 2.4 2.3 1 to extract Lumpy 47.1% 59.7% 59.1 Almschlas basic 14. ^ 30.6 31.2 12.3 Almstkhalhy Ahamady 6.o 9.7 / kJ grassroots% turbidity = Alpher in trouble OD 405 nano Molar door Article start. table RTM 15: Special Allowavq 150 mg / 0 for 1niAb-316P for 14 days and 40 ° C steel Babmdo poly-poly ^ 1 - Crown not serine propylene carbonate ΰ of storage, storage 1 35355Β1 nest 0 01 0.01 0.01. 0.00 0.00 0.00 1 2 turbidity 6.0 6.0 6.0 6.0 6.1 6.0 broom Aadlogeni 1-04105 Wu 10 497 100% total touched ^ played 1 95.5 95.7 95.7 95.8 95.9 97.4% families Mstkhalas an 2.6 2.1 2.6 2.5 1..7% Almsthelmy · bloc's 45 45.6 44.7 45.8 45.8 53.3 1 the Mmtkhalsn 1% of basic 33.5 33.0 33.8 32.9 33.0 26.9 0 Adstehala any acid% 4.a 2 21..5 2.1..6 21.6 21.3 19.8 Almstkhalhy grassroots% 35355Β1 10 milli Molar histidine, their pH, 0.2 / poly 0 Morbac 20, 10 (Λ sucrose, and 150 mg of 0 / ml mAb Aekarz T. OD at 405 Anu Molar ratio d «birth start. Table 16: Compatibility your po 175 coke, niAb-316P for 14 days ml E 0 40 d y jolt percentage Salso not for 4 for 1 Boy "Seyran poly" Br.uyaan poly &amp; quot; Krbwa T. category of lack of storage, Ehazeen category 0.01 0.00 0.00 0.00 0.00 0.00 Turbidity 3 6.1 6.1 6.0 6 0.1 6.1, 6.1. Artem pH 98,105,100 SYP 04 98 100% total Mstkhalam 94.9 95.2 95.1 95.2 95.3 96.6% families Mstkhalas Wu 3.1 3.2 A · 3 3.0 2.4% bloc Ofajlam 50.4 51..0 50.6 51.0 51.3 1.1 of î / AàJs 85

85 MA 35355Β1 basic% 35.2 34.5 35.0 34.5 34.5 30.0 Abstract acid 14.4 14.4 1,4.4 14.5 14.2 12.3 A y Li grassroots% 1.0 milli Molar histidine, number. PH, .0.0.1% poly Solda't 20, 5. / sucrose, 50 mM Molar Orahinin, and 175 mg / ml niAb turbidity = OD at 405 nano Molar for Y starting material.

Adul No. 17: Far lack Altjadhan of mAb-316P by IF block 1: 1 to 2 block (a mixture of 1: 1) 1 to 2 block '1 for 1 block summit area,% pi summit area,% pi summit area,% pi Expand summit. 0.7 (0.1) 7.98 (0.01) 0.8 (0.0) 7.99 (0.01) 0.8 (0.1.) 7.99 (0.01) 1 2.6 (0.1) 8., 1.4 (0.01) 2.6 (0.1) 8.15 (0.01) 2.6 (0.1) (.0.) 2 6.9 8.28 7.0 8.29 6.9 8.29 3 86 86 1 35355Β1 (0.1.) (0.01.) (0.0) (0.00) (0.1) (0.00) 18.5 (0.1) 8.42 (0.01) -.1.8.6 (0.2) (0.00) (0.2) 8.42 (0.00) 4 67.3 (0.1) 8.54 (0.00) (0.3) 8.55 (0.0.1.), 66.4 (0.3) 8.54 (0.01.) 5 (00) (0.01) 2.8 OH 0 of 0); 0) (0.00) 6 (01) (0.01) &amp; lt; 000,; 555) (0.1) (0.00) 6 table 18: mAb-316P peptides have been processed Paljlaakoppel Aktbd't Olney bloc has observed (Da) Hheldh heavy Aceh Ram summit. 1 to 2 block Alktha E'a (Fi; c) i ((jlc: NAc) 2 (Man) 3 (GlcN0Ac) 2 (Garb 2957.19 2957.15 -294 302 ÎFuc) i (GlcNAc) 2 (Man) 3 ((jicNAc) 2 (Gai) i 2795.1.1 2795.11 -294 302 (GlcNAc) 2 ^ an) 5 2404.94 2404.94 -294 302; (cNAc) i (GaJ; G)?. (Fu.c) i (G {C'NAc) 2 (Ma.n) 2591.96 2592.02 -294 302 (Fuc) i (GlcNAc) 2 (Man) 2 (Ci; cNAc) i 2267.92 2267.94 -294 302 (GlcNAc) 2 (Man) 2 (G0cNAc) j 212-1 .. 80 2121.82 -294 302 (GlcNAc) 2 (Man) 3 ((} fcNAc) [2283.91. 2283.91 -294 302 5 August (Fuc) i (GlcNAc) 2 (Man) .3 (GlcNAc) i 2429.98 2429.98 -294 1 35355Β1 302 (GlcNAc) 2 (Man) 3 (GlcNAc) 2 2486.97 2486.99 -294 302 (Fuc) i (GlcNA.c ^ 2 (Man.) 3 (GlcNAc) 2 2633.06 2633.05 -294 302 non-glycosylated NST site 1188.53 1.188. 52 -294 302 16 (Fuc) i (Glc.NAe) 2 (Man) 3 (GleNAc) 2 (Gal) 2 3439.44 3439.44 -290 302 17; (Fuc) i (GIcNAc) 1 (Man) 3 (GlcNAc) 2 (Gal) i 3277.35 3278.40 .290 302 (GlcNAc) 2 (Man) 5 2887.26 288-7.20 -290 302 (GlcNAc) 2 (M3n) 3 (GlcNAc) i 2766.21 2766.24 -290 302 17 (GlcNAc) 2 (Man) 3 (GlcNAc) 2 2969.25 2969.34 -290 302 (Fw.c) i (G; c-NAc) 2 (Man) 3 (GlcNA.c) i 2912.25 291.2.28 -290 302; Fuc) i (G (le.NAc ^ 2 (.Man) 3 (GlcNAc) 2 31.15.35 3115.32 -290 302 table 19: integrated summit areas of Mztbaat Glican Olney identified by capillary electrophoresis Ala_i_rad Glicav Jukav 1:11 to 2 block bloc Albgah 1 '2 I &amp; quot; Huye block area Mnalqh mixture Summit, Summit%% Mnalqh summit,% 1 35355Β1

000 &amp; gt; 1 1 GO-Fuc Ί.6 (0.2) 6.8 (0.1) (0.2) 1} / ** Rjd 5 2.3 (0.1) 2.9 (0.1) (0 0 2) not including a challenge i 0 summit Olsverh 0.6 (0.0) 0.5 ( 0.0) 0.7 (0.0) 3 not Ham Thdld summit Elsafarh less than LOQ less than LOQ Ash LOQ of 4 m betrays determine summit Elsaferv Oqay of less than LOQ LOQ Ash 0 n's LOQ &amp; lt; GO 40.4 (0.2) 45.8 (0.2) 34.4 (0.1) 6 not including 0 Thdld Summit 1 small (0.0) ¾.1 (0.0) 1.5 (0.0) 7 to M.bm Thdld Summit 0.6 (0.0) 0.9 (0.0) less than the LOQ 89 35355Β1 Elsafarh did not identify the blood summit Elsafarh (0.0) (00 less than the LOQ 9 (6-1) .1. 27.0 24.7 29.5 10 ··· War: 1.0 (3.1) or the 02-Ftic 9.3 (0.1) 8.6 ( 0.0) aA 00 a 11 did Q 0 j did 1: determine the small hill less than LOQ less than LOQ less than LOQ 1.2 did -h 9 a challenge LED Summit Ansgarh less Q LOQ less than LOQ less than LOQ 13's (02 9.4 (0.2) &amp; lt; 0, ') 11.7 (0.0) .14 # G # -fuc and G: refers to Myat Glicat not' sniff processed customer and Glican Balfahil have been processed, the Albertab. # symbol refers to the small 0.9 or 0.2 2. Mgtah Glican: ▼ Vakoz , &amp; quot; N -osatal Gelhoz 1 min 0.0 mannose 0.0 galactose 0 ÎOQ limits account 90 9035355Β1 list of sequences .Regeneron Pharmaceuticals, lue. &amp; lt; i 10 &amp; gt; &amp; lt; 20 a &amp; gt; pumping installed contain antibodies y 9.PCSK &amp; lt; 130 &amp; gt; 7050 a 9 &amp; lt; 160 &amp; gt;

Patentln version 3.5 &amp; lt; 170 &amp; gt; 1 &amp; lt; 210 &amp; gt; 118 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; &amp; Lt; 213 &amp; gt; MTW 1 Mechanism 1 Stmaeah &amp; lt; 220 &amp; gt; &amp; Lt; 223 &amp; gt; Thivih &amp; lt; 400 &amp; gt; 1 35355Β1

Glu Val Gin Leu Val (Jlu Ser Lily Gly Gly Leu Val, Gin Pro Gly Gly15 10 5 1

Ser leu Arg Leu Ser Cys Ala Ala Ser Gly Plie Thr Plie Asn .Asn Tyt '30 25 20, Ala Met Asn,' Lrp Val, Arg Gin A, l, a Pro Gly Lys Gly Leu Asp Trp Val 10

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35

Ser Thr Ile Ser Gly Ser Gly Gly Tlir Thr Asn Tyr A!, A Asp Ser Val60 55 50 .15: Lys Gly Arg Plie lie Ile Sel 'Arg Asp Ser Ser Lys His Thr Leu Tyr70 65 75 20 1 35355Β1

Leu (In Met Asn Ser Leu Arg Ala Glti -Asp Tilt 'Ala Val Tyr Tyr Cys 95 90 85

Ala Lys Asp Ser Asn, Trp Gly Asm Phe Asp Leu Trp Gly Arg Gly Thr 1-10 1.05 100 5

Leu Val Thr Val Ser Ser 115 2 &amp; lt; 210 &amp; gt; 10 8 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; &amp; Lt; 213 &amp; gt; MTW 1 Mechanism 1 Stmaeah 1-5 &amp; lt; 220 &amp; gt; &amp; Lt; 223 &amp; gt; Badgers &amp; lt; 400 &amp; gt; 2 20

Gly Phe Till 'Phe Asn Asn Tyr Ala

93 MK 35355Β1 1 5 3 &amp; lt; 210 &amp; gt; 5 8 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; &amp; Lt; 21,3 &amp; gt; MTW 1 1 Vision Stmab 10 &amp; lt; 220 &amp; gt; &amp; Lt; 223 &amp; gt; Violated by &amp; lt; 400 &amp; gt; 31.5

Ile Ser Gly Sel 'Gly Gly Thr Tl;,!' 5 1, 4 &amp; lt; 210 &amp; gt; 20 11 &amp; lt; 211 &amp; gt; 94 1 35355Β1 ïrt &amp; lt; 212 &amp; gt; &amp; Lt; 213 &amp; gt; MTW; any single hypothalamic 0 &amp; lt; 220 &amp; gt; 5 &amp; ​​lt; 223 &amp; gt; Frighten 4 &amp; lt; 400 &amp; gt;

Ala Lys Asp Ser Asa Trp Gly Asa Phe Asp Leu 10 10 5 1 5 &amp; lt; 210 &amp; gt; 113 &amp; lt; 211 &amp; gt; 15 PRT &amp; lt; 212 &amp; gt; &amp; Lt; 213 &amp; gt; MTW 1 Mechanism 1 Staeah &amp; lt; 220 &amp; gt; 1) 2 &amp; lt; 223 &amp; gt; Badgers 1 35355Β1 5 &amp; lt; 400 &amp; gt;

Asp Ile Val Met Th ( 'Gill Ser Pro Asp Ser Leu Ala Val Set' Leu Gly 15 10 5 1 5

Glu Arg Ala Thr .Ile Asn Cys Lys Set 'Ser Glu Ser Val Leu Tyr Arg 30 25 20 10

Ser Asn Asn Arg Astt Phe Leu Gly Tt'p Tyr Gin Gin Lys Pro Gly Gin 45 40 35 1.5

Pro Pro Asn Leu Leu Ile Tyr Trp Al.a Ser Thr Arg Glu Set 'Gly Val 60 55 50

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 20 75 65 96 96 1 35355Β1

Ile Ser Se; 'Leu Gin Ala Glu Asp Val Ala Val. Tyr Tyr Cys Gin Gin 95 90 85 5

Tyr Tyr Thr Thr Pro Tyr Thr Phe Gly Glu Gly Thr Lys Leu Glu Ile 110 105 100 10 s

Ly 6 &amp; lt; 210 &amp; gt; 15 12 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; &amp; Lt; 213 &amp; gt; MTW 1 Mechanism 1 Stmaeah 20 &amp; lt; 220 &amp; gt; &amp; Lt; 223 &amp; gt; SYNTHETIC 97 1 35355Β1 6 &amp; lt; 400 &amp; gt;

Gin Ser Val Leu Tyr Arg Ser Asn Asn Arg Asn Phe 5 10 5 i. 7 &amp; lt; 210 &amp; gt; 3 &amp; lt; 211 &amp; gt; 10 PRT &amp; lt; 212 &amp; gt; &amp; Lt; 213 &amp; gt; MTW; Rh 1 Stmaeah &amp; lt; 220 &amp; gt; 1,5 &amp; lt; 223 &amp; gt; Takiqih 7 &amp; lt; 400 &amp; gt; 20

Trp Ala Ser 01

MK 35355Β1 8 &amp; lt; 210 &amp; gt; 9 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; 5 &amp; ​​lt; 213 &amp; gt; MTW 1 Mechanism 1 Assalmaeah &amp; lt; 220 &amp; gt; &amp; Lt; 223 &amp; gt; SYNTHETIC 10 8 &amp; lt; 400 &amp; gt;

Gin Gin Tyr Tyr Thr Thr ProTyrThr 5 .1 1.5 9 &amp; lt; 210 &amp; gt; 692 &amp; lt; 211 &amp; gt; PRT &amp; lt; 212 &amp; gt; 20

Homo sapiens &amp; lt; 213 &amp; gt; 99 1 35355Β1 9 &amp; lt; 400 &amp; gt;

Met Gly Thr Val Set 'Set' Arg Arg Ser Trp l ip Pro Leu Pro Leu Pro 5 15 10 5 1.

Leu Leu Leu. Leu Leu Leu Leu Gly Pro Ala Gly Ala Arg Ala Glu Glu 30 25 20 10

Asp Glu Asp Gly Asp Tyr G1.U Glu Leu Val leu Ala Leu Arg Ser Glu

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35

Glu Asp Gly Leu Ala Asp Ala Pro Glu His Gly Ala Thr Ala Thr Phe 60 55 50 1.5

His Arg Cys Ala Lys Asp Ρι'ο Trp Arg Leu, Pro Gly Thr Tyr Val Val 80 75 70 65

Val Leu Lys Glu Glu Thr His .Arg Ser Gin Sei 'Glu Arg Thr Ala Arg 20 100 35355Β1

Arg Leu Gin Ala Gin, Ala, Ala Arg, Arg Gly Tyr Leu Thr Lys lie Leu 1,10 105 100

His Val Phe His His Leu Leu Pro Gly Phe Leu Val Lys Met Set 'Gly 1.25 120 1,1.5

Asp Leu Leu Glu, Leu Ala Leu Lys Leu Pro His Val Asp Tyr Ile Glu 1-40 135 130

Glu Asp Ser Ser Val Phe Ala Gill Set 'll, e Pro Trp Asn Leu Giti Arg 160 155 150 1,45 fie Thr Pro .Ala Arg Tyr, Arg Ala Asp Glu Tyr Gin Pro Pro Lys Gly 175 1,70 1.65

Gly Ser Leu Val Glu Val Tyr Leu Leu Asp Thr Ser lie Gin Set 'Asp, 190 1.85 1-80

His Arg Glu Ile Glu Gly -Arg Val Met Val Thr Asp Plie Glu Ser Val

<img img-format="tif" img-content="drawing" file="MA-35355-B1D01021.tif" id="idf0010" />

<img img-format="tif" img-content="drawing" file="MA-35355-B1D01022.tif" id="idf0011" />

-1-95 10 1035355Β1

Pro Glu Glu Asp Gly Thr Arg Phe His .Arg Gin Aia Ser Lys Cys Asp 220 21-5 210

Ser His Gly Thr His Leu Ala Gly Val Val Set 'Gly .Arg Asp Ala Gly 240 235 230 225

Val Ala Lys Gly Ala Gly Leu Arg Ser Leu Arg Val Leu Asn Cys Gin 255 250 245

Gly Lys Gly Tlrr Val Ser Gly Thr Leu Ile Gly Leu Glu Phe Ile Arg 270 265 260 lys Ser Gin Leu Val. Gin Pro Val Gly Pro Leu Val Val. Leu Leu Pro 285 280 275

Leu Ala Gly Gly Tyr Ser Arg Val Phe Asn Ala. Ala Cys Gin Arg Leu 300 295 290

Ala Arg Ala Gly Val Vil! Leu Val Tlrr Ala. Ala Gly Asn Plie Ai'g Asp 320 3.1.5 310 305 102 102 1 35355Β1

Asp Aia Cys [; eu Tyr Ser Pro Ala Ser Ala Pro Glu Val Ile Thr Val. 335 330 325

Gly Ala Thr Asn Ala Gin Asp Gin Pro Val Thr Leu Gly Thr Leu Gly 5 35 () 345 340

Thr Asn Phe Gly Arg Cys Val Asp Leu Phe Ala Pro Gly Glu, Asp lie 365 360 355 10 lie Gly A0, a Ser Ser Asp Cys Ser Thr Cys Phe Val Ser Arg Ser Gly 375 370

Th.r Ser Gin Ala Ala Ala His Val Ala Gly lie Ala Ala Met Met L.eu 400 395 390 385 1.5

Ser Ala, Glu Pro Glu Leu Tltr Leu Ala Glu Leu Arg Gin Arg Leu lie 415 410 405

His Phe Se.r Ala Lys Asp Val lie Asn Glu. Ala Trp [ »he Pro Glu Asp 20 4.25 420 35355Β1 03 A (: 111; Arg Val Leu Thr Pro Asn Leu Val. Ala Ala Leu Pro Pro Ser Thr 445 440 435

His Arg A), a, Gly Τι'ρ Gin Leu Phe Cys Arg Tin 'Val Trp Ser Ala His 460 455 450

Ser Gly Pro Thr Arg Met Ala Tin 'Ala Val Ala Arg Cys Ala (Tin Asp 480 475 470 465

Glu Glu Leu Leu Ser Cys Ser Ser Phe Set 'Arg Ser Gly Lys Arg Arg 495 490 485

Gly Glu Arg Ile Glu Ala (Tin Gly Gly Lys Arg Val Cys Arg Ala His 51.0 505 500

Asn. Ala .Phe Gly Gly Glu Gly Val Tyr Ala. lie Ala. Arg Cys Cys Leu. 525 520 515

Leu Pro Gin Val Asn Cys Ser Val His Tin 'Ala Pro Pro Ala Gly Ala. 540 535 530 104 35355Β1

Set. Met Gly Thr Arg Val His Cys His Gin Gin Gly His Val Lett Thr 560 555 550 545

Gly Cys Ser Ser His Trp Glu Val Glu Asp Leu Gly Thr His Lys Pro 575 570 565

Pro Val Leu Arg Pro Arg Gly Gin Pro Asn Gin Cys Val Gly His Arg 590

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<img img-format="tif" img-content="drawing" file="MA-35355-B1D01062.tif" id="idf0013" />

Glu Ala Ser lie His Ala Ser Cys Cys His Ala P't'o Gly Leu Glu Cys

<img img-format="tif" img-content="drawing" file="MA-35355-B1D01063.tif" id="idf0014" />

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595

Lys Val Lys Glu His Gly lie Pro Ala Pro Girt Glu Gin Val lie Val 620 615 61.0 .Ala Cys Glu ASP Gly Trp Tilt 'Leu Thr Gly' Cys Ser Pro Leu Pro Gly

<img img-format="tif" img-content="drawing" file="MA-35355-B1D01065.tif" id="idf0016" />

630 625

Thr Ser His Val Leu Gly Ala Tyr Ala Val Asp Asn Thr Cys Val Val 655 650 645 35355Β1

<img img-format="tif" img-content="drawing" file="MA-35355-B1D01071.tif" id="idf0017" />

Arg Ser Arg Asp Val Ser Thr Thr Gly Ser Thr Ser Lys Giu Ala Val 670 665 660 .Ala Ala Val Ala. lie Cys Gys Arg Ser Arg His Leu Va.1. Gin Ala Sei '685 680 675

Gin Glu. Leu Glir 690