Compositions comprising irna agents, pharmaceutical formulations comprising same and use thereof in the manufacture of medicaments for reducing the levels of a respiratory syncytial virus (rsv) protein, rsv mrna or rsv titer

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COMPOSITIONS COMPRISING iRNA AGENTS, PHARMACEUTICAL FORMULATIONS

COMPRISING SAME AND USE THEREOF IN THE MANUFACTURE OF MEDICAMENTS FOR REDUCING THE LEVELS OF A RESPIRATORY SYNCYTIAL VIRUS (RSV) PROTEIN, RSV mRNA OR RSV TITER 184162/2

TECHNICAL FIELD

The invention relates to the field of respiratory syncytial viral (RSV) therapy and compositions and methods for modulating viral replication, and more particularly to the down- 5 regulation of a gene(s) of a respiratory syncytial virus by oligonucleotides via RNA interference which are administered locally to the lungs and nasal passage via inhalation/intranasally or systemically via injection/intravenous.

BACKGROUND

By virtue of its natural function the respiratory tract is exposed to a slew of airborne 10 pathogens that cause a variety of respiratory ailments. Viral infection of the respiratory tract is the most common cause of infantile hospitalization in the developed world with an estimated 91,000 annual admissions in the US at a cost of $300 M. Human respiratory syncytial virus (RSV) and parainfluenza virus (PIV) are two major agents of respiratory illness; together, they infect the upper and lower respiratory tracts, leading to croup, pneumonia and bronchiolitis 15 (Openshaw, P.J.M.. Respir. Res. 3 (Suppl 1), S15-S20 (2002), Easton, A.J., et al., Clin.

Microbiol. Rev. 17, 390-412 (2004)). RSV alone infects up to 65% of all babies within the first year of life, and essentially all within the first 2 years. It is a significant cause of morbidity and mortality in the elderly as well. Immunity after RSV infection is neither complete nor lasting, and therefore, repeated infections occur in all age groups. Infants experiencing RSV 20 bronchiolitis are more likely to develop wheezing and asthma later in life. Research for effective treatment and vaccine against RSV has been ongoing for nearly four decades with few successes (Openshaw, P.J.M.. Respir. Res. 3 (Suppl 1), S15-S20 (2002), Maggon, K. et al, Rev. Med. Virol. 1 WO 2006/074346 PCT/US2006/000425 14,149-168 (2004)). Currently, no vaccine is clinically approved for either RSV. Strains ofboth viruses also exist for nonhuman animals such as the cattle, goat, pig and sheep, causing loss to agriculture and the dairy and meat industry (Easton, A.J., et al., Clin. Microbiol. Rev. Yl, 390-412 (2004)). 5 Both RSV contain nonsegmented negative-strand RNA genomes and belong to the

Paramyxoviridae family. A number of features of these viruses have contributed to the difficulties of prevention and therapy. The viral genomes mutate at a high rate due to the lack of a replicational proof-reading mechanism of the RNA genomes, presenting a significant challenge in designing a reliable vaccine or antiviral (Sullender, W.M. Clin. Microbiol. Rev. 13,1-15 10 (2000)). Promising inhibitors of the RSV fusion protein (F) were abandoned partly because the virus developed resistant mutations that were mapped to the F gene (Razinkov, V, et. al., Antivir. Res. 55,189-200 (2002), Morton, C.J. et al. Virology 311,275-288 (2003)). Both viruses associate with cellular proteins, adding to the difficulty of obtaining cell-free viral material for vaccination (Burke, E., et al., Virology 252,137-148 (1998), Burke, E., et al., J. Virol. 74,669- 15 675 (2000), Gupta, S., et al., J. Virol. 72,2655-2662 (1998)). Finally, the immunology ofboth, and especially that of RSV, is exquisitely complex (Peebles, R.S., Jr., et al., Viral. Immunol. 16, 25-34 (2003), Haynes, L.M., et al., J. Virol. 77, 9831-9844 (2003)). Use of denatured RSV proteins as vaccines leads to "immunopotentiation" or vaccine-enhanced disease (Polack, F.P. et al. J. Exp. Med. 196, 859-865 (2002)). The overall problem is underscored by the recent closure 20 of a number of anti-RSV biopharma programs.

The RSV genome comprises a single strand of negative sense RNA that is 15,222 nucleotides in length and yields eleven major proteins. (Falsey, A. R., and Ε. E. Walsh, 2000, Clinical Microbiological Reviews 13:371-84.) Two of these proteins, the F (fusion) and G (attachment) glycoproteins, axe the major surface proteins and the most important for inducing 25 protective immunity. The SH (small hydrophobic) protein, the M (matrix) protein, and the M2 (22 kDa) protein are associated with the viral envelope but do not induce a protective immune response. The N (major nucleocapsid associated protein), P (phosphoprotein), and L (major polymerase protein) proteins are found associated with virion RNA. The two non-structural 2 WO 2006/074346 PCT/US2006/000425 proteins, NS 1 and NS2, presumably participate in host-virus interaction but are not present in infectious virions.

Human RSV strains have been classified into two major groups, A and B. The G glycoprotein has been shown to be the most divergent among RSV proteins. Variability of the 5 RSV G glycoprotein between and within the two RSV groups is believed to be important to the ability of RSV to cause yearly outbreaks of disease. The G glycoprotein comprises 289-299 amino acids (depending on RSV strain), and has an intracellular, transmembrane, and highly glycosylated stalk structure of 90 kDa, as well as heparin-binding domains. The glycoprotein exists in secreted and membrane-bound forms. 10 Successful methods of treating RSV infection are currently unavailable (Maggon K and S. Barik, 2004, Reviews in Medical Virology 14:149-68). Infection of the lower respiratory tract with RSV is a self-limiting condition in most cases. No definitive guidelines or criteria exist on how to treat or when to admit or discharge infants and children with the disease. Hypoxia, which can occur in association with RSV infection, can be treated with oxygen via a nasal cannula. 15 Mechanical ventilation for children with respiratory failure, shock, or recurrent apnea can lower mortality. Some physicians prescribe steroids. However, several studies have shown that steroid therapy does not affect the clinical course of infants and children admitted to the hospital with bronchiolitis. Thus corticosteroids, alone or in combination with bronchodilators, maybe useless in the management of bronchiolitis in otherwise healthy unventilated patients. In infants and 20 children with underlying cardiopulmonary diseases, such as bronchopulmonary dysphasia and asthma, steroids have also been used.

Ribavirin, a guanosine analogue with antiviral activity, has been used to treat infants and children with RSV bronchiolitis since the mid 1980s, but many studies evaluating its use have shown conflicting results. In most centers, the use of ribavirin is now restricted to 25 immunocompromised patients and to those who are severely ill.

The severity of RSV bronchiolitis has been associated with low serum retinol concentrations, but trials in hospitalized children with RSV bronchiolitis have shown that vitamin A supplementation provides no beneficial effect. Therapeutic trials of 1500 mg/kg 3 184162/2 intravenous RSV immune globulin or 100 mg/kg inhaled immune globulin for RSV lower-respiratory-tract infection have also failed to show substantial beneficial effects.

In developed countries, the treatment of RSV lower-respiratory-tract infection is generally limited to symptomatic therapy. Antiviral therapy is usually limited to life-threatening 5 situations due to its high cost and to the lack of consensus on efficacy. In developing countries, oxygen is the main therapy (when available), and the only way to lower mortality is through prevention. RNA interference or “RNAi” is a term initially coined by Fire and co-workers to describe the observation that double-stranded RNA (dsRNA) can block gene expression when it is 10 introduced into worms (Fire etal., Nature 391:806-811,1998). Short dsRNA directs gene-specific, post-transcriptional silencing in many organisms, including vertebrates, and has provided a new tool for studying gene function. RNAi has been suggested as a method of developing a new class of therapeutic agents. However, to date, these have remained mostly as suggestions with no demonstrate proof that RNAi can be used therapeutically.

Zhang J. et al., Current Pharmaceutical Biotechnology, 2004, 5, 1-7, relates to targeted gene silencing by small interfering RNA-based knock-down technology.

Barik S., Virus Research, 2004, 102, 27-35, relates to control of nonsegmented negative strand RNA virus replication by siRNA. 20

Bitko V. et al., BMC Microbiology, 2001, 1, 1-11, relates to phenotypic silencing of cytoplasmic genes using sequence-specific double-stranded short interfering RNA and its application in the reverse genetics of wild type negative-strand RNA viruses. US 2004/0259247 relates to isolated double-stranded RNA molecules having from 19-25 25 nucleotides, capable of target-specific nucleic acid modifications. WO 98/12312 relates to antisense gene therapy for RNA viruses, and discloses vectors and methods for treating a respiratory syncytial virus infection. US 6,214,805 relates to RNase L activators and antisense oligonucleotides effective to treat RSV infections. 4 184162/1 WO 2004/090108 relates to therapeutic sRNA agents and methods of making and using the same.

Therefore, there is a need for safe and effective vaccines against RSV, especially for infants and children. There is also a need for therapeutic agents and methods for treating RSV infection at all ages and in immuno-compromised individuals. There is also a need for scientific methods to characterize the protective immune response to RSV so that the pathogenesis of the disease can be studied, and screening for therapeutic agents and vaccines can be facilitated. The present invention overcomes previous shortcomings in tlie art by providing methods and compositions effective for modulating or preventing RSV infection. Specifically, the present invention advances the art by providing iRNA agents that have been shown to reduce RSV levels in vitro and in vivo, as well as being effective against both major subtypes of RSV, and a showing of therapeutic activity of this class of molecules.

SUMMARY

The present invention relates to a composition comprising an iRNA agent, wherein the iRNA agent comprises a sense strand and an antisense strand, wherein the sense strand consists of SEQ ID NO: 267 and the antisense strand consists of SEQ ID NO: 268.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is based on the in vitro and in vivo demonstration that RSV can be inhibited through intranasal administration of iRNA agents, as well as by parenteral 4a WO 2006/074346 PCT/US2006/000425 administration of such agents, and the identification of potent iRNA agents from the P, N and L gene of RSV that can reduce RNA levels with both the A and B subtype of RSV. Based on these findings, the present invention provides specific compositions and methods that are useful in reducing RSV mRNA levels, RSV protein levels and RSV viral titers in a subject, e.g., a 5 mammal, such as a human.

The present invention specifically provides iRNA agents consisting of, consisting essentially of or comprising at least 15 or more contiguous nucleotides of one of the genes of RSV, particularly the P, N and L genes of RSV, and more particularly agents that comprising 15 or more contiguous nucleotides from one of the sequence provided in Table 1 (a-c). The iRNA 10 agent preferably consists of less than 30 nucleotides per strand, e.g., 21-23 nucleotides, such as those provided in Tables 1 (a-c). The double stranded iRNA agent can either have blunt ends or more preferably have overhangs of 1 -4 nucleotides from one or both 3’ ends of the agent.

Further, the iRNA agent can either contain only naturally occurring ribonucleotide subunits, or can be synthesized so as to contain one or more modifications to the sugar or base of 15 one or more of the ribonucleotide subunits that is included in the agent. The iRNA agent can be further modified so as to be attached to a ligand that is selected to improve stability, distribution or cellular uptake of the agent, e.g. cholesterol. The iRNA agents can further be in isolated form or can be part of a pharmaceutical composition used for the methods described herein, particularly as a pharmaceutical composition formulated for delivery to the lungs or nasal 20 passage or formulated for parental administration. The pharmaceutical compositions can contain one or more iRNA agents, and in some embodiments, will contain two or more iRNA agents, each one directed to a different seqment of a RSV gene or to two different RSV genes.

The present invention further provides methods for reducing the level of RSV viral mRNA in a cell. Such methods comprise the step of administering one of the iRNA agents of the 25 present invention to a subject as further described below. The present methods utilize the cellular mechanisms involved in RNA interference to selectively degrade the viral mRNA in a cell and are comprised of the step of contacting a cell with one of the antiviral iRNA agents of the present invention. Such methods can be performed directly on a cell or can be performed on a 5 WO 2006/074346 PCT/US2006/000425 mammalian subject by administering to a subject one of the iRNA agents/pharmaceutical compositions of the present invention. Reduction of viral mRNA in a cells results in a reduction in the amount of viral protein produced, and in an organism, results in a decrease in replicating viral titer (as shown in the Examples). 5 The methods and compositions of the invention, e.g., tire methods and iRNA agent compositions can be used with any dosage and/or formulation described herein, as well as with any route of administration described herein. Particularly important is the showing herein of intranasal administration of an iRNA agent and its ability to inhibit viral replication in respiratory tissues. 10 The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from this description, the drawings, and from the claims. This application incorporates all cited references, patents, and patent applications by references in their entirety for all purposes.

15 BRIEF DESCRIPTION OF DRAWINGS FIG. 1: In vitro inhibition of RSV using iRNA agents. iRNA agents provided in Table 1 (a-c) were tested for anti-RSV activity in a plaque formation assay as described in the Examples. Each column (bar) represents an iRNA agent provided in Table 1 (a-c), e.g. column 1 is the first agent in Table la etc. Active iRNA agents were identified. 20 FIG. 2: In vitro dose response inhibition of RSV using iRNA agents. Examples of active agents from Table 1 were tested for anti-RSV activity in a plaque formation assay as described in the Examples at four concentrations. A dose dependent response was found with active iRNA agent tested. FIG. 3: In vitro inhibition of RSV B subtype using iRNA agents. iRNA agents provided 25 in FIG. 2 were tested for anti-RSV activity against subtype B in a plaque formation assay as described in the Examples. Subtype B was inhibited by the iRNA agents tested. 6 WO 2006/074346 PCT/US2006/000425 FIG. 4: In vivo inhibition of RSV using iRNA agents. Agents as described in the figure were tested for anti-RSV activity in a mouse model as described in the Examples. The iRNA agents were effective at reducing viral titers in vivo. FIG. 5: In vivo inhibition of RSV using AL-DP-1730. AL-DP-1730 was tested for dose 5 dependent activity using the methods provided in the Examples. The agents showed a dose dependent response. FIG. 6: In vivo inhibition of RSV using iRNA agents. iRNA agents described in the Figure were tested for anti-RSV activity in vivo as described in the Examples. FIG. 7: In vivo inhibition of RSV using iRNA agents. iRNA agents described in the 10 Figure were tested for anti-RSV activity in vivo as described in the Examples. FIG. 8 A: In vivo inhibition of RSV using iRNA agents delivered topically. FIG. 8B: In vivo inhibition of RSV using iRNA agents delivered via aerosol. iRNA agents described in the Figure were tested for anti-RSV activity in vivo as described in the Example. 15 FIG. 9: In vivo protection against RSV infection using iRNA agents. iRNA agents described in the Figure were tested prior to RSV challenge to test for protective activity.

DETAILED DESCRIPTION

For ease of exposition the term "nucleotide" or "ribonucleotide" is sometimes used herein in reference to one or more monomeric subunits of an RNA agent. It will be understood that the 20 usage of the term “ribonucleotide” or “nucleotide” herein can, in the case of a modified RNA or nucleotide surrogate, also refer to a modified nucleotide, or surrogate replacement moiety, as further described below, at one or more positions.

An “RNA agent” as used herein, is an unmodified RNA, modified RNA, or nucleoside surrogate, all of which are described herein or are well known in the RNA synthetic art. While 25 numerous modified RNAs and nucleoside surrogates are described, preferred examples include 7 WO 2006/074346 PCT/US2006/000425 those which have greater resistance to nuclease degradation than do unmodified RNAs.

Preferred examples include those that have a 2’ sugar modification, a modification in a single strand overhang, preferably a 3’ single strand overhang, or, particularly if single stranded, a 5’-modification which includes one or more phosphate groups or one or more analogs of a 5 phosphate group.

An “iRNA agent” (abbreviation for “interfering RNA agent”) as used herein, is an RNA agent, which can down-regulate the expression of a target gene, e.g., RSV. While not wishing to be bound by theory, an iRNA agent may act by one or more of a number of mechanisms, including post-transcriptional cleavage of a target mRNA sometimes referred to in the art as 10 RNAi, or pre-transcriptional or pre-translational mechanisms. An iRNA agent can be a double stranded (ds) iRNA agent. A "ds iRNA agent" (abbreviation for “double stranded iRNA agent”), as used herein, is an iRNA agent which includes more than one, and preferably two, strands in which interchain hybridization can form a region of duplex structure. A "strand" herein refers to a contigouous 15 sequence of nucleotides (including non-naturally occurring or modified nucleotides). The two or more strands may be, or each form a part of, separate molecules, or they may be covalently interconnected, e.g. by a linker, e.g. a polyethyleneglycol linker, to form but one molecule. At least one strand can include a region which is sufficiently complementary to a target RNA. Such strand is termed the "antisense strand". A second strand comprised in the dsRNA agent which 20 comprises a region complementary to the antisense strand is termed the "sense strand".

However, a ds iRNA agent can also be formed from a single RNA molecule which is, at least partly; self-complementary, forming, e.g., a hairpin or panhandle structure, including a duplex region. In such case, the term "strand" refers to one of the regions of the RNA molecule that is complementary to another region of the same RNA molecule. 25 Although, in mammalian cells, long ds iRNA agents can induce the interferon response which is frequently deleterious, short ds iRNA agents do not trigger the interferon response, at least not to an extent that is deleterious to the cell and/or host. The iRNA agents of the present invention include molecules which are sufficiently short that they do not trigger a deleterious 8 WO 2006/074346 PCT/US2006/000425

interferon response in mammalian cells. Thus, the administration of a composition of an iRNA agent (e.g., formulated as described herein) to a mammalian cell can be used to silence expression of an RSV gene while circumventing a deleterious interferon response. Molecules that are short enough that they do not trigger a deleterious interferon response are termed siRNA 5 agents or siRNAs herein. “siRNA agent" or "siRNA" as used herein, refers to an iRNA agent, e.g., a ds iRNA agent, that is sufficiently short that it does not induce a deleterious interferon response in a human cell, e.g., it has a duplexed region of less than 30 nucleotide pairs.

The isolated iRNA agents described herein, including ds iRNA agents and siRNA agents, can mediate silencing of a gene, e.g., by RNA degradation. For convenience, such RNA is also 10 referred to herein as the RNA to be silenced. Such a gene is also referred to as a target gene. Preferably, the RNA to be silenced is a gene product of an RSV gene, particularly the P, N or L gene product.

As used herein, the phrase “mediates RNAi” refers to the ability of an agent to silence, in a sequence specific manner, a target gene. "Silencing a target gene" means the process whereby 15 a cell containing and/or secreting a certain product of the target gene when not in contact with the agent, will contain and/or secret at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% less of such gene product when contacted with the agent, as compared to a similar cell which has not been contacted with the agent. Such product of the target gene can, for example, be a messenger RNA (mRNA), a protein, or a regulatory element. 20 In the anti viral uses of the present invention, silencing of a target gene will result in a reduction in “viral titer” in the cell or in the subject. As used herein, “reduction in viral titer” refers to a decrease in the number of viable virus produced by a cell or found in an organism undergoing the silencing of a viral target gene. Reduction in the cellular amount of virus produced will preferably lead to a decrease in the amount of measurable virus produced in the 25 tissues of a subject undergoing treatment and a reduction in the severity of the symptoms of the viral infection. iRNA agents of the present invention are also referred to as “antiviral iRNA agents”. 9 WO 2006/074346 PCT/US2006/000425

As used herein, a “RSV gene” refers to any one of the genes identified in the RSV virus genome (See Falsey, A. R., and Ε. E. Walsh, 2000, Clinical Microbiological Reviews 13:371-84). These genes are readily known in the art and include the N, P and L genes which are exemplified herein. 5 As used herein, the term “complementary” is used to indicate a sufficient degree of complementarity such that stable and specific binding occurs between a compound of the invention and a target RNA molecule, e.g. an RSV viral mRNA molecule. Specific binding requires a sufficient degree of complementarity to avoid non-specific binding of the oligomeric compound to non-target sequences under conditions in which specific binding is desired, i.e., 10 under physiological conditions in the case of in vivo assays or therapeutic treatment, or in the case of in vitro assays, under conditions in which the assays are performed. The non-target sequences typically differ by at least 4 nucleotides.

As used herein, an iRNA agent is “sufficiently complementary” to a target RNA, e.g., a target mRNA (e.g., a target RSV mRNA) if the iRNA agent reduces the production of a protein 15 encoded by the target RNA in a cell. The iRNA agent may also be “exactly complementary” to the target RNA, e.g., the target RNA and the iRNA agent anneal, preferably to form a hybrid made exclusively of Watson-Crick base pairs in the region of exact complementarity. A “sufficiently complementary” iRNA agent can include an internal region (e.g., of at least 10 nucleotides) that is exactly complementary to a target viral RNA. Moreover, in some 20 embodiments, the iRNA agent specifically discriminates a single-nucleotide difference. In this case, the iRNA agent only mediates RNAi if exact complementarity is found in the region (e.g., within 7 nucleotides of) the single-nucleotide difference. Preferred iRNA agents will be based on or consist or comprise the sense and antisense sequences provided in the Examples.

As used herein, "essentially identical" when used referring to a first nucleotide sequence 25 in comparison to a second nucleotide sequence means that the first nucleotide sequence is identical to the second nucleotide sequence except for up to one, two or three nucleotide substitutions (e.g. adenosine replaced by uracil). 10 WO 2006/074346 PCT/US2006/000425

As used herein, a “subject” refers to a mammalian organism undergoing treatment for a disorder mediated by viral expression, such as RSV infection or undergoing treatment prophylactically to prevent viral infection. The subject can be any mammal, such as a primate, cow, horse, mouse, rat, dog, pig, goat. In the preferred embodiment, the subject is a human. 5 As used herein, treating RSV infection refers to the amelioration of any biological or pathological endpoints that 1) is mediated in part by the presence of the virus in the subject and 2) whose outcome can be affected by reducing the level of viral gene products present.

Design and Selection of iRNA agents

The present invention is based on the demonstration of target gene silencing of a 10 respiratory viral gene in vivo following local administration to the lungs and nasal passage of an iRNA agent either via intranasal administration/inhalation or systemically/parenterally via injection and the resulting treatment of viral infection. The present invention is further extended to the use of iRNA agents to more than one respiratory virus and the treatment of both virus infections with co-administration of two or more iRNA agents. 15 Based on these results, the invention specifically provides an iRNA agent that can be used in treating viral infection, particularly respiratory viruses and in particular RSV infection, in isolated form and as a pharmaceutical composition described below. Such agents will include a sense strand having at least 15 or more contiguous nucleotides that are complementary to a viral gene and an antisense strand having at least 15 or more contiguous nucleotides that are 20 complementary to the sense strand sequence. Particularly useful are iRNA agents that consist of, consist essentially of or comprise a nucleotide sequence from the P N and L gene of RSV as provided in Table 1 (a-c).

The iRNA agents of the present invention are based on and comprise at least 15 or more contiguous nucleotides from one of the iRNA agents shown to be active in Table 1 (a-c). In such 25 agents, the agent can consist of consist essentially of or comprise the entire sequence provided in the table or can comprise 15 or more contiguous residues provided in Tablela-c along with additional nucleotides from contiguous regions of the target gene. 11 WO 2006/074346 PCT/US2006/000425

An iRNA agent can be rationally designed based on sequence information and desired characteristics and the information provided in Table 1 (a-c). For example, an iRNA agent can be designed according to sequence of the agents provided in the Tables as well as in view of the entire coding sequence of the target gene. 5 Accordingly, the present invention provides iRNA agents comprising a sense strand and antisense strand each comprising a sequence of at least 15,16,17,18,19,20,21 or 23 nucleotides which is essentially identical to, as defined above, a portion of a gene from a respiratory virus, particularly the P, N or L protein genes of RSV. Exemplified iRNA agents include those that comprise 15 or more contiguous nucleotides from one of the agents provided 10 in Table 1 (a-c).

The antisense strand of an iRNA agent should be equal to or at least, 15,16 17,18,19, 25,29, 40, or 50 nucleotides in length. It should be equal to or less than 50,40, or 30, nucleotides in length. Preferred ranges are 15-30,17 to 25,19 to 23, and 19 to 21 nucleotides in length. Exemplified iRNA agents include those that comprise 15 or more nucleotides from one 15 of the antisense strands of one of the agents in Table 1 (a-c).

The sense strand of an iRNA agent should be equal to or at least 15,16 17,18,19,25,29, 40, or 50 nucleotides in length. It should be equal to or less than 50, 40, or 30 nucleotides in length. Preferred ranges are 15-30,17 to 25,19 to 23, and 19 to 21 nucleotides in length. Exemplified iRNA agents include those that comprise 15 or more nucleotides from one of the 20 sense strands of one of the agents in Table 1 (a-c).

The double stranded portion of an iRNA agent should be equal to or at least, 15,16 17, 18, 19, 20, 21, 22, 23, 24, 25,29, 40, or 50 nucleotide pairs in length. It should be equal to or less than 50, 40, or 30 nucleotides pairs in length. Preferred ranges are 15-30,17 to 25,19 to 23, and 19 to 21 nucleotides pairs in length. 25 The agents provided in Table 1 (a-c) are 21 nucleotide in length for each strand. The iRNA agents contain a 19 nucleotide double stranded region with a 2 nucleotide overhang on each of the 3’ ends of the agent. These agents can be modified as described herein to obtain 12 WO 2006/074346 PCT/US2006/000425 equivalent agents comprising at least a portion of these sequences (15 or more contiguous nucleotides) and or modifications to the oligonucleotide bases and linkages.

Generally, the iRNA agents of the instant invention include a region of sufficient complementarity to the viral gene, e.g. the P, N or L protein of RSV, and are of sufficient length

5 in terms of nucleotides, that the iRNA agent, or a fragment thereof, can mediate down regulation of the specific viral gene. The antisense strands of the iRNA agents of the present invention are preferably fully complementary to the mRNA sequences of viral gene, as is herein for the P, L or N proteins of RSV. However, it is not necessary that there be perfect complementarity between the iRNA agent and the target, but the correspondence must be sufficient to enable the iRNA 10 agent, or a cleavage product thereof, to direct sequence specific silencing, e.g., by RNAi cleavage of an RSV mRNA.

Therefore, the iRNA agents of the instant invention include agents comprising a sense strand and antisense strand each comprising a sequence of at least 16,17 or 18 nucleotides which is essentially identical, as defined below, to one of the sequences of a viral gene, particularly the 15 P, N or L protein of RSV, such as those agent provided in Table 1 (a-c), except that not more than 1,2 or 3 nucleotides per strand, respectively, have been substituted by other nucleotides (e.g. adenosine replaced by uracil), while essentially retaining the ability to inhibit RSV expression in cultured human cells, as defined below. These agents will therefore possess at least 15 or more nucleotides identical to one of the sequences of a viral gene, particularly the P, 20 L or N protein gene of RSV, but 1, 2 or 3 base mismatches with respect to either the target viral mRNA sequence or between the sense and antisense strand are introduced. Mismatches to the target viral mRNA sequence, particularly in the antisense strand, are most tolerated in the terminal regions and if present are preferably in a terminal region or regions, e.g., within 6,5,4, or 3 nucleotides of a 5’ and/or 3’ terminus, most preferably within 6, 5, 4, or 3 nucleotides of the 25 5'-terminus of the sense strand or the 3'-terminus of the antisense strand. The sense strand need only be sufficiently complementary with the antisense strand to maintain the overall double stranded character of the molecule. 13 WO 2006/074346 PCT/US2006/000425

It is prefened that the sense and antisense strands be chosen such that the iRNA agent includes a single strand or unpaired region at one or both ends of the molecule, such as those exemplified in Table 1 (a-c). Thus, an iRNA agent contains sense and antisense strands, preferably paired to contain an overhang, e.g., one or two 5’ or 3’ overhangs but preferably a 3'

5 overhang of 2-3 nucleotides. Most embodiments will have a 3’ overhang. Preferred siRNA agents will have single-stranded overhangs, preferably 3’ overhangs, of 1 to 4, or preferably 2 or 3 nucleotides, in length, on one or both ends of the iRNA agent. The overhangs can be the result of one strand being longer than the other, or the result of two strands of the same length being staggered. 5'-ends are preferably phosphorylated. 10 Preferred lengths for the duplexed region is between 15 and 30, most preferably 18,19, 20,21,22, and 23 nucleotides in length, e.g., in the siRNA agent range discussed above. Embodiments in which the two strands of the siRNA agent are linked, e.g., covalently linked are also included. Hairpin, or other single strand structures which provide the required double stranded region, and preferably a 3' overhang are also within the invention. 15 Evaluation of Candidate iRNA Agents A candidate iRNA agent can be evaluated for its ability to down regulate target gene expression. For example, a candidate iRNA agent can be provided, and contacted with a cell, e.g. a human cell, that has been infected with or will be infected with the virus of interest, e.g., a virus containing the target gene,. Alternatively, the cell can be transfected with a construct from 20 which a target viral gene is expressed, thus preventing the need for a viral infectivity model. The level of target gene expression prior to and following contact with the candidate iRNA agent can be compared, e.g. on an RNA, protein level or viral titer. If it is determined that the amount of RNA, protein or virus expressed from the target gene is lower following contact with the iRNA agent, then it can be concluded that the iRNA agent down-regulates target gene expression. The 25 level of target viral RNA or viral protein in the cell or viral titer in a cell or tissue can be determined by any method desired. For example, the level of target RNA can be determined by Northern blot analysis, reverse transcription coupled with polymerase chain reaction (RT-PCR), bDNA analysis, or RNAse protection assay. The level of protein can be determined, for 14 WO 2006/074346 PCT/US2006/000425 example, by Western blot analysis or immuno-fluorescence. Viral titer can be detected through a plaque formation assay.

Stability testing, modification, and retesting of iRNA agents A candidate iRNA agent can be evaluated with respect to stability, e.g., its susceptibility 5 to cleavage by an endonuclease or exonuclease, such as when the iRNA agent is introduced into the body of a subject. Methods can be employed to identify sites that are susceptible to modification, particularly cleavage, e.g., cleavage by a component found in the body of a subject.

When sites susceptible to cleavage are identified, a further iRNA agent can be designed and/or synthesized wherein the potential cleavage site is made resistant to cleavage, e.g. by 10 introduction of a 2'-modification on the site of cleavage, e.g. a 2'-O-methyl group. This further iRNA agent can be retested for stability, and this process may be iterated until an iRNA agent is found exhibiting the desired stability.

In Vivo Testing

An iRNA agent identified as being capable of inhibiting viral gene expression can be 15 tested for functionality in vivo in an animal model (e.g., in a mammal, such as in mouse, rat or primate) as shown in the examples. For example, the iRNA agent can be administered to an animal, and the iRNA agent evaluated with respect to its biodistribution, stability, and its ability to inhibit viral, e.g. RSV, gene expression or reduce viral titer.

The iRNA agent can be administered directly to the target tissue, such as by injection, or 20 the iRNA agent can be administered to the animal model in the same manner that it would be administered to a human. As shown herein, the agent can be preferably administered via inhalation as a means of treating viral infection.

The iRNA agent can also be evaluated for its intracellular distribution. The evaluation can include detennining whether the iRNA agent was taken up into the cell. The evaluation can 25 also include determining the stability (e.g., the half-life) of the iRNA agent. Evaluation of an iRNA agent in vivo can be facilitated by use of an iRNA agent conjugated to a traceable marker 15 WO 2006/074346 PCT/US2006/000425 (e.g., a fluorescent marker such as fluorescein; a radioactive label, such as 35S, 32P, 33Ρ,όγ 3H; gold particles; or antigen particles for immunohistochemistry) or other suitable detection method.

The iRNA agent can be evaluated with respect to its ability to down regulate viral gene expression. Levels of viral gene expression in vivo can be measured, for example, by in situ 5 hybridization, or by the isolation of RNA from tissue prior to and following exposure to the iRNA agent. Where the animal needs to he sacrificed in order to harvest the tissue, an untreated control animal will serve for comparison. Target viral mRNA can be detected by any desired method, including but not limited to RT-PCR, Northern blot, branched-DNA assay, or RNAase protection assay. Alternatively, or additionally, viral gene expression can be monitored by 10 performing Western blot analysis on tissue extracts treated with the iRNA agent or by ELISA. Viral titer can be determined using a pfu assy. iRNA Chemistry

Described herein are isolated iRNA agents, e.g., ds RNA agents, that mediate RNAi to inhibit expression of a viral gene, e.g. the P protein of RSV. 15 RNA agents discussed herein include otherwise unmodified RNA as well as RNA which have been modified, e.g., to improve efficacy, and polymers of nucleoside surrogates. Unmodified RNA refers to a molecule in which the components of the nucleic acid, namely sugars, bases, and phosphate moieties, are the same or essentially the same as that which occur in nature, preferably as occur naturally in the human body. The art has referred to rare or unusual, 20 but naturally occurring, RNAs as modified RNAs, see, e.g., Limbach et al., (1994) Nucleic Acids Res. 22: 2183-2196. Such rare or unusual RNAs, often termed modified RNAs (apparently because these are typically the result of a post-transcriptional modification) are within the term unmodified RNA, as used herein. Modified RNA as used herein refers to a molecule in which one or more of the components of the nucleic acid, namely sugars, bases, and phosphate 25 moieties, are different from that which occurs in nature, preferably different from that which occurs in the human body. While they are referred to as modified “RNAs,” they will of course, because of the modification, include molecules which are not RNAs. Nucleoside surrogates are molecules in which the ribophosphate backbone is replaced with a non-ribophosphate construct 16 184162/2 that allows the bases to the presented in the correct spatial relationship such that hybridization is substantially similar to what is seen with a ribophosphate backbone, e.g., non-charged mimics of the ribophosphate backbone. Examples of each of the above are discussed herein.

Modifications described herein can be incorporated into any double-stranded RNA and RNA-like molecule described herein, e.g., an iRNA agent It may be desirable to modify one or both of the antisense and sense strands of an iRNA agent. As nucleic acids are polymers of subunits or monomers, many of the modifications described below occur at a position which is repeated within a nucleic acid, e.g., a modification of a base, or a phosphate moiety, or the nonlinking 0 of a phosphate moiety. In some cases the modification will occur at all of the subject positions in the nucleic acid but in many, and in fact in most, cases it will not. By way of example, a modification may only occur at a 3’ or 5’ terminal position, may only occur in a terminal region, e.g. at a position on a terminal nucleotide or in tlie last 2,3,4,5, or 10 nucleotides of a strand. A modification may occur in a double strand region, a single strand region, or in both. E.g., a phosphorothioate modification at a non-linking 0 position may only occur at one or both termini, may only occur in a terminal regions, e.g., at a position on a terminal nucleotide or in the last 2,3,4, 5, or 10 nucleotides of a strand, or may occur in double strand and single strand regions, particularly at termini. Similarly, a modification may occur on the sense strand, antisense strand, or both, hi some cases, the sense and antisense strand will have the same modifications or tlie same class of modifications, but in other cases the sense and antisense strand will have different modifications, e.g., in some cases it may be desirable to modify only one strand, e.g. the sense strand.

Two prime objectives for tlie introduction of modifications into iRNA agents is their stabilization towards degradation in biological environments and the improvement of pharmacological properties, e.g. pharmacodynamic properties, which are further discussed below. Other suitable modifications to a sugar, base, or backbone of an iRNA agent are described in co-owned WO 2004/064737 January 16,2004. An iRNA agent can include a non-naturally occurring base, such as the bases described in co-owned WO 2004/094345 filed April 16, 2004. An iRNA agent can include a non-naturally occurring sugar, such as a non-carbohydrate cyclic carrier molecule. Exemplary 17 184162/2 features of non-naturally occurring sugars for use in iRNA agents are described, in co-owned WO 2004/094595 filed April 16,2003.

An iRNA agent can include an intemucleotide linkage (e.g., the chiral phosphorothioate linkage) useful for increasing nuclease resistance. In addition, or in die alternative, an iRNA 5 agent can include a ribose mimic for increased nuclease resistance. Exemplary intemucleotide linkages and ribose mimics for increased nuclease resistance are described in co-owned WO 2004/080406 Sled on March 8,2004.

An iRNA agent can include ligand-conjugated monomer subunits and monomers for oligonucleotide synthesis. Exemplary monomers are described in co-owned U.S. 7,745,608, 10 filed on August 10,2004.

An iRNA agent can have a ZXY structure, such as is described in co-owned WO 2004/080406 filed on March 8,2004.

An iRNA agent can be complexed with an amphipathic moiety. Exemplary amphipathic moieties for use with iRNA agents are described in co-owned WO 2004/080406 15 filed on March 8,2004.

In another embodiment, the iRNA agent can be complexed to a delivery agent that features a modular complex. The complex can include a carrier agent linked to one or more of (preferably two or more, more preferably all three of): (a) a condensing agent (e.g., an agent capable of attracting, e.g., binding, a nucleic acid, e.g., through ionic or electrostatic 20 interactions); (b) a fusogenic agent (e.g., an agent capable of fusing and/or being transported through a cell membrane); and (c) a targeting group, e.g., a cell or tissue targeting agent, e.g., a lectin, glycoprotein, lipid or protein, e.g., an antibody, that binds to a specified cell type. iRNA agents complexed to a delivery agent are described in co-owned WO 2004/080406 filed on March 8,2004. 25 An iRNA agent can have non-canonical pairings, such as between the sense and antisense sequences of the iRNA duplex. Exemplary features of non-canonical iRNA agents are described in co-owned WO 2004/080406 filed on March 8,2004. 18 WO 2006/074346 PCT/US2006/000425

Enhanced nuclease resistance

An iRNA agent, e.g., an iRNA agent that targets RSV, can have enhanced resistance to nucleases.

For increased nuclease resistance and/or binding affinity to the target, an iRNA agent, 5 e.g., the sense and/or antisense strands of the iRNA agent, can include, for example, 2'-modified ribose units and/or phosphorothioate linkages. E.g., the 2' hydroxyl group (OH) can be modified or replaced with a number of different “oxy” or “deoxy” substituents.

Examples of “oxy”-2' hydroxyl group modifications include alkoxy or aryloxy (OR, e.g., R = H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or sugar); polyethyleneglycols (PEG), 10 O(CH2CH2O)nCH2CH2OR; “locked” nucleic acids (LNA) in which the 2' hydroxyl is connected, e.g., by a methylene bridge, to the 4' carbon of the same ribose sugar; O-AMINE and aminoalkoxy, O(CH2)nAMINE, (e.g., AMINE = NH2; alkylamino, dialkylamino, heterocyclyl amino, arylamino, diaryl amino, heteroaryl amino, or diheteroaryl amino, ethylene diamine, polyamino). It is noteworthy that oligonucleotides containing only the methoxyethyl group 15 (MOE), (OCH2CH2OCH3, a PEG derivative), exhibit nuclease stabilities comparable to those modified with the robust phosphorothioate modification. “Deoxy” modifications include hydrogen (i.e. deoxyribose sugars, which are of particular relevance to the overhang portions of partially ds RNA); halo (e.g., fluoro); amino (e.g. NH2; alkylamino, dialkylamino, heterocyclyl, arylamino, diaryl amino, heteroaryl amino, diheteroaryl 20 amino, or amino acid); NH(CH2CH2NH)nCH2CH2-AMINE (AMINE = NH2; alkylamino, dialkylamino, heterocyclyl amino, arylamino, diaryl amino, heteroaryl amino,or diheteroaryl amino), -NHC(O)R (R = alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or sugar), cyano; mercapto; alkyl-thio-alkyl; thioalkoxy; and alkyl, cycloalkyl, aryl, alkenyl and alkynyl, which may be optionally substituted with e.g., an amino functionality. 25 Preferred substitutents are 2'-methoxyethyl, 2'-OCH3,2'-O-allyl, 2'-C- allyl, and 2'- fluoro. 19 WO 2006/074346 PCT/US2006/000425

One way to increase resistance is to identify cleavage sites and modify such sites to inhibit cleavage, as described in co-owned U.S. Application No. 60/559,917, filed on May 4, 2004. For example, the dinucleotides 5’-UA-3’, 5’-UG-3’, 5’-CA-3’, 5’-UU-3’, or 5’-CC-3’ can serve as cleavage sites. Enhanced nuclease resistance can therefore be achieved by modifying 5 the 5’ nucleotide, resulting, for example, in at least one 5’-uridine-adenine-3’ (5’-UA-3’) dinucleotide wherein the uridine is a 2’-modified nucleotide; at least one 5’-uridine-guanine-3’ (5’-UG-3’) dinucleotide, wherein the 5’-uridine is a 2’-modified nucleotide; at least one 5’-cytidine-adenine-3’ (5’-CA-3’) dinucleotide, wherein the 5’-cytidine is a 2’-modified nucleotide; at least one 5’-uridine-uridine-3’ (5’-UU-3’) dinucleotide, wherein the 5’-uridine is a 2’-modified 10 nucleotide; or at least one 5’-cytidine-cytidine-3’ (5’-CC-3’) dinucleotide, wherein the 5’- cytidine is a 2’-modified nucleotide. The iRNA agent can include at least 2, at least 3, at least 4 or at least 5 of such dinucleotides. In certain embodiments, all the pyrimidines of an iRNA agent carry a 2'-modification, and the iRNA agent therefore has enhanced resistance to endonucleases.

To maximize nuclease resistance, the 2' modifications can be used in combination with 15 one or more phosphate linker modifications (e.g., phosphorothioate). The so-called “chimeric” oligonucleotides are those that contain two or more different modifications.

The inclusion of furanose sugars in the oligonucleotide backbone can also decrease endonucleolytic cleavage. An iRNA agent can be further modified by including a 3’ cationic group, or by inverting the nucleoside at the 3'-terminus with a 3’-3’ linkage. In another 20 alternative, the 3'-terminus can be blocked with an aminoalkyl group, e.g., a 3’ C5-aminoalkyl dT. Other 3’ conjugates can inhibit 3’-5’ exonucleolytic cleavage. While not being bound by theory, a 3’ conjugate, such as naproxen or ibuprofen, may inhibit exonucleolytic cleavage by sterically blocking the exonuclease from binding to the 3'-end of oligonucleotide. Even small alkyl chains, aryl groups, or heterocyclic conjugates or modified sugars (D-ribose, deoxyribose, 25 glucose etc.) can block 3’-5’-exonucleases.

Similarly, 5' conjugates can inhibit 5-3' exonucleolytic cleavage. While not being bound by theory, a 5' conjugate, such as naproxen or ibuprofen, may inhibit exonucleolytic cleavage by sterically blocking the exonuclease from binding to the 5'-end of oligonucleotide. Even small 20 WO 2006/074346 PCT/US2006/000425 alkyl chains, aryl groups, or heterocyclic conjugates or modified sugars (D-ribose, deoxyribose, glucose etc.) can block 3'-5'-exonucleases.

An iRNA agent can have increased resistance to nucleases when a duplexed iRNA agent includes a single-stranded nucleotide overhang on at least one end. In preferred embodiments, 5 the nucleotide overhang includes 1 to 4, preferably 2 to 3, unpaired nucleotides. In a preferred embodiment, the unpaired nucleotide of the single-stranded overhang that is directly adjacent to the terminal nucleotide pair contains a purine base, and the terminal nucleotide pair is a G-C pair, or at least two of the last four complementary nucleotide pairs are G-C pairs. In further embodiments, the nucleotide overhang may have 1 or 2 unpaired nucleotides, and in an 10 exemplary embodiment the nucleotide overhang is 5’-GC-3’. In preferred embodiments, the nucleotide overhang is on the 3'-end of the antisense strand. In one embodiment, the iRNA agent includes the motif 5'-CGC-3' on the 3'-end of the antisense strand, such that a 2-nt overhang 5'-GC-3' is formed.

Thus, an iRNA agent can include modifications so as to inhibit degradation, e.g., by 15 nucleases, e.g., endonucleases or exonucleases, found in the body of a subject. These monomers are referred to herein as NRMs, or Nuclease Resistance promoting Monomers, the corresponding modifications as NRM modifications. In many cases these modifications will modulate other properties of the iRNA agent as well, e.g., the ability to interact with a protein, e.g., a transport protein, e.g., serum albumin, or a member of the RISC, or the ability of the first and second 20 sequences to form a duplex with one another or to form a duplex with another sequence, e.g., a target molecule.

One or more different NRM modifications can be introduced into an iRNA agent or into a sequence of an iRNA agent. An NRM modification can be used more than once in a sequence or in an iRNA agent. 25 NRM modifications include some which can be placed only at the terminus and others which can go at any position. Some NRM modifications that can inhibit hybridization are preferably used only in terminal regions, and more preferably not at the cleavage site or in the cleavage region of a sequence which targets a subject sequence or gene, particularly on the 21 WO 2006/074346 PCT/US2006/000425 antisense strand. They can be used anywhere in a sense strand, provided that sufficient hybridization between the two strands of the ds iRNA agent is maintained. In some embodiments it is desirable to put the NRM at the cleavage site or in the cleavage region of a sense strand, as it can minimize off-target silencing. 5 In most cases, the NRM modifications will be distributed differently depending on whether they are comprised on a sense or antisense strand. If on an antisense strand, modifications which interfere with or inhibit endonuclease cleavage should not be inserted in the region which is subject to RISC mediated cleavage, e.g., the cleavage site or the cleavage region (As described in Elbashir et al., 2001, Genes and Dev. 15:188, hereby incorporated by 10 reference). Cleavage of the target occurs about in the middle of a 20 or 21 nt antisense strand, or about 10 or 11 nucleotides upstream of the first nucleotide on the target mRNA which is complementary to the antisense strand. As used herein cleavage site refers to the nucleotides on either side of the site of cleavage, on the target mRNA or on the iRNA agent strand which hybridizes to it. Cleavage region means the nucleotides within 1,2, or 3 nucleotides of the 15 cleavage site, in either direction.

Such modifications can be introduced into the terminal regions, e.g., at the terminal position or with 2, 3,4, or 5 positions of the terminus, of a sequence which targets or a sequence which does not target a sequence in the subject.

Tethered Ligands 20 The properties of an iRNA agent, including its pharmacological properties, can be influenced and tailored, for example, by the introduction of ligands, e.g. tethered ligands. A wide variety of entities, e.g., ligands, can be tethered to an iRNA agent, e.g., to the carrier of a ligand-conjugated monomer subunit. Examples are described below in the context of a ligand-conjugated monomer subunit but that is only preferred, entities can be coupled at other 25 points to an iRNA agent.

Preferred moieties are ligands, which are coupled, preferably covalently, either directly or indirectly via an intervening tether, to the carrier. In preferred embodiments, the ligand is 22 WO 2006/074346 PCT/US2006/000425 attached to the carrier via an intervening tether. The ligand or tethered ligand may be present on the ligand-conjugated monomer when the ligand-conjugated monomer is incorporated into the growing strand. In some embodiments, the ligand may be incorporated into a “precursor” ligand-conjugated monomer subunit after a “precursor” ligand-conjugated monomer subunit has 5 been incorporated into the growing strand. For example, a monomer having, e.g., an amino-terminated tether, e.g., TAP-(CH2)nNH2 may be incorporated into a growing sense or antisense strand. In a subsequent operation, i.e., after incorporation of the precursor monomer subunit into the strand, a ligand having an electrophilic group, e.g., a pentafluorophenyl ester or aldehyde group, can subsequently be attached to the precursor ligand-conjugated monomer by coupling 1 o the electrophilic group of the ligand with the terminal nucleophilic group of the precursor ligand-conjugated monomer subunit tether.

In preferred embodiments, a ligand alters the distribution, targeting or lifetime of an iRNA agent into which it is incorporated. In preferred embodiments a ligand provides an enhanced affinity for a selected target, e.g., molecule, cell or cell type, compartment, e.g., a 15 cellular or organ compartment, tissue, organ or region of the body, as, e.g., compared to a species absent such a ligand.

Preferred ligands can improve transport, hybridization, and specificity properties and may also improve nuclease resistance of the resultant natural or modified oligoribonucleotide, or a polymeric molecule comprising any combination of monomers described herein and/or natural or 20 modified ribonucleotides.

Ligands in general can include therapeutic modifiers, e.g., for enhancing uptake; diagnostic compounds or reporter groups e.g., for monitoring distribution; cross-linking agents; nuclease-resistance conferring moieties; and natural or unusual nucleobases. General examples include lipophilic moleculeses, lipids, lectins, steroids (e.g.,uvaol, hecigenin, diosgenin), 25 terpenes (e.g., triterpenes, e.g., sarsasapogenin, Friedelin, epifriedelanol derivatized lithocholic acid), vitamins, carbohydrates(e.g., a dextran, pullulan, chitin, chitosan, inulin, cyclodextrin or hyaluronic acid), proteins, protein binding agents, integrin targeting molecules,polycationics, peptides, polyamines, and peptide mimics. 23 WO 2006/074346 PCT/US2006/000425

The ligand may be a naturally occurring or recombinant or synthetic molecule, such as a synthetic polymer, e.g., a synthetic polyamino acid. Examples of polyamino acids include polyamino acid is a polylysine (PLL), poly L-aspartic acid, poly L-glutamic acid, styrene-maleic acid anhydride copolymer, poly(L-lactide-co-glycolied) copolymer, divinyl ether-maleic 5 anhydride copolymer, N-(2-hydroxypropyl)methacrylamide copolymer (HMPA), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyurethane, poly(2-ethylacrylic acid), N-isopropylacrylamide polymers, or polyphosphazine. Example of polyamines include: polyethylenimine, polylysine (PLL), spermine, spermidine, polyamine, pseudopeptide-polyamine, peptidomimetic polyamine, dendrimer polyamine, arginine, amidine, protamine, 10 cationic moieties, e.g., cationic lipid, cationic porphyrin, quaternary salt of a polyamine, or an alpha helical peptide.

Ligands can also include targeting groups, e.g., a cell or tissue targeting agent, e.g.,, a thyrotropin, melanotropin, surfactant protein A, Mucin carbohydrate, a glycosylated polyaminoacid, transferrin, bisphosphonate, polyglutamate, polyaspartate, or an RGD peptide or 15 RGD peptide mimetic.

Ligands can be proteins, e.g., glycoproteins, lipoproteins, e.g. low density lipoprotein (LDL), or albumins, e.g. human serum albumin (HSA), or peptides, e.g., molecules having a specific affinity for a co-ligand, or antibodies e.g., an antibody, that binds to a specified cell type such as a cancer cell, endothelial cell, or bone cell. Ligands may also include hormones and 20 hormone receptors. They can also include non-peptidic species, such as cofactors, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-glucosamine, multivalent mannose, or multivalent fucose. The ligand can be, for example, a lipopolysaccharide, an activator of p38 MAP kinase, or an activator of NF-kB.

The ligand can be a substance, e.g, a drug, which can increase the uptake of the iRNA 25 agent into the cell, for example, by disrupting the cell’s cytoskeleton, e.g., by disrupting the cell’s microtubules, microfilaments, and/or intermediate filaments. The drug can be, for example, taxon, vincristine, vinblastine, cytochalasin, nocodazole, japlakinolide, latrunculin A, phalloidin, swinholide A, indanocine, or myoservin. 24 WO 2006/074346 PCT/US2006/000425

In one aspect, the ligand is a lipid or lipid-based molecule. Such a lipid or lipid-based molecule preferably binds a serum protein, e.g., human serum albumin (HSA). Other molecules that can bind HSA can also be used as ligands. For example, neproxin or aspirin can be used. A lipid or lipid-based ligand can (a) increase resistance to degradation of the conjugate, (b) increase 5 targeting or transport into a target cell or cell membrane, and/or (c) can be used to adjust binding to a serum protein, e.g., HSA. A lipid based ligand can be used to modulate, e.g., control the binding of the conjugate to a target tissue. For example, a lipid or lipid-based ligand that binds to HSA more strongly will be less likely to be targeted to the kidney and therefore less likely to be cleared from the body. 10 A lipid or lipid-based ligand that binds to HSA less strongly can be used to target the conjugate to the kidney.

In a preferred embodiment, the lipid based ligand binds HSA. Preferably, it binds HSA with a sufficient affinity such that the conjugate will be preferably distributed to a non-kidney tissue. However, it is preferred that the affinity not be so strong that the HSA-ligand binding 15 cannot be reversed.

In another aspect, the ligand is a moiety, e.g., a vitamin or nutrient, which is taken up by a target cell, e.g., a proliferating cell. These are particularly useful for treating disorders characterized by unwanted cell proliferation, e.g., of the malignant or non-malignant type, e.g., cancer cells. Exemplary vitamins include vitamin A, E, and K. Other exemplary vitamins 20 include the B vitamins, e.g., folic acid, B12, riboflavin, biotin, pyridoxal or other vitamins or nutrients taken up by cancer cells.

In another aspect, the ligand is a cell-permeation agent, preferably a helical cell-permeation agent. Preferably, the agent is amphipathic. An exemplary agent is a peptide such as tat or antennapedia. If the agent is a peptide, it can be modified, including a peptidylmimetic, 25 invertomers, non-peptide or pseudo-peptide linkages, and use of D-amino acids. The helical agent is preferably an alpha-helical agent, which preferably has a lipophilic and a lipophobic phase. 25 WO 2006/074346 PCT/US2006/000425 S'-Phosphate modifications

In preferred embodiments, iRNA agents are 5’ phosphorylated or include a phosphoryl analog at the 5’ prime terminus. 5'-phosphate modifications of the antisense strand include those which are compatible with RISC mediated gene silencing. Suitable modifications include: 5'- 5 monophosphate ((HO)2(O)P-O-5'); 5'-diphosphate ((HO)2(O)P-O-P(HO)(O)-O-5'); 5’- triphosphate ((HO)2(O)P-O-(HO)(O)P-O-P(H0)(0)-O-5'); 5'-guanosine cap (7-methylated or non-methylated) (7m-G-O-5'-(HO)(O)P-O-(HO)(O)P-O-P(HO)(O)-O-5’); 5’-adenosine cap (Appp), and any modified or unmodified nucleotide cap structure. Other suitable 5'-phosphate modifications will be knoen to the skilled person. 10 The sense strand can be modified in order to inactivate the sense strand and prevent formation of an active RISC, thereby potentially reducing off-target effects. This can be accomplished by a modification which prevents 5'-phosphorylation of the sense strand, e.g., by modification with a 5'-O-methyl ribonucleotide (see Nykanen et al., (2001) ATP requirements and small interfering RNA structure in the RNA interference pathway. Cell 107, 309-321.) 15 Other modifications which prevent phosphorylation can also be used, e.g., simply substituting the 5'-OH by H rather than Ο-Me. Alternatively, a large bulky group may be added to the 5'-phosphate turning it into a phosphodiester linkage.

Delivery of iRNA agents to tissues and cells

Formulation 20 The iRNA agents described herein can be formulated for administration to a subject, preferably for administration locally to the lungs and nasal passage (respiratory tissues) via inhalation or intranasally administration, or parenterally, e.g. via injection.

For ease of exposition, the formulations, compositions, and methods in this section are discussed largely with regard to unmodified iRNA agents. It should be understood, however, 25 that these fonnulations, compositions, and methods can be practiced with other iRNA agents, e.g., modified iRNA agents, and such practice is within the invention. 26 WO 2006/074346 PCT/US2006/000425 A formulated iRNA agent composition can assume a variety of states. In some examples, the composition is at least partially crystalline, uniformly crystalline, and/or anhydrous (e.g., less than 80,50,30,20, or 10% water). In another example, the iRNA agent is in an aqueous phase, e.g., in a solution that includes water, this form being the preferred form for administration via 5 inhalation.

The aqueous phase or the crystalline compositions can be incorporated into a delivery vehicle, e.g., a liposome (particularly for the aqueous phase), or a particle (e.g., a microparticle as can be appropriate for a crystalline composition). Generally, the iRNA agent composition is formulated in a manner that is compatible with the intended method of administration. 10 An iRNA agent preparation can be formulated in combination with another agent, e.g., another therapeutic agent or an agent that stabilizes an iRNA agent, e.g., a protein that complexes with the iRNA agent to form an iRNP. Still other agents include chelators, e.g., EDTA (e.g., to remove divalent cations such as Mg2+), salts, RNAse inhibitors (e.g., abroad specificity RNAse inhibitor such as RNAsin) and so forth. 15 In one embodiment, the iRNA agent preparation includes another iRNA agent, e.g., a second iRNA agent that can mediate RNAi with respect to a second gene. Still other preparations can include at least three, five, ten, twenty, fifty, or a hundred or more different iRNA species. In some embodiments, the agents are directed to the same virus but different target sequences. In another embodiment, each iRNA agents is directed to a different virus. As 20 demonstrated in the Example, more than one virus can be inhibited by co-administering two iRNA agents simultaneously, or at closely time intervals, each one directed to one of the viruses being treated.

Treatment Methods and Routes of Delivery A composition that includes an iRNA agent of the present invention, e.g., an iRNA agent

25 that targets RSV, can be delivered to a subject by a variety of routes. Exemplary routes include inhalation, intravenous, nasal, or oral delivery. The preferred means of administering the iRNA 27 WO 2006/074346 PCT/US2006/000425 agents of the present invention is through direct administration to the lungs and nasal passage or systemically through parental administration.

An iRNA agent can be incorporated into pharmaceutical compositions suitable for administration. For example, compositions can include one or more iRNA agents and a 5 pharmaceutically acceptable carrier. As used herein the language “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is 1 o incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including intranasal or intrapulmonary), oral 15 or parenteral. Parenteral administration includes intravenous drip, subcutaneous, intraperitoneal or intramuscular injection.

In general, the delivery of the iRNA agents of the present invention is done to achieve delivery into the subject to the site of infection. The preferred means of achieving this is through either a local administration to the lungs or nasal passage, e.g. into the respiratory tissues via 20 inhalation, nebulization or intranasal administration, or via systemic administration, e.g. parental administration.

Formulations for inhalation or parenteral administration are well known in the art. Such formulation may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives, an example being PBS or Dextrose 5% in water. For intravenous use, 25 the total concentration of solutes should be controlled to render the preparation isotonic.

The active compounds disclosed herein are preferably administered to the lung(s) or nasal passage of a subject by any suitable means. Active compounds may be administered by 28 WO 2006/074346 PCT/US2006/000425 administering an aerosol suspension of respirable particles comprised of the active compound or active compounds, which the subject inhales. The active compound can he aerosolized in a variety of forms, such as, but not limited to, dry powder inhalants, metered dose inhalants, or liquid/liquid suspensions. The respirable particles may be liquid or solid. The particles may 5 optionally contain other therapeutic ingredients such as amiloride, benzamil or phenamil, with the selected compound included in an amount effective to inhibit the reabsorption of water from airway mucous secretions, as described in U.S. Pat. No. 4,501,729.

The particulate pharmaceutical composition may optionally be combined with a carrier to aid in dispersion or transport. A suitable carrier such as a sugar (i.e., dextrose, lactose, sucrose, 10 trehalose, mannitol) may be blended with the active compound or compounds in any suitable ratio (e.g., a 1 to 1 ratio by weight).

Particles comprised of the active compound for practicing the present invention should include particles of respirable size, that is, particles of a size sufficiently small to pass through the mouth or nose and larynx upon inhalation and into the bronchi and alveoli of the lungs. In 15 general, particles ranging from about 1 to 10 microns in size (more particularly, less than about 5 microns in size) are respirable. Particles of non-respirable size which are included in the aerosol tend to deposit in the throat and be swallowed, and the quantity of non-respirable particles in the aerosol is preferably minimized. For nasal administration, a particle size in the range of 10-500 micons is preferred to ensure retention in the nasal cavity. 20 Liquid pharmaceutical compositions of active compound for producing an aerosol may be prepared by combining the active compound with a suitable vehicle, such as sterile pyrogen free water. The hypertonic saline solutions used to carry out the present invention are preferably sterile, pyrogen-free solutions, comprising from one to fifteen percent (by weight) of the physiologically acceptable salt, and more preferably from three to seven percent by weight of the 25 physiologically acceptable salt.

Aerosols of liquid particles comprising the active compound may be produced by any suitable means, such as with a pressure-driven jet nebulizer or an ultrasonic nebulizer. See, e.g., U.S. Pat. No. 4,501,729. Nebulizers are commercially available devices which transform 29 WO 2006/074346 PCT/US2006/000425 solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of compressed gas, typically air or oxygen, through a narrow venturi orifice or by means of ultrasonic agitation.

Suitable formulations for use in nebulizers consist of the active ingredient in a liquid 5 carrier, the active ingredient comprising up to 40% w/w of the formulation, but preferably less than 20% w/w. The carrier is typically water (and most preferably sterile, pyrogen-free water) or a dilute aqueous alcoholic solution, preferably made isotonic, but may be hypertonic with body fluids by the addition of, for example, sodium chloride. Optional additives include preservatives if the formulation is not made sterile, for example, methyl hydroxybenzoate, antioxidants, 10 flavoring agents, volatile oils, buffering agents and surfactants.

Aerosols of solid particles comprising the active compound may likewise be produced with any solid particulate therapeutic aerosol generator. Aerosol generators for administering solid particulate therapeutics to a subject produce particles which are respirable and generate a volume of aerosol containing a predetermined metered dose of a therapeutic at a rate suitable for 15 human administration. One illustrative type of solid particulate aerosol generator is an insufflator. Suitable formulations for administration by insufflation include finely comminuted powders which may be delivered by means of an insufflator or taken into the nasal cavity in the manner of a snuff. In the insufflator, the powder (e.g., a metered dose thereof effective to carry out the treatments described herein) is contained in capsules or cartridges, typically made of 20 gelatin or plastic, which are either pierced or opened in situ and the powder delivered by air drawn through the device upon inhalation or by means of a manually-operated pump. The powder employed in the insufflator consists either solely of the active ingredient or of a powder blend comprising the active ingredient, a suitable powder diluent, such as lactose, and an optional surfactant. The active ingredient typically comprises from 0.1 to 100 w/w of the 25 formulation. A second type of illustrative aerosol generator comprises a metered dose inhaler. Metered dose inhalers are pressurized aerosol dispensers, typically containing a suspension or solution formulation of the active ingredient in a liquefied propellant. During use these devices discharge 30 WO 2006/074346 PCT/US2006/000425 the formulation through a valve adapted to deliver a metered volume, typically from 10 to 200 ul, to produce a fine particle spray containing the active ingredient. Suitable propellants include certain chlorofluorocarbon compounds, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof. The formulation may 5 additionally contain one or more co-solvents, for example, ethanol, surfactants, such as oleic acid or sorbitan trioleate, antioxidant and suitable flavoring agents.

Administration can be provided by the subject or by another person, e.g., a caregiver. A caregiver can be any entity involved with providing care to the human: for example, a hospital, hospice, doctor’s office, outpatient clinic; a healthcare worker such as a doctor, nurse, or other 10 practitioner; or a spouse or guardian, such as a parent. The medication can be provided in measured doses or in a dispenser which delivers a metered dose.

The term “therapeutically effective amount” is the amount present in the composition that is needed to provide the desired level of drug in the subject to be treated to give the anticipated physiological response, hi one embodiment, therapeutically effective amounts of two or more 15 iRNA agents, each one directed to a different respiratory virus, e.g. RSV, are administered concurrently to a subject.

The tenn “physiologically effective amount” is that amount delivered to a subject to give the desired palliative or curative effect.

The term “pharmaceutically acceptable carrier” means that the carrier can be taken into 20 the lungs with no significant adverse toxicological effects on the lungs.

The term “co-administration” refers to administering to a subject two or more agents, and in particular two or more iRNA agents. The agents can be contained in a single pharmaceutical composition and be administered at the same time, or the agents can be contained in separate formulation and administered serially to a subject. So long as the two agents can be detected in 25 the subject at the same time, the two agents are said to be co-administered.

The types of pharmaceutical excipients that are useful as carrier include stabilizers such as human serum albumin (HSA), bulking agents such as carbohydrates, amino acids and 31 WO 2006/074346 PCT/US2006/000425 polypeptides; pH adjusters or buffers; salts such as sodium chloride; and the like. These earners may be in a crystalline or amorphous form or may be a mixture of the two.

Bulking agents that are particularly valuable include compatible carbohydrates, polypeptides, amino acids or combinations thereof. Suitable carbohydrates include 5 monosaccharides such as galactose, D-mannose, sorbose, and the like; disaccharides, such as lactose, trehalose, and the like; cyclodextrins, such as 2-hydroxypropyl-.beta.-cyclodextrin; and polysaccharides, such as raffmose, maltodextrins, dextrans, and the like; alditols, such as mannitol, xylitol, and the like. A preferred group of carbohydrates includes lactose, threhalose, raffmose maltodextrins, and mannitol. Suitable polypeptides include aspartame. Amino acids 10 include alanine and glycine, with glycine being preferred.

Suitable pH adjusters or buffers include organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate, and the like; sodium citrate is prefened.

Dosage. An iRNA agent can be administered at a unit dose less than about 75 mg per kg of bodyweight, or less than about 70,60, 50,40, 30,20,10, 5,2,1,0.5,0.1,0.05,0.01,0.005, 15 0.001, or 0.0005 mg per kg of bodyweight, and less than 200 nmol of iRNA agent (e.g., about 4.4 x 1016 copies) per kg of bodyweight, or less than 1500,750, 300,150,75,15,7.5,1.5,0.75, 0.15, 0.075, 0.015, 0.0075,0.0015, 0.00075, 0.00015 nmol of iRNA agent per kg of bodyweight. The unit dose, for example, can be administered by an inhaled dose or nebulization or by injection. In one example, dosage ranges of .02-25 mg/kg is used. 20 Delivery of an iRNA agent directly to the lungs or nasal passage can be at a dosage on the order of about 1 mg to about 150 mg/nasal passage.

The dosage can be an amount effective to treat or prevent a disease or disorder.

In one embodiment, the unit dose is administered once a day. In other usage, a unit dose is administered twice the first day and then daily. Alternatively, unit dosing can be less than 25 once a day, e.g., less than every 2,4, 8 or 30 days. In another embodiment, the unit dose is not administered with a frequency (e.g., not a regular frequency). For example, the unit dose may be administered a single time. Because iRNA agent mediated silencing can persist for several days 32 WO 2006/074346 PCT/US2006/000425 after administering the iRNA agent composition, in many instances, it is possible to administer the composition with a frequency of less than once per day, or, for some instances, only once for the entire therapeutic regimen.

In one embodiment, a subject is administered an initial dose, and one or more 5 maintenance doses of an iRNA agent, e.g., a double-stranded iRNA agent, or siRNA agent, (e.g., a precursor, e.g., a larger iRNA agent which can be processed into an siRNA agent, or a DNA which encodes an iRNA agent, e.g., a double-stranded iRNA agent, or siRNA agent, or precursor thereof). The maintenance dose or doses are generally lower than the initial dose, e.g., one-half less of the initial dose. A maintenance regimen can include treating the subject with a dose or 10 doses ranging from 0.01 pg to 75 mg/kg of body weight per day, e.g., 70, 60, 50,40,30,20,10, 5,2,1, 0.5, 0.1,0.05, 0.01, 0.005,0.001, or 0.0005 mg per kg of bodyweight per day. The maintenance doses are preferably administered no more than once every 5-14 days. Further, the treatment regimen may last for a period of time which will vary depending upon the nature of the particular disease, its severity and the overall condition of the patient. In preferred embodiments 15 the dosage may be delivered no more than once per day, e.g., no more than once per 24,36,48, or more hours, e.g., no more than once every 5 or 8 days. Following treatment, the patient can be monitored for changes in his condition and for alleviation of the symptoms of the disease state. The dosage of the compound may either be increased in the event the patient does not respond significantly to current dosage levels, or the dose may be decreased if an alleviation of 20 the symptoms of the disease state is observed, if the disease state has been ablated, or if undesired side-effects are observed.

In one embodiment, the iRNA agent pharmaceutical composition includes a plurality of iRNA agent species. The iRNA agent species can have sequences that are non-overlapping and non-adjacent with respect to a naturally occurring target sequence, e.g., a target sequence of the 25 RSV gene. In another embodiment, the plurality of iRNA agent species is specific for different naturally occurring target genes. For example, an iRNA agent that targets the P protein gene of RSV can be present in the same pharmaceutical composition as an iRNA agent that targets a different gene, for example the N protein gene. In another embodiment, the iRNA agents are specific for different viruses, e.g. RSV. 33 WO 2006/074346 PCT/US2006/000425

The concentration of the iRNA agent composition is an amount sufficient to be effective in treating or preventing a disorder or to regulate a physiological condition in humans. The concentration or amount of iRNA agent administered will depend on the parameters determined for the agent and the method of administration, e.g. nasal, buccal, or pulmonary. For example, 5 nasal formulations tend to require much lower concentrations of some ingredients in order to avoid irritation or burning of the nasal passages. It is sometimes desirable to dilute an oral formulation up to 10-100 times in order to provide a suitable nasal formulation.

Certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health 10 and/or age of the subject, and other diseases present. It will also be appreciated that the effective dosage of an iRNA agent such as an siRNA agent used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays. For example, the subject can be monitored after administering an iRNA agent composition. Based on information from the monitoring, an 15 additional amount of the iRNA agent composition can be administered.

The invention is further illustrated by the following examples, which should not be construed as further limiting.

EXAMPLES

Designing antiviral siRNAs against RSV mRNA 20 siRNA against RSV P, N and L mRNA were synthesized chemically using know procedures. The siRNA sequences and some inhibition cross-subtype activity and IC50 values are listed (Table 1 (a-c)).

In vitro assay and Virus infection

Vero E6 cells were cultured to 80% confluency in DMEM containing 10% heat- 25 inactivated FBS. For siRNA introduction, 4 μΐ of Transit-TKO was added to 50 μΐ of serum-free DMEM and incubated at room temperature for 10 minutes. Then, indicated concentration of 34 WO 2006/074346 PCT/US2006/000425 siRNA was added to media/TKO reagent respectively and incubated at room temperature for 10 minutes. RNA mixture was added to 200 μΐ of DMEM containing 10% FBS and then to cell monolayer. Cells were incubated at 37°C, 5% CO2 for 6 hours. RNA mixture was removed by gentle washing with lx Hank s Balanced Salt Solutions (HBSS) and 300 plaque-forming units 5 (pfu) per well of RSV/A2 (MOI = 30) was added to wells and adsorbed for 1 hour at 37°C, 5% CO2. Virus was removed and cells were washed with lx HBSS. Cells were overlaid with 1 % methylcellulose in DMEM containing 10% FBS media, and incubated for 6 days at 37°C, 5% CO2. Cells were unmunostained for plaques using anti-F protein monoclonal antibody 131-2A. siRNA delivery and virus infection in vivo

Pathogen-free 4 week old female BALB/c mice were purchased from Harlan. Mice were under anesthesia during infection and intranasal instillation (i.n.). Mice were immunized by mtranasal instillation with indicated amount of siRNA, either uncomplexed, or complexed with 5 ul Transit TKO. 150 pg of Synagis (monoclonal antibody clone 143-6C, anti-RSV F protein) and Mouse Isotype control (IgGl) were administered intraperitoneal (i.p.) four hours prior to RSV 15 challenge (10 PFU of RSV/A2). Ten mice per group were used. Animal weights were monitored at days 0,2, 4, and 6 post-infection. Lungs were harvested at day 6 post-infection, and assayed for RSV by immunostaining plaque assay.

Immunostaining Plaque Assay 24-well plates of Vero E6 cells were cultured to 90% confluency in DMEM containing 20 10% heat inactivated FBS. Mice lungs were homogenized with hand-held homogenizer in 1 ml stenle Dulbecco’s PBS (D-PBS) and 10 fold diluted in serum-free DMEM. Virus containing lung lysate dilutions were plated onto 24 well plates in triplicate and adsorbed for 1 hour at 37°C, 5% CO2. Wells were overlaid with 1% methylcellulose in DMEM containing 10% FBS. Then, plates were incubated for 6 days at 37°C, 5% CO2. After 6 days, overlaid media was removed 25 and cells were fixed in acetone:methanol (60:40) for 15 minutes. Cells were blocked with 5% dry

Milk/PBS for 1 hour at 37°C. 1:500 dilution of anti-RSV F protein antibody (131-2A) was added to wells and incubated for 2 hours at 37°C. Cells were washed twice in PBS/0.5% Tween 20. 1.500 dilution of goat anti-mouse IgG-Alkaline Phosphatase was added to wells and incubated 35 WO 2006/074346 PCT/US2006/000425 for 1 hour at 37°C. Cells were washed twice in PBS/0.5% Tween 20. Reaction was developed using Vector’s Alkaline Phosphatase substrate kit Π (Vector Black), and counterstained with Hematoxylin. Plaques were visualized and counted using an Olympus Inverted microscope.

Treatment assay 5 Mice were challenged with RSV (106 PFU of RSV/A2) by intranasal instillation at day 0 and treated with 50 ug of indicated siRNA, delivered by intranasal instillation, at the indicated times (day 1-4 post viral challenge). 3-5 mice per group were used and viral titers were measured from lung lysates at day 5 post viral challenge, as previously described.

In vitro inhibition of RSV using iRNA agents. 10 iRNA agents provided in Table 1 (a-c) were tested for anti-RSV activity in a plaque formation assay as described above (Figure 1). Each column (bar) represents an iRNA agent provided in Table 1 (a-c), e.g. column 1 is the first agent in Table la, second column is the second agent and so on. Active iRNA agents were identified by the % of virus remaining.

Several agents were identified that showed as much as 90% inhibition. The results are 15 summarized in Table 1 (a-c).

In vitro dose response inhibition of RSV using iRNA agents was determined. Examples of active agents from Table 1 were tested for anti-RSV activity in a plaque formation assay as described above at four concentrations. A dose dependent response was found with active iRNA agent tested (Figure 2) and is summarized in Tables l(a-c). 20 In vitro inhibition of RSV B subtype using iRNA agents was tested as described above. iRNA agents provided in Figure 2 were tested for anti-RSV activity against subtype B (Figure 3). RSV subtype B was inhibited by the iRNA agents tested to varying degrees and is summarized in Table l(a-c). 36 WO 2006/074346 PCT/US2006/000425

In vivo inhibition of RSV using iRNA agents.

In vivo inhibition of RSV using AL1729 and AL1730 was tested as described above. Agents as described in Figure 4 were tested for anti-RSV activity in a mouse model. The iRNA agents were effective at reducing viral titers in vivo and more effective than a control antibody 5 (Mab 143-6c, a mouse IgGl Ab that is approved for RSV treatment). AL1730 was tested for dose dependent activity using the methods provided above. The agents showed a dose dependent response (Figure 5). iRNA agents showing in vitro activity were tested for anti-RSV activity in vivo as outlined above. Several agents showed a reduction in viral titers of >4 logs when given 10 prophylactically (Figure 6). iRNA agents showing in vitro and/or in vivo activity were tested for anti-RSV activity m vivo as in the treatment protocol outlined above. Several agents showed a reduction in viral titers of 2-3 logs (Figure 7) when given 1-2 days following viral infection.

Sequence analysis of isolates across target sequence 15 Method:

Growth of isolates and RNA isolation: Clinical isolates from RSV infected patients were obtained from Larry Anderson at the CDC in Atlanta Georgia (4 strains) and John DeVincenzo at the University of Tenn., Memphis (15 strains). When these were grown in HEp-2, human epithelial cells (ATCC, Cat# CCL-23) cells, it was noted that the 4 isolates from Georgia were 20 slower growing than the 15 strains from Tennessee; hence, these were processed and analyzed separately. The procedure is briefly described as follows:

Vero E6, monkey kidney epithelial cells (ATCC, Cat# CRL-1586) were grown to 95% confluency and infected with a 1/10 dilution of primary isolates. The virus was absorbed for 1 hour at 37 °C, then cells were supplemented with D-MEM and incubated at 37 °C. On a daily 25 basis, cells were monitored for cytopathic effect (CPE) by light microscopy. At 90% CPE, the 37 WO 2006/074346 PCT/US2006/000425 cells were harvested by scraping and pelleted by centrifugation at 3000 rpm for 10 minutes. RNA preparations were performed by standard procedures according to manufacturer’s protocol.

Amplification of RSV N gene: Viral RNAs were collected post-infection and used as templates in PCR reactions, using primers that hybridize upstream and downstream of the 5 ALDP-2017 target site to amplify an ~450 bp fragment. Total RNA was denatured at 65 °C for 5 minutes in the presence of forward and reverse RSV N gene primers, stored on ice, and then reverse-transcribed with Superscript III (Invitrogen) for 60 minutes at 55 °C and for 15 minutes at 70 °C. PCR products were analyzed by gel electrophoresis on a 1% agarose gel and purified by standard protocols. 10 Results: Sequence analysis of the first 15 isolates confirmed that the target site for ALDP-2017 was completely conserved across every strain. Importantly, this conservation was maintained across the diverse populations, which included isolates from both RSV A and B subtypes. Interestingly, when the 4 slower-growing isolates were analyzed, we observed that one of the 4 (LAP6824) had a single base mutation in the ALDP-2017 recognition site. This 15 mutation changed the coding sequence at position 13 of the RSV N gene in this isolate from an A to a G.

Conclusions:

From 19 patient isolates, the sequence of the RSV N gene at the target site for ALDP-2017 has been determined. In 18 of 19 cases (95%), the recognition element for ALDP-2017 is 20 1 00% conserved. In one of the isolates, there is a single base alteration changing the nucleotide at position 13 from an A to a G within the RSV N gene. This alteration creates a single G:U wobble between the antisense strand of ALDP-2017 and the target sequence. Based on an understanding of the hybridization potential of such a G:U wobble, it is predicted that ALDP-2017 will be effective in silencing the RSV N gene in this isolate. 38 WO 2006/074346 PCT/US2006/000425

Silencing data on isolates

Methods

Vero E6 cells were cultured to 80% confluency in DMEM containing 10% heat-inactivated FBS. For siRNA introduction, 4 μΐ of Transit-TKO was added to 50 μΐ of serum-free 5 DMEM and incubated at room temperature for 10 minutes. Then, indicated concentration of siRNA was added to media/TKO reagent respectively and incubated at room temperature for 10 minutes. RNA mixture was added to 200 μΐ of DMEM containing 10% FBS and then to cell monolayer. Cells were incubated at 37°C, 5% CO2 for 6 hours. RNA mixture was removed by gentle washing with lx Hank’s Balanced Salt Solutions (HBSS) and 300 plaque-forming units 10 (pfu) per well of RSV/A2 (MOI - 30) was added to wells and adsorbed for 1 hour at 37°C, 5% CO2. Virus was removed and cells were washed with lx HBSS. Cells were overlaid with 1% methylcellulose in DMEM containing 10% FBS media, and incubated for 6 days at 37°C, 5% CO2. Cells were immunostained for plaques using anti-F protein monoclonal antibody 131-2A.

Results: Silencing was seen for all isolates (Table 2)

Isolate name 2017 %plaques remaining 2153 %plaques remaining RSV/A2 4.49 80.34 RSV/96 5.36 87.50 RSV/87 10.20 79.59 RSV/110 5.41 81.08 RSV/37 4.80 89.60 RSV/67 2.22 91.67 RSV/121 6.25 82.50 RSV/31 4.03 96.77 39 WO 2006/074346 PCT/US2006/000425 RSV/38 2.00 92.67 RSV/98 5.13 91.03 RSV/124 3.74 90.37 RSV/95 7.32 64.02 RSV/32 5.45 92.73 RSV/91 8.42 95.79 RSV/110 12.07 94.83 RSV/54 1.90 89.87 RSV/53 7.41 94.07 RSV/33 7.69 95.19

Table 2

Conclusion: All clinical isolates tested were specifically inhibited by siRNA 2017 by greater than 85%. No isolates were significantly inhibited the mismatch control siRNA 2153.

Silencing in plasmid based assay 5 Method A 24-well plate is seeded with HeLa S6 cells and grown to 80 % confluence. For each well, mix 1 ug of RSV N-V5 plasmid with siRNA (at indicated concentration), in 50 ul OPTI-MEM and add to Lipofectamine 2000 (Invitrogen)-Optimem mixture prepared according to manufacturer’s instructions, and let sit 20 minutes at r.t. to form complex. Add complex to cells 10 and incubate 37°C overnight. Remove the media, wash the cells with PBS and lyse with 50 ul Lysis buffer (RIPA buffer (50mM Tris-HCl pH 8.0,150 mM NaCl, ImM EDTA, 0.5% Na deoxycholate, 1% NP-40, 0.05% SDS) for 1-2 min. Inhibition is quantified by measuring the level of RSV protein in cell lysates, detected by western blotting with an anti-V5 antibody 40 WO 2006/074346 PCT/US2006/000425

Results: Transient plasmid expression was shown to be an effective assay for RNAi agents (Table 3).

Protein % Activity% 1 ALDP2017 10nM 0 100 2 1nM 0 100 3 100pM 0 100 4 10pM 11.78 88.22 5 1pM 70.63 29.37 6 100fM 72.7 27.3 7 Control PBS 100 0 8 2153 10nM 94.54 4.5 Tai ble 3

Conclusions 5 siRNA 2017 specifically and dose dependently inhibits the production of RSV N protein when transiently cotranfected with plasmid expressing the RSV N gene. Inhibition is not observed with mismatch control siRNA 2153.

Silencing of RSV via aerosol delivery of siRNA

Method 10 A 2 mg/ml solution of ALDP-1729 or ALDP-1730 is delivered via nebulization using an aerosol device for a total of 60 sec. Virus was prepared from lung as described above and measured by an ELISA instead of a plaque assay. The ELISA measures the concentration of the RSV N protein in cells infected with virus obtained from mouse lung lysates.

ELISA 41 WO 2006/074346 PCT/US2006/000425

Lung lystate is diluted 1:1 with carbonate-bicarbonate buffer (NaHCCbpH 9.6) to a working concentration of 6-10pg/100pL, added to each test well and incubated at 37°C for 1 hour or overnight at 4°C. Wells washed 3 X with PBS/0.5% Tween 20 then blocked with 5% dry milk/PBS for 1 hour at 37°C or overnight at 4°C. Primary antibody (F protein positive control =

5 clone 131-2A; G protein positive control = 130-2G; negative control = normal IgGl,(BD

Pharmingen, cat. #553454, test sera, or hybridoma supernatant) is added to wells at 1:1000 and incubated at 37°C for 1 houi’ or overnight at 4°C. Wells washed 3 X with PBS/0.5% Tween 20. Secondary antibody (Goat Anti-mouse IgG (H+L) whole molecule-alkaline phosphatase conjugated) diluted 1:1000 to wells (100 μΙ/well) is added and incubated at 37°C for 1 hour or 10 overnight at 4°C. Wash 3 X with PBS/0.5% Tween 20 then add Npp (Sigmafast) substrate Sigma Aldrich N2770 accordingly to manufacturers instructions. Add 200 μΐ of substrate/well and incubate for 10-15. Measure absorbance at OD 405/495.

Conclusion 15 Delivery of RSV specific siRNA decreases the levels of RSV N protein in mouse lungs as compared to the mismatch control siRNA (Figure 8a-b).

In vivo inhibition at day -3-prophylaxis

Method 20 In vivo prophylaxis was tested using the in vivo method described above except that the siRNA is delivered at different times prior to infection with RSV from 3 days before to 4 hrs before.

Results siRNA delivered intranasally up to 3 days prior to viral challenge show significant 25 silencing in vivo (Figure 9). 42 4*.

CO

Table 1 (a-c). siRNA sequences Table la. RSV L gene

Actual start Whitehead Start Pas Sense SEP ID 22= Antisense SEQ ID NO: AL-DP# % inh RSVA2 (5nM) % inh RSVA2 500 pM % inh RSV A2 SOpM % inh RSVA2 SpM % inh RSVB (5nM) 3 1 GGAUCCCAUGAUUAAUGGAdTdT 1 UCCAUUAAUAAUGGGAUCCdTdT 2 AL-DP-20M 92 4 2 GAUCCCAUUAUUAAUGGAAdTdT 3 UUCCAUUAAUAAUGGGAUCdTdT 4 AL-DP-2026 82 49 47 AGUUAUUUAAAAGGUGUUAdTdT 5 UAACACCUUUUAAAUAACUdTdT 6 AL-DP-2116 50 48 GUUAUUUAAAAGGUGUUAUdTdT 7 AUAACACCUUUUAAAUAACdTdT 8 AL-DP-2117 53 51 AUUUAAAAGGUCUUAUCUCdTdT 9 GAGAUAACACCUUUUAAAUdTdT 12 AL- DP-2118 55 53 UUAAAAGGUGUUAUCUCUUdTdT ϋ AAGAGAUAACACCUUUUAAdTdT 12 AL-DP-Z119 156 154 AAGUCCACUACUAGAGCAUdTdT 13 AUGCUCUAGUAGUGGACUUdTdT 14 AL-DP-2027 86 157 155 AGUCCACUACUAGAGCAUAdTdT 15 UAUGCUCUAGUAGUGGACUdTdT 16 AL-DP-2028 90 158 156 GUCCACUACUACAOCAUAUdTdT 17 AUAUGCUCUAGUAGUGGACdTdT 12 AL-DP-2029 89 159 157 UCCACUACUAGAGCAUAUGdTdT 19 CAUAUGCUCUAGUAGUGGAdTdT 20 ΑΙ^>Ρ-2030 86 341 339 GAAGAGCUAUAGAAAUAAGdTdT 21 CUUAUUUCUAUAGCUCUUCdTdT 22 AL-DP-2120 344 342 GAGCUAUAGAAAUAAGUGAdTdT 23 UCACUUAUUUCUAUAGCUCdTdT 24 AL-DP-2121 347 345 CUAUAGAAAUAAGUGAUGUdTdT 25 ACAUCACUUAUUUCUAUAGdTdT 2S AL-DP-2031 Ϊ5 554 552 UCAAAACAACACUCUUGAAdTdT 27 UUCAAGAGUGUUGUUUUGAdTdT 28 AL-DP-2122 1004 1002 UAGAGGGAUUUAUUAUGUCdTdT 19 GACAUAAUAAAUCCCUCUAdTdT 30 AL-DP-2123 1408 1406 AUAAAAGGGUUUGUAAAUAdTdT 31 UAUUUACAAACCCUUUUAUdTdT 32 AL-DP-2124 1867 1865 CUCAGUGUAGGUAGAAUGUdTdT 33 ACAUUCUACCUACACUGAGdTdT 34 AL-DP-2032 90 1868 1866 UCAGUGUACGUAGAAUGUUdTdT 35 AACAUUCUACCUACACUGAdTdT 35 AL-DP-2033 84 1869 1867 CAGUGUAGGUAGAAUGUUUdTdT 37 AAACAUUCUACCUACACUGdTdT 38 AL-DP-2034 86 1870 1868 AGUGUAGGUAGAAUGUUUGdTdT 32 CAAACAUUCUACCUACACUdTdT 40 AL-DP-2I12 1871 1869 GUGUAGGUAGAAUGUUUGCdTdT 41 GCAAACAUUCUACCUACACdTdT 42 AL-DP-2113 1978 1976 ACAAGAUAUGGUGAUCUAGdTdT 43 CUAGAUCACCAUAUCUUGUdTdT 44 AL-DP-2035 89 2104 2102 AGCAAAUUCAAUCAAGCAUdTdT 45 AUGCUUGAUUGAAUUUGCUdTdT 46 AL-DP-2036 87 184162/2, 2105 2103 GCAAAUUCAAUCAAGCAIRWTdT 47 AAUCCUUGAUUOAAUUUGCdTdT AL-DP-2037 91 2290 2288 GAUGAAGAAAGUGGAUUAUdTdT 49 AUAAUCCACUUUGUUCAUCdTdT 52 AL-DP-2038 It 2384 2382 UAAUAUCUCUCAAAGGGAAdTdT 51 UUCCCUUUGAGAGAUAUUAdTdT 52 AL-DP-2125 2386 2384 AUAUCUCUCAAAGGGAAAUdTcIT S3 AUUUCCCUUUGAGAGAUAUdTdT 54 AL-DP-2126 2387 2385 UAUCUC0CAAAGGCAAAUUdTdT 55 AAUUUCCCUUUGAGAGAUAdTdT 56 AL-DP-2127 2485 2483 CAUGCUCAAGCAGAUUAUUdTdT 57 AAUAAUCUGCUUGAGCAUGdTdT SS AL-DP-2039 87 2487 2485 UGCUCAAGCAGAUUAUUUGdTdT S9 CAAAUAAUCUGCUUGAGCAdTdT 60 AL-DP-2040 88 2507 2505 UAGCAUUAAAUAGCCUUAAdTdT 61 UUAAGGCUAUUUAAUGCUAdTdT 62 AL-DP-2041 96 76 73 69 94 2508 2506 AGCAUUAAAUAGCCUUAAAdTdT 22 UUUAAGGCUAUUUAAUGCUdTdT 64 AL-DP-2114 2509 2507 GCAUUAAAUAGCCUUAAAUdTdT 65 AUUUAAGGCUAUUUAAUGCdTdT 66 AL-DP-2042 96 98 97 97 90 2510 2508 CAUUAAAUAOCCUUAAAUUdTdT SI AAUUUAAGGCUAUUUAAUGdTdT 68 AL-DP-2043 97 86 79 75 94 2765 2763 UAUUAUGCAGUUUAAUAUUdTdT 69 AAUAUUAAACUGCAUAAUAdTdT 22 AL-DP-2044 97 79 72 67 B4 2767 2765 UUAUGCACUUUAAUAUUUAdTdT 21 UAAAUAUUAAACUGCAUAAdTdT s AL-DP-2045 15 c 3283 3281 AAAAGUGCACAACAUUAUAdTdT 22 UAUAAUGUUGUGCACUUUUdTdT 74 AL-DP-2128 3284 3282 AAAGUOCACAACAUUAUACdTdT 25 GUAUAAUGUUGUGCACUUUdTdT 76 AL-DP-2046 94 94 91 91 93 3338 3336 AUAUAGAACCUACAUAUCCdTdT 22 GGAUAUGUAGGUUCUAUAUdTdT 78 AL-DP-2047 87 3339 3337 UAUAGAACCUACAUAUCCUdTdT 79 AGGAUAUGUAGGUUCUAUAdTdT SS AL-DP-2048 84 3365 3363 UAAGAGUUGUUUAUGAAAGdTdT SI CUUUCAUAAACAACUCUUAdTdT 52 AL-DP-2129 4021 4019 ACAGUCAGUAGUAGACCAUdTdT 83 AUGGUCUACUACUGACUGUdTdT 84 AL-DP-2049 24 4022 4020 CAGUCAGUAGUAGACCAUGdTdT 85 CAUOGUCUACUACUGACUGtfTdT 86 AL-DP-20SO 15 4023 4021 AGUCAGUAGUAGACCAUGUdTdT 87 ACAUGGUCUACUACUGACUdTdT SS AL-DP-205I 87 4024 4022 GUCAGUAGUAGACCAUGUGdTdT 82 CACAUGGUCUACUACUGACdTdT go AL-DP-205Z 96 84 76 69 87 4025 4023 UCAGUAGUAGACCAUGUGAdTdT 91 UCACAUGGUCUACUACUGAdTdT 22 AL-DP-2053 92 84 79 76 74 4037 4035 CAUGUGAAUUCCCUGCAUCdTdT 93 GAUGCAGGGAAUUCACAUGdTdT 94 AL-DP-2054 97 79 78 69 96 4038 4036 AUGUGAAUUCCCUGCAUCAdTdT 25 UGAUGCAGGGAAUUCACAUdTdT 96 AL-DP-2055 88 4039 4037 UGUGAAUUCCCUGCAUCAAdTdT 22 UUGAUGCAGGGAAUUCACAdTdT 98 AVDP-2056 16 4040 4U38 GUGAAUUCCCUGCAUCAAUdTdT 99 AUUGAUGCAGGGAAUUCACdTdT 100 AL-DP-2115 4043 4041 AAUUCCCUGCAUCAAUACCdTdT 101 GGUAUUGAUGCAGGGAAUUdTdT 102 AVDP-20S7 94 91 86 79 69 4051 4049 GCAUCAAUACCAGCUUAUAdTdT 103 UAUAAGCUGGUAUUGAUGCdTdT 123 AL-DP-2058 86 4052 4050 CAUCAAUACCAGCUUAUAGdTdT 105 CUAUAAGCUOGUAUUGAUGdTdT 106 AL-DP-2059 91 4057 4055 AUACCAGCUUAUAGAACAAdTdT 107 UUGUUCUAUAAGCUGGUAUdTdT 108 AL-DP-2060 92 4058 4056 UACCAGCUUAUAGAACAACdTdT 109 GUUGUUCUAUAAGCUGGUAdTdT 110 AL-DP-2061 88 § S3 -μ. tn 4059 4057 ACCAGCUUAUAGAACAACAdTdT 111 UGUUGUUCUAUAAGCUGGUdTdT 112 AL-DP-2062 95 79 78 72 94 4000 4058 CCAGCUUAUAGAACAACAAdTdT 113 UUGUUGUUCUAUAAGCUGGdTdT 114 AL-DP-2063 90 4061 4059 CAGCUUAUAGAACAACAA AdTdT 115 UUUGUUGUUCUAUAAGCUGdTdT 116 AL-DP-2064 94 86 76 67 83 4067 4065 AUAGAACAACAAAUUAUCAdTdT 117 UGAUAAUUUGUUGUUCUAUdTdT 118 AL-DP-2065 91 4112 4110 UAUUAACAGAAAAGUAUGGdTdT 112 CCAUACUUUUCUGUUAAUAdTdT 120 AL-DP-2130 4251 4249 UGAGAUACAUUUGAUGAAAdTdT 111 UUUCAUCAAAUGUAUCUCAdTdT 122 AL-DP-2066 86 4252 4250 GAGAUACAUUUGAUGAAACdTdT 123 GUUUCAUCAAAUGUAUCUCdTdT 124 AL-DP-2067 92 4254 4252 GAUACAUUUG AUG A AACCUdldT 12S AGGUUUCAUCAAAUGUAUCdTdT 126 AL-DP-2068 93 4255 4253 AUACAUUUGAUGAAACCUCdTdT 122 GAGGUUUCAUCAAAUGUAUdTdT 128 AL-DP-2069 89 4256 4254 UACAUUUGAUGAAACCUCCdTdT 129 GGAGGUUUCAUCAAAUGUAdTdT 123 AL-DP-2074 4313 4311 AAGUGAUACAAAAACAGCAdTdT 131 UGCUGUUUUUGUAUCACUUdTdT 122 AL-DP-2131 4314 4312 AGUGAUACAAAAACAGCAUdTdT 122 AUGCUGUUUUUGUAUCACUdTdT 134 AL-DP-2132 4316 4314 UGAUACAAAAACAGCAUAUdTdT 13S AUAUGCUGUUUUUGUAUCAdTdT 136 AL-DP-2133 4473 4471 UUUAAGUACUAAUUUAGCUdTdT 132 AGCUAAAUUAGUACUUAAAdTdT 12S AL-DP-2075 4474 4472 UUAAGUACUAAUUUACCUGdTdT 139 CAGCUAAAUUAGUACUUAAdTdT 140 AL-DP-2076 4475 4473 UAAGUACUAAUUUAGCUGGdTdT 141 CCAGCUAAAUUAGUACUUAdTdT 142 AL-DP-2077 4476 4474 AAGUACUAAUUUAGCUGGAdTdT 143 UCCAGCUAAAUUAGUACUUdTdT 144 AL-DP-2078 4477 4475 AGUACUAAUUUAGCUGGACdTdT 155 GUCCAGCU AAAUUAGUACUdTdT 146 AL-DP-2079 4478 4476 GUACUAAUUUAGCUGGACAdTdT 147 UGUCCAGCUAAAUUAGUACdTdT 148 AL-DP-2080 4480 4478 ACUAAUUUAGCUGGACAUUdTdT 149 AAUGUCCAGCUAAAUUAGUdTdT 150 AL-DP-2081 4483 4481 AAUUUAGCUGGACAUUGGAdTdT 151 UCCAAUGUCCAGCUAAAUUdTdT 152 AL-DP-2082 4484 4482 AUUUAGCUGGACAUUCGAUdTdT 153 AUCCAAUGUCCAGCUAAAUdTdT 154 AL-DP-2083 4486 4484 UUACCUGGACAUUCOAUUCdTUT ISS C AAUCCA A UGUCCAGCU A AdTdT 156 AL-DP-20&4 4539 4537 UUUUGAAAAAGAUUGGGGAdTdT 157i UCCCCAAUCUUUUUCAAAAdTdT 158 AL-DP-2134 4540 4538 UUUGAAAAAGAUUGGGGAGdTdT 152 CUCCCCAAUCUUUUUCAAAdTdT 160 AL-DP-2135 4542 4540 UGAAAAAGAUUGGGGAGAGdTdT 161 CUCUCCCCAAUCUUUUUCAdTdT 162 AL-DP-2136 4543 4541 GAAAAAGAUUGGGGAGAGGdTcrT 163 CCUCUCCCCAAUCUUUUUCdTdT 164 AL-DP-2137 4671 4669 UAUGAACACUUCAGAUCUUdTdT 165 AAGAUCUGAAGUGUUCAUAdTdT 166 AL-DP-2085 4672 4670 AUGAACACUUCAGAUCUUCdTdT 152 GAACAUCUGAAGUGUUCAUdTdT 168 AL-DP-2086 4867 4865 UGCCCUUGGGUUGUUAACAdTdT 169 UGUUAACAACCCAAGGGCAdTdT 123 AL-DP-2087 4868 4866 GCCCUUGGOUUGUUAACA UdTdT 171 AUGUUAACAACCCAAGGGCdTdT 172 AL-DP-2088 5544 5542 UAUAGCAUUCAUAGGUGAAdTdT 173 UUCACCUAUGAAUGCUAUAdTdT 174 AL-DP-2089 5545 5543 AUAGCAUUCAUAGGUGAAGdTdT 175 CUUCACCUAUGAAUGCUAUdTdT 176 AL-DP-2090 5546 5544 UAGCAUUCAUAGGUGAAGGdTdT 177 CCUUCACCUAUGAAUGCUAdTdT 178 AL-DP-2091 5550 5548 AUUCAUAGGUGAAGGAGCAdTdT 179 UGCUCCUUCACCUAUGAAUdTdT 133 AL-DP-2092

I 184162/2 Φ αί 5Μ0 5638 UUGCAAUGAUCAUAGUUUAdTdT 181 UAAACUAUGAUCAUUGCAAdTdT 182 AL-DP-2093 5641 5639 UGCAAUGAUCAUAGUUUACdTdT 183 GUAAACUAUGAUCAUUCCAdTdT 184 AL-DP-2094 5642 5640 GCAAUGAUCAUAGUUUACCdTdT 185 GGUAAACUAUGAUCAUUCCdTdT lag AL-DP-2095 5643 5641 CAAUGAUCAUAGUUUACCUdTdT 187 AGGUAAACUAUGAUCAUUGdTdT 188 AVDP-2096 5644 5642 AAUCAUCAUAGUUUACCUAdTdT 189 UAGGUAAACUAUGAUCAUUdTdT 190 AL-DP-2097 5645 5643 AUGAUCAUAGUUUACCUAUdTdT 121 AUAGGUAAACUAUGAUCAUdTdT 192 AL-DP-2098 5647 5645 GAUCAUAGUUUACCUAUUGdTdT 122 CAAUAGGUAAACUAUGAUCdTdT 194 AL-DP-2138 5648 5646 AUCAUAGUUUACCUAUUGAdTdT 195 UCAAUAGGUAAACUAUGAUdTdT 196 AL-DP-2139 5649 5647 UCAUAGUUUACCUAUUGAGdTdT 197 CUCAAUAGGUAAACUAUGAdTdT 198 AL-DP-2140 5650 5648 CAUAGUUUACCUAUUGAGUdTdT 199 ACUCAAUAGGUAAACUAUGdTdT 200 AL-DP-2099 5651 5649 AUAGUUUACCUAUUGAGUUdTdT 201 AACUCAAUAGGUAAACUAUdTdT 202 AL-DP-2100 5752 5750 CAUUGGUCUUAUUUACAUArfTdT 203 (JAUGUAAAUAAGACCAAUGdTdT . 204 AL-DP-2101 5754 5752 UUGGUCUUAUUUACAUAUAdTdT 205 UAUAUGUAAAUAAGACCAAdTdT 20$ AL-DP-2I02 5755 5753 UGGUCUUAUUUACAUAUAAdTdT 207 UUAUAUGUAAAUAAGACCAdTdT 208 AL-DP-2I03 5756 5754 GGUCUUAUUUACAUAUAAAdTdT 209 UUUAUAUGUAAAUAAGACCdTdT 210 AL-DP-2M1 5919 5917 AUAUCAUGCUCAAGAUGAUdTdT 211 AUCAUCUUGAGCAUGAUAUdTdT 212 AL-DP-2142 5920 5918 UAUCAUGCUCAAGAUGAUAdTdT 213 UAUCAUCUUGAGCAUGAUAdTdT 214 AL-DP-2104 5934 5932 UGAUAUUGAUUUCAAAUUAdTdT Z15 UAAUUUGAAAUCAAUAUCAdTdT 216 AI^DP-2105 6016 6014 UACUUAGUCCUUACAAUAGdTdT 217 CUAUUGUAAGGACUAAGUAdTrfr 218 AL-DP-2106 6019 6017 UUAGUCCUUACAAUAGGUCdTdT 219 GACCUAUUGUAAGGACUAAdTdT 220 AL-DP-2J07 6020 6018 UAOUCCUUACAAUAGGUCCdTdT 221 GGACCUAUUGUAAGGACUAdTdT 222 AI^DP-2108 6252 6250 AUAUUCUAUAGCUGGACGUdTdT 222 ACGUCCAGCUAUAGAAUAUdTdT 224 AL-DP-2109 6253 6251 . UAUUCUAUAGCUGGACGUAdTdT 225 UACGUCCAGCUAUAGAAUAdTdT 226 AL-DP-ZllO 6254 6252 AUUCUAUAGCUGCACGUAAdTdT 227 UUACG UCCAGCUAU ACAA UcITdT 228 AI^DP-Ull 184162/2

Table lb. RSV P gene

Actual SEQ ID SEQ ID NO: % inhibition % inhibition RSV A2 % inhibition RSVA2 % inhibition RSV A2 % inhibition RSV 8 Start NO: start Pos Sense Antisense AL- DP # (5nM) 500 pM 50 pM 5pM (5nM) 55 53 AAAUUCCUAGAAUCAAUAAdTdT 229 UUAUUGAUUCUAGGAAUUUdTdT 230 AL-DP-2000 3 56 54 AAUUCCUAGAAUCAAUAAAdTdT 231 UUUAUUGAUUCUAGGAAUUdTdT 232 AL-DP-2001 4 58 56 UUCCUAGAAUCAAUAAAGGdTdT 233 CCUUUAUUGAUUCUAGGAAdTdT 234 AL-DP-2002 7 59 57 UCCUAGAAUCAAUAAAGGGdTdT 235 CCCUUUAUUGAUUCUAGGAdTdT 236 AL-DP-2003 98 93 92 84 97 61 59 CUAGAAUCAAUAAAGGGCAdTdT 237 UGCCCUUUAUUGAUUCUAGcfTdT 238 AL-DP-2004 3 322 320 ACAUUUGAUAACAAUGAAGdTdT 239 CUUCAUUGUUAUCAAAUGUdTdT 240 AL-DP-2005 7 323 321 CAUUUGAUAACAAUGAAGAdTdT 241 UCUUCAUUGUUAUCAAAUGdTdT 242 AL-DP-2006 5 324 322 AUUUGAUAACAAUGAAGAAdTdT 243 UUCUUCAUUGUUAUCAAAUdTdT 244 AL-DP-2007 4 325 323 UUUGAUAACAAUGAAGAAGdTdT 245 CUUCUUCAUUGUUAUCAAAdTdT 246 AL-DP-2008 7 426 424 AAGUGAAAUACUAGGAAUGdTdT 247 CAUUCCUAGUAUUUCACUUdTdT 248 AL-DP-2009 2 427 425 AGUGAAAUACUAGGAADGCdTdT 249 GCAUUCCUAGUAUUUCACUdTdT 250 AL-DP-2010 7 428 426 GUGAAAUACUAGGAAUGCUdTdT 251 AGCAUUCCUAGUAUUUCACdTdT 252 AL-DP-2011 4 429 427 UGAAAUACUAGGAAUGCUUdTdT 253 AAGCAUUCCUAGUAUUUCAdTdT 254 AL-DP-2012 96 77 68 66 92 430 428 GAAAUACUAGGAAUGCUUCdTdT 255 GAAGCAUUCCUAGUAUUUCdTdT 256 AL-DP-2013 98 85 76 75 89 431 429 AAAUACUAGGAAUGCUUCAdTdT 257 UGAAGCAUUCCUAGUAUUUdTdT 258 AL-DP-2014 98 85 81 68 66 550 548 GAAGCAUUAAUGACCAAUGdTdT 259 CAUUGGUCAUUAAUGCUUCdTdT 260 AL-DP-2015 7 551 549 AAGCAUUAAUGACCAAUGAdTdT 261 UCAUUGGUCAUUAAUGCUUdTdT 262 AL-DP-2016 98 88 82 75 94 CGAUAAUAUAACAGCAAGAdTsdT 263 UCUUGCUGUUAUAUUAUCGdTsdT 264 AL-DP-1729 90 CGAUUAUAUUACAGGAUGAdTsdT 265 UCAUCCUGUAAUAUAAUCGdTsdT 266 AL-DP-1730

Table lc, RSV N gene

Actual start Sense SEO ID NO: Antisense SEQ ID NO: AL-DP # % inhibition (5nM) % inhibition RSV A2 500 pM % inhibition RSV A2 50 pM % inhibition RSVA2 5pM •A inhibition RSVB (5nM) 3 GGCUCUUAGCAAAGUCAAGdTdT 267 CUUGACUUUGCUAAGAGCCdTdT 268 AL-DP-2017 98 86 84 80 93 5 CUCUUAGCAAAGUCAAGUUdTdT 269 AACUUGACUUUGCUAAGAGdTdT 270 AL-DP-2018 2 52 CUGUCAUCCAGCAAAUACAdTdT 271 UGUAUUUGCUGGAUGACAGdTdT 272 AL-DP-2019 5 S3 UGUCAUCCAGCAAAUACACdTdT 273 GUGUAUUUGCUGGAUGACAdTdT 274 AL-DP-2020 2 191 UAAUAGGUAUGUUAUAUGCdTdT 2Z§ GCAUAUAACAUACCUAUUAdTdT 276 AL-OP-2021 3 379 AUUGAGAUAGAAUCUAGAAdTdT 277 UUCUAGAUUCUAUCUCAAUdTdT 278 AL-DP-2022 98 78 77 75 94 897 AUUCUACCAUAUAUUGAACdTdT 279 GUUCAAUAUAUGGUAGAAUdTdT 280 AL-DP-2023 1 898 UUCUACCAUAUAUUGAACAdTdT 281 UGUUCAAUAUAUGGUAGAAdTdT 282 AL-DP-2024 7 839 UCUACCAUAUAUUGAACAAdTdT 283 UUGUUCAAUAUAUGGUAGAdTdT 284 AL-DP-2025 96 89 84 77 SS 184162/2 Q'DD^an , mnxan rw:n ατα inia^a pnow pnszn irn ητ naoa ,Ρ’ηη ηχΰπ iaoana naavra noirmaa np’ioo .muwan rwaa mpnan ρηυ1? oxnna mnnn iv

<img img-format="tif" img-content="drawing" file="IL184162AD00021.tif" id="idf0001" />

.(mnma nmnn) mos^an mwa 184162/2

SEQUENCE LISTING &lt;110&gt; ALNYLAM PHARMACEUTICALS, INC.

&lt;120&gt; RNAI MODULATION OF RSV AND THERAPEUTIC USES THEREOF

&lt;130&gt; 26421-13805EP &lt;140&gt; EP 06717600.8-1223 &lt;141&gt; 2008-03-04 &lt;150&gt; PCT/US2006/000425 &lt;151&gt; 2006-01-06 &lt;150&gt; 60/642,364 &lt;151&gt; 2005-01-07 &lt;150&gt; 60/659,828 &lt;151&gt; 2005-03-09 &lt;160&gt; 284 &lt;170&gt; Patentln Ver. 3.3 &lt;210&gt; 1 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oli gonucleoti de &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oli gonucleoti de &lt;400&gt; 1 ggaucccauu auuaauggat t 21 &lt;210&gt; 2 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oli gonucleoti de &lt;400&gt; 2 uccauuaaua augggaucct t 21 &lt;210&gt; 3 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oli gonucleoti de 49 184162/2 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oli gonucleoti de &lt;400&gt; 3 gaucccauua uuaauggaat t 21 &lt;210&gt; 4 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 4 uuccauuaau aaugggauct t 21 &lt;210&gt; 5 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oli gonucleoti de &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 5 aguuauuuaa aagguguuat t 21 &lt;210&gt; 6 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oli gonucleoti de &lt;400&gt; 6 uaacaccuuu uaaauaacut t 21 &lt;210&gt; 7 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oli gonucleoti de 50 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 7 guuauuuaaa agguguuaut t 21 &lt;210&gt; 8 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 8 auaacaccuu uuaaauaact t 21 &lt;210&gt; 9 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 9 auuuaaaagg uguuaucuct t 21 &lt;210&gt; 10 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oli gonucleoti de &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 10 gagauaacac cuuuuaaaut t 21 &lt;210&gt; 11 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 51 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 11 uuaaaaggug uuaucucuut t 21 &lt;210&gt; 12 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 12 aagagauaac accuuuuaat t 21 &lt;210&gt; 13 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 13 aaguccacua cuagagcaut t 21 &lt;210&gt; 14 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence': Synthetic oligonucleotide &lt;400&gt; 14 augcucuagu aguggacuut t 21 &lt;210&gt; 15 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide 52 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 15 aguccacuac uagagcauat t 21 &lt;210&gt; 16 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 16 uaugcucuag uaguggacut t 21 &lt;210&gt; 17 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 17 guccacuacu agagcauaut t 21 &lt;210&gt; 18 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 18 auaugcucua guaguggact t 21 &lt;210&gt; 19 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 53 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Syntnetic oligonucleotide &lt;400&gt; 19 uccacuacua gagcauaugt t 21 &lt;210&gt; 20 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 20 cauaugcucu aguaguggat t 21

&lt;210&gt; 21 1 W5EP &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 21 gaagagcuau agaaauaagt t 21 &lt;210&gt; 22 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oli gonucleoti de &lt;220&gt; &lt;223&gt; Description of Artificial Sequence; Synthetic oligonucleotide &lt;400&gt; 22 cuuauuucua uagcucuuct t 21 &lt;210&gt; 23 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oli gonucleoti de 541 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 23 gagcuauaga aauaagugat t 21 &lt;210&gt; 24 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 24 ucacuuauuu cuauagcuct t 21 &lt;210&gt; 25 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 25 cuauagaaau aagugaugut t 21 &lt;210&gt; 26 &lt;211&gt; 21 &lt;212&gt; DNA . &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 26 acaucacuua uuucuauagt t 21 &lt;210&gt; 27 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid seauence: Synthetic oligonucleotide 55

I &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 27 ucaaaacaac acucuugaat t 21 &lt;210&gt; 28 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 28 uucaagagug uuguuuugat t 21 &lt;210&gt; 29 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 29 uagagggauu uauuauguct t 21 &lt;210&gt; 30 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 30 gacauaauaa aucccucuat t 21 &lt;210&gt; 31 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 56 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 31 7 auaaaagggu uuguaaauat t 21 &lt;210&gt; 32 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 32 uauuuacaaa cccuuuuaut t 21 &lt;210&gt; 33 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 33 cucaguguag guagaaugut t 21 &lt;210&gt; 34 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 34 acauucuacc uacacugagt t 21 &lt;210&gt; 35 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide 57 &lt;220&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 35 ucaguguagg uagaauguut t 21 &lt;210&gt; 36 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; ., &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 36 aacauucuac cuacacugat t 21 &lt;210&gt; 37 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 37 caguguaggu agaauguuut t 21 &lt;210&gt; 38 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 38 aaacauucua ccuacacugt t 21 &lt;210&gt; 39 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 58 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 39 aguguaggua gaauguuugt t 21 &lt;210&gt; 40 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 40 caaacauucu accuacacut t 21 &lt;210&gt; 41 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 41 guguagguag aauguuugct t &lt;210&gt; 42 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;220&gt; , . &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 42 gcaaacauuc uaccuacact t &lt;210&gt; 43 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oli gonucleoti de 59 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 43 acaagauaug gugaucuagt t 21 &lt;210&gt; 44 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 44 cuagaucacc auaucuugut t 21 &lt;210&gt; 45 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 45 agcaaauuca aucaagcaut t &lt;210&gt; 46 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; , . &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 46 augcuugauu gaauuugcut t &lt;210&gt; 47 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; , . &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 60 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 47 gcaaauucaa ucaagcauut t 21 &lt;210&gt; 48 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 48 aaugcuugau ugaauuugct t 21 &lt;210&gt; 49 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 49 gaugaacaaa guggauuaut t 21 &lt;210&gt; 50 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 50 auaauccacu uuguucauct t 21 &lt;210&gt; 51 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 61 &lt;22Ο&gt; &lt;223&gt; Description of Artificial sequence: synthetic oligonucleotide &lt;400&gt; 51 uaauaucucu caaagggaat t 21 &lt;210&gt; 52 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 52 uucccuuuga gagauauuat t 21 &lt;210&gt; 53 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 53 auaucucuca aagggaaaut t 21 &lt;210&gt; 54 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 54 auuucccuuu gagagauaut t 21 &lt;210&gt; 55 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 62 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 55 uaucucucaa agggaaauut t 21 &lt;210&gt; 56 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 56 aauuucccuu ugagagauat t 21 &lt;210&gt; 57 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 57 caugcucaag cagauuauut t &lt;210&gt; 58 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 58 aauaaucugc uugagcaugt t &lt;210&gt; 59 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; , . &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide 63 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 59 ugcucaagca gauuauuugt t 21 &lt;210&gt; 60 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 60 caaauaaucu gcuugagcat t 21 &lt;210&gt; 61 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 61 uagcauuaaa uagccuuaat t 21 &lt;210&gt; 62 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oli gonucleoti de &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 62 uuaaggcuau uuaaugcuat t 21 &lt;210&gt; 63 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oli gonucleoti de 64 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 63 agcauuaaau agccuuaaat t 21 &lt;210&gt; 64 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial sequence: synthetic oligonucleotide &lt;400&gt; 64 uuuaaggcua uuuaaugcut t 21 &lt;210&gt; 65 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 65 gcauuaaaua gccuuaaaut t 21 &lt;210&gt; 66 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 66 auuuaaggcu auuuaaugct t 21 &lt;210&gt; 67 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 65 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 67 cauuaaauag ccuuaaauut t 21 &lt;210&gt; 68 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 68 aauuuaaggc uauuuaaugt t 21 &lt;210&gt; 69 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence - &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 69 uauuaugcag uuuaauauut t 21 &lt;210&gt; 70 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 70 aauauuaaac ugcauaauat t 21 &lt;210&gt; 71 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide 66 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 71 uuaugcaguu uaauauuuat t 21 &lt;210&gt; 72 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 72 uaaauauuaa acugcauaat t 21 &lt;210&gt; 73 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence — &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 73 aaaagugcac aacauuauat t 21 &lt;210&gt; 74 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 74 uauaauguug ugcacuuuut t 21 &lt;210&gt; 75 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide 67 &lt;220&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 75 aaagugcaca acauuauact t 21 &lt;210&gt; 76 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;22O&gt; ..,, &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 76 guauaauguu gugcacuuut t 21 &lt;210&gt; 77 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 77 auauagaacc uacauaucct t 21 &lt;210&gt; 78 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 78 ggauauguag guucuauaut t 21 &lt;210&gt; 79 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide 68 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 79 uauagaaccu acauauccut t &lt;210&gt; 80 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 80 aggauaugua gguucuauat t &lt;210&gt; 81 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence s- &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 81 uaagaguugu uuaugaaagt t 21 &lt;210&gt; 82 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 82 cuuucauaaa caacucuuat t 21 &lt;210&gt; 83 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide 69 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 83 acagucagua guagaccaut t 21 &lt;210&gt; 84 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 84 auggucuacu acugacugut t 21 &lt;210&gt; 85 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence ' &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 85 cagucaguag uagaccaugt t 21 &lt;210&gt; 86 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 86 cauggucuac uacugacugt t 21 &lt;210&gt; 87 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 70 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 87 agucaguagu agaccaugut t 21 &lt;210&gt; 88 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 88 acauggucua cuacugacut t 21 &lt;210&gt; 89 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence . X- &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 89 gucaguagua gaccaugugt t 21 &lt;210&gt; 90 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 90 cacauggucu acuacugact t 21

71 I &lt;210&gt; 91 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 91 ucaguaguag accaugugat t 21 &lt;210&gt; 92 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 92 ucacaugguc uacuacugat t 21 &lt;210&gt; 93 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 93 caugugaauu cccugcauct t 21 &lt;210&gt; 94 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 94 gaugcaggga auucacaugt t 21 &lt;210&gt; 95 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide 72 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 95 augugaauuc ccugcaucat t 21 &lt;210&gt; 96 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial sequence: synthetic oligonucleotide &lt;400&gt; 96 ugaugcaggg aauucacaut t 21 &lt;210&gt; 97 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 97 ugugaauucc cugcaucaat t 21 &lt;210&gt; 98 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 98 uugaugcagg gaauucacat t 21 &lt;210&gt; 99 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 73 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 99 gugaauuccc ugcaucaaut t 21 &lt;210&gt; 100 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 100 auugaugcag ggaauucact t 21 &lt;210&gt; 101 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence .c &lt; &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 101 aauucccugc aucaauacct t 21 &lt;210&gt; 102 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 102 gguauugaug cagggaauut t 21 &lt;210&gt; 103 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 74 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 103 gcaucaauac cagcuuauat t 21 &lt;210&gt; 104 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;22O&gt; 0 &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 104 uauaagcugg uauugaugct t 21 &lt;210&gt; 105 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 105 caucaauacc agcuuauagt t 21 &lt;210&gt; 106 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 106 cuauaagcug guauugaugt t 21 &lt;210&gt; 107 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid seauence: Synthetic oligonucleotide 75 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 107 auaccagcuu auagaacaat t 21 &lt;210&gt; 108 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 108 uuguucuaua agcugguaut t 21 &lt;210&gt; 109 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 109 uaccagcuua uagaacaact t 21 &lt;210&gt; 110 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 110 guuguucuau aagcugguat t 21 7ft &lt;210&gt; 111 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 111 accagcuuau agaacaacat t 21 &lt;210&gt; 112 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 112 uguuguucua uaagcuggut t 21 &lt;210&gt; 113 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 113 ccagcuuaua gaacaacaat t 21 &lt;210&gt; 114 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial sequence: synthetic oligonucleotide &lt;400&gt; 114 uuguuguucu auaagcuggt t 21 &lt;210&gt; 115 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oli gonucleoti de 77 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 115 cagcuuauag aacaacaaat t &lt;210&gt; 116 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial sequence: synthetic oligonucleotide &lt;400&gt; 116 uuuguuguuc uauaagcugt t 21 &lt;210&gt; 117 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial sequence: synthetic oligonucleotide &lt;400&gt; 117 auagaacaac aaauuaucat t 21 &lt;210&gt; 118 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 118 ugauaauuug uuguucuaut t 21 &lt;210&gt; 119 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide 78 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence·; Synthetic oligonucleotide &lt;400&gt; 119 uauuaacaga aaaguauggt t &lt;210&gt; 120 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oli gonucleoti de &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 120 ccauacuuuu cuguuaauat t &lt;210&gt; 121 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 121 ugagauacau uugaugaaat t 21 &lt;210&gt; 122 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 122 uuucaucaaa uguaucucat t 21 &lt;210&gt; 123 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oli gonucleoti de 79 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide 1' &lt;400&gt; 123 gagauacauu ugaugaaact t 21 &lt;210&gt; 124 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 124 guuucaucaa auguaucuct t 21 &lt;210&gt; 125 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 125 gauacauuug augaaaccut t 21 &lt;210&gt; 126 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 126 agguuucauc aaauguauct t 21 &lt;210&gt; 127 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 80 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 127 auacauuuga ugaaaccuct t 21 &lt;210&gt; 128 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 128 gagguuucau caaauguaut t 21 &lt;210&gt; 129 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 129 uacauuugau gaaaccucct t 21 &lt;210&gt; 130 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 130 ggagguuuca ucaaauguat t 21 &lt;210&gt; 131 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oli gonucleoti de 81 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 131 aagugauaca aaaacagcat t 21 &lt;210&gt; 132 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 132 ugcuguuuuu guaucacuut t 21 &lt;210&gt; 133 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oli gonucleoti de &lt;400&gt; 133 agugauacaa aaacagcaut t &lt;210&gt; 134 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 134 augcuguuuu uguaucacut t 21 &lt;210&gt; 135 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 82 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 135 ugauacaaaa acagcauaut t 21 &lt;210&gt; 136 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 136 auaugcuguu uuuguaucat t 21 &lt;210&gt; 137 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 137 uuuaaguacu aauuuagcut t 21 &lt;210&gt; 138 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 138 agcuaaauua guacuuaaat t 21 &lt;210&gt; 139 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 83 &lt;220&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 139 uuaaguacua auuuagcugt t 21 &lt;210&gt; 140 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 140 cagcuaaauu aguacuuaat t 21 &lt;210&gt; 141 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; c223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 141 uaaguacuaa uuuagcuggt t 21 &lt;210&gt; 142 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 142 ccagcuaaau uaguacuuat t 21 &lt;210&gt; 143 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide 84 &lt;22Ο&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 143 aaguacuaau uuagcuggat t &lt;210&gt; 144 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 144 uccagcuaaa uuaguacuut t 21 &lt;210&gt; 145 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 145 aguacuaauu uagcuggact t 21 &lt;210&gt; 146 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 146 guccagcuaa auuaguacut t 21 &lt;210&gt; 147 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid seauence: Synthetic oligonucleotide 85 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 147 guacuaauuu agcuggacat t 21 &lt;210&gt; 148 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 148 uguccagcua aauuaguact t 21 &lt;210&gt; 149 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 149 acuaauuuag cuggacauut t 21 &lt;210&gt; 150 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 150 aauguccagc uaaauuagut t 21 &lt;210&gt; 151 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide 86 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 151 aauuuagcug gacauuggat t 21 &lt;210&gt; 152 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 152 uccaaugucc agcuaaauut t 21 &lt;210&gt; 153 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 153 auuuagcugg acauuggaut t 21 &lt;210&gt; 154 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 154 auccaauguc cagcuaaaut t 21 &lt;210&gt; 155 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 87 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 155 uuagcuggac auuggauuct t 21 &lt;210&gt; 156 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 156 gaauccaaug uccagcuaat t 21 &lt;210&gt; 157 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 157 uuuugaaaaa gauuggggat t 21 &lt;210&gt; 158 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 158 uccccaaucu uuuucaaaat t 21 &lt;210&gt; 159 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 88 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 159 uuugaaaaag auuggggagt t 21 &lt;210&gt; 160 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 160 cuccccaauc uuuuucaaat t 21 &lt;210&gt; 161 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 161 ugaaaaagau uggggagagt t 21 &lt;210&gt; 162 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 162 cucuccccaa ucuuuuucat t 21 &lt;210&gt; 163 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide 89 &lt;22Ο&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 163 gaaaaagauu ggggagaggt t &lt;210&gt; 164 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 164 ccucucccca aucuuuuuct t &lt;210&gt; 165 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 165 uaugaacacu ucagaucuut t 21 &lt;210&gt; 166 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 166 aagaucugaa guguucauat t 21 &lt;210&gt; 167 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic ol i gonucleoti de 90 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 167 augaacacuu cagaucuuct t 21 &lt;210&gt; 168 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial sequence: synthetic oligonucleotide &lt;400&gt; 168 gaagaucuga aguguucaut t 21 &lt;210&gt; 169 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;223&gt; Description of Artificial sequence: synthetic oligonucleotide &lt;400&gt; 169 ugcccuuggg uuguuaacat t 21 &lt;210&gt; 170 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 170 uguuaacaac ccaagggcat t 21 &lt;210&gt; 171 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 91 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 171 gcccuugggu uguuaacaut t 21 &lt;210&gt; 172 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 172 auguuaacaa cccaagggct t 21 &lt;210&gt; 173 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 173 uauagcauuc auaggugaat t &lt;210&gt; 174 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 174 uucaccuaug aaugcuauat t &lt;210&gt; 175 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 92 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 175 auagcauuca uaggugaagt t 21 &lt;210&gt; 176 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oli gonucleoti de &lt;400&gt; 176 cuucaccuau gaaugcuaut t 21 &lt;210&gt; 177 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 177 uagcauucau aggugaaggt t 21 &lt;210&gt; 178 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 178 ccuucaccua ugaaugcuat t 21 &lt;210&gt; 179 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 93 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 179 auucauaggu gaaggagcat t 21 &lt;210&gt; 180 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 180 ugcuccuuca ccuaugaaut t 21 &lt;210&gt; 181 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 181 uugcaaugau cauaguuuat t 21 &lt;210&gt; 182 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 182 uaaacuauga ucauugcaat t 21 &lt;210&gt; 183 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oli gonucleoti de 94 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 183 ugcaaugauc auaguuuact t 21 &lt;210&gt; 184 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oli gonucleoti de &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 184 guaaacuaug aucauugcat t 21 &lt;210&gt; 185 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 185 gcaaugauca uaguuuacct t &lt;210&gt; 186 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial sequence: synthetic oligonucleotide &lt;400&gt; 186 gguaaacuau gaucauugct t 21 &lt;210&gt; 187 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleoti de 95 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 187 0, .· caaugaucau aguuuaccut t 21 &lt;210&gt; 188 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid .sequence: Synthetic oli gonucleoti de &lt;22O&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 188 agguaaacua ugaucauugt t 21 &lt;210&gt; 189 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial sequence: synthetic oligonucleotide &lt;400&gt; 189 aaugaucaua guuuaccuat t &lt;210&gt; 190 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oli gonucleoti de &lt;400&gt; 190 uagguaaacu augaucauut t 21 &lt;210&gt; 191 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oli gonucleoti de 96 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 191 augaucauag uuuaccuaut t 21 &lt;210&gt; 192 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oli gonucleoti de &lt;400&gt; 192 auagguaaac uaugaucaut t 21 &lt;210&gt; 193 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 193 gaucauaguu uaccuauugt t &lt;210&gt; 194 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 194 caauagguaa acuaugauct t 21 &lt;210&gt; 195 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; , . &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide 97 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 195 aucauaguuu accuauugat t 21 &lt;210&gt; 196 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 196 ucaauaggua aacuaugaut t 21 &lt;210&gt; 197 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; , . &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 197 ucauaguuua ccuauugagt t &lt;210&gt; 198 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; , . &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 198 cucaauaggu aaacuaugat t &lt;210&gt; 199 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; , . &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide 98 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 199 cauaguuuac cuauugagut t 21 &lt;210&gt; 200 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 200 acucaauagg uaaacuaugt t 21 &lt;210&gt; 201 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 201 auaguuuacc uauugaguut t 21 &lt;210&gt; 202 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 202 aacucaauag guaaacuaut t 21 &lt;210&gt; 203 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 99 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 203 cauuggucuu auuuacauat t 21 &lt;210&gt; 204 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 204 uauguaaaua agaccaaugt t 21 &lt;210&gt; 205 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 205 uuggucuuau uuacauauat t &lt;210&gt; 206 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oli gonucleoti de &lt;400&gt; 206 uauauguaaa uaagaccaat t &lt;210&gt; 207 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; , . &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oli gonucleoti de 100 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 207 uggucuuauu uacauauaat t 21 &lt;210&gt; 208 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 208 uuauauguaa auaagaccat t 21 &lt;210&gt; 209 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 209 ggucuuauuu acauauaaat t 21 &lt;210&gt; 210 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 210 uuuauaugua aauaagacct t 21 &lt;210&gt; 211 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 101 &lt;220&gt; &lt;223&gt; Description of Artificial sequence: synthetic oligonucleotide &lt;400&gt; 211 auaucaugcu caagaugaut t 21 &lt;210&gt; 212 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 212 aucaucuuga gcaugauaut t 21 &lt;210&gt; 213 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; , . &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 213 uaucaugcuc aagaugauat t &lt;210&gt; 214 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 214 uaucaucuug agcaugauat t &lt;210&gt; 215 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 102 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 215 ugauauugau uucaaauuat t 21 &lt;210&gt; 216 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 216 uaauuugaaa ucaauaucat t 21 &lt;210&gt; 217 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; , . &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 217 uacuuagucc uuacaauagt t &lt;210&gt; 218 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; , . &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 218 cuauuguaag gacuaaguat t &lt;210&gt; 219 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; , . &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide 1031 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 219 uuaguccuua caauagguct t 21 &lt;210&gt; 220 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 220 gaccuauugu aaggacuaat t 21 &lt;210&gt; 221 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oli gonucleoti de &lt;400&gt; 221 uaguccuuac aauaggucct t 21 &lt;210&gt; 222 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oli gonucleoti de &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 222 ggaccuauug uaaggacuat t 21 &lt;210&gt; 223 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 104 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 223 auauucuaua gcuggacgut t 21 &lt;210&gt; 224 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 224 acguccagcu auagaauaut t 21 &lt;210&gt; 225 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 225 uauucuauag cuggacguat t 21 &lt;210&gt; 226 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 226 uacguccagc uauagaauat t 21 &lt;210&gt; 227 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide 105 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 227 auucuauagc uggacguaat t 21 &lt;210&gt; 228 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 228 uuacguccag cuauagaaut t 21 &lt;210&gt; 229 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 229 aaauuccuag aaucaauaat t &lt;210&gt; 230 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 230 uuauugauuc uaggaauuut t 21 &lt;210&gt; 231 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 106 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 231 aauuccuaga aucaauaaat t 21 &lt;210&gt; 232 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 232 uuuauugauu cuaggaauut t 21 &lt;210&gt; 233 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial sequence: synthetic oligonucleotide &lt;400&gt; 233 uuccuagaau caauaaaggt t 21 &lt;210&gt; 234 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 234 ccuuuauuga uucuaggaat t 21 &lt;210&gt; 235 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide 107' &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 235 uccuagaauc aauaaagggt t 21 &lt;210&gt; 236 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 236 cccuuuauug auucuaggat t 21 &lt;210&gt; 237 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 237 cuagaaucaa uaaagggcat t 21 &lt;210&gt; 238 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 238 ugcccuuuau ugauucuagt t 21 &lt;210&gt; 239 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oli gonucleoti de 108 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 239 acauuugaua acaaugaagt t 21 &lt;210&gt; 240 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oli gonucleoti de &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oli gonucleoti de &lt;400&gt; 240 cuucauuguu aucaaaugut t 21 &lt;210&gt; 241 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 241 cauuugauaa caaugaagat t 21 &lt;210&gt; 242 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial sequence: synthetic oligonucleotide &lt;400&gt; 242 ucuucauugu uaucaaaugt t 21 &lt;210&gt; 243 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide 109 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 243 auuugauaac aaugaagaat t 21 &lt;210&gt; 244 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 244 uucuucauug uuaucaaaut t 21 &lt;210&gt; 245 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 245 uuugauaaca augaagaagt t 21 &lt;210&gt; 246 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; , . &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 246 cuucuucauu guuaucaaat t 21 &lt;210&gt; 247 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oli gonucleoti de 110 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence:-Synthetic oligonucleotide * -- - &lt;400&gt; 247 aagugaaaua cuaggaaugt t 21 &lt;210&gt; 248 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid seque/ice: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial sequence/Synthetic oligonucleotide &lt;400&gt; 248 cauuccuagu auuucacuut t 21 &lt;210&gt; 249 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; ’ &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oli gonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 249 agugaaauac uaggaaugct t 21 &lt;210&gt; 250 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 250 gcauuccuag uauuucacut t 21 &lt;210&gt; 251 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide 111 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oli gonucleoti de &lt;400&gt; 251 gugaaauacu aggaaugcut t 21 &lt;210&gt; 252 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oli gonucleoti de &lt;400&gt; 252 agcauuccua guauuucact t 21 &lt;210&gt; 253 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;220&gt; , . &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 253 ugaaauacua ggaaugcuut t 21 &lt;210&gt; 254 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; , . &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; , . &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 254 aagcauuccu aguauuucat t 21 &lt;210&gt; 255 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide 112 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 255 gaaauacuag gaaugcuuct t 21 &lt;210&gt; 256 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 256 gaagcauucc uaguauuuct t 21 &lt;210&gt; 257 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 257 aaauacuagg aaugcuucat t &lt;210&gt; 258 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 258 ugaagcauuc cuaguauuut t 21 &lt;210&gt; 259 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide 113 &lt;22Ο&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 259 gaagcauuaa ugaccaaugt t 21 &lt;210&gt; 260 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 260 cauuggucau uaaugcuuct t 21 &lt;210&gt; 261 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 261 aagcauuaau gaccaaugat t 21 &lt;210&gt; 262 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oli gonucleoti de &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 262 ucauugguca uuaaugcuut t 21 &lt;210&gt; 263 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide 114 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 263 cgauaauaua acagcaagat t 21 &lt;210&gt; 264 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 264 ucuugcuguu auauuaucgt t 21 &lt;210&gt; 265 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 265 cgauuauauu acaggaugat t 21 &lt;210&gt; 266 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 266 ucauccugua auauaaucgt t 21 &lt;210&gt; 267 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide 115 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 267 ggcucuuagc aaagucaagt t 21 &lt;210&gt; 268 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 268 cuugacuuug cuaagagcct t 21 &lt;210&gt; 269 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial sequence: Synthetic oligonucleotide &lt;400&gt; 269 cucuuagcaa agucaaguut t 21 &lt;210&gt; 270 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; , . &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;22O&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 270 aacuugacuu ugcuaagagt t 21 &lt;210&gt; 271 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 116 &lt;220&gt; &lt;223&gt; Description of Artificial sequence: synthetic oli gonucleoti de &lt;400&gt; 271 cugucaucca gcaaauacat t 21 &lt;210&gt; 272 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 272 uguauuugcu ggaugacagt t 21 &lt;210&gt; 273 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 273 ugucauccag caaauacact t &lt;210&gt; 274 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; , . &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 274 guguauuugc uggaugacat t &lt;210&gt; 275 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial sequence &lt;22O&gt; , . &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 117 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 275 uaauagguau guuauaugct t 21 &lt;210&gt; 276 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 276 gcauauaaca uaccuauuat t 21 &lt;210&gt; 277 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 277 auugagauag aaucuagaat t 21 &lt;210&gt; 278 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 278 uucuagauuc uaucucaaut t 21 &lt;210&gt; 279 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;22O&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 118 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 279 auucuaccau auauugaact t. 21 &lt;210&gt; 280 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oligonucleotide &lt;400&gt; 280 guucaauaua ugguagaaut t 21 &lt;210&gt; 281 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of dna/rna hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 281 uucuaccaua uauugaacat t 21 &lt;210&gt; 282 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: synthetic oli gonucleoti de &lt;400&gt; 282 uguucaauau augguagaat t 21 &lt;210&gt; 283 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide 119 &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 283 ucuaccauau auugaacaat t 21 &lt;210&gt; 284 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Artificial Sequence &lt;220&gt; &lt;223&gt; Description of DNA/RNA hybrid sequence: Synthetic oligonucleotide &lt;220&gt; &lt;223&gt; Description of Artificial Sequence: Synthetic oligonucleotide &lt;400&gt; 284 uuguucaaua uaugguagat t 21 120