MX2008005572A - Rnai inhibition of influenza virus replication - Google Patents

Abstract

The invention relates to compositions and methods for modulating the expression of influenza viral genes, and more particularly to the downregulation of influenza viral genes by chemically modified oligonucleotides

Description

INHIBITION OF RNAi OR REPLICATION OF INFLUENZA VIRUS FIELD OF THE INVENTION The invention relates to the field of influenza viral therapy and compositions and methods for modulating viral replication, and more particularly to the sub-requisition of genes of an influenza virus by oligonucleotides by means of RNA interference that is administered locally to the lungs and nasal passage by means of inhalation / intranasal administration, or are administered systemically, for example, by intravenous injection.

BACKGROUND OF THE INVENTION RNA interference or "RNAi" is a term initially coined by FIRE et al. To describe the observation that double-stranded RNA (dsRNA) can block gene expression when introduced into worms.

(Fire et al, Nature 391: 806-811, 1998). Short dsRNAs targeted to specific genes, silenced after transcription in many organisms, including vertebrates, and have provided a new tool to study the function of genes. This technology has been revised numerous times recently, see, for example, Novina, CD :, and Sharp, P., Nature 2004, 430: 161, and Sandy, P., et al., Biotechniques 2005, 39: 215, therefore incorporated for reference. Ref.: 192502 Influenza is one of the most widely spread infections worldwide. It can be deadly; an estimated 20 to 40 million people died during the pandemic influenza A virus in 1918. In the United States of America between 20 and 40 thousand people die from infection with influenza A virus or its complications each year. During epidemics, the number of hospitalizations related to influenza can reach over 300,000 in a single winter season. Several properties contribute to the epidemiological success of the influenza virus. First, it expands widely from person to person by aerosol (drip infection). Second, small changes in influenza virus antigens are frequent (antigenic flux) so that the virus quickly escapes the protective immunity induced by previous exposure to a different variant of the virus. Third, new strains of influenza virus can be easily generated by rearrangement or mixing of genetic material between different strains (antigenic change). In the case of influenza A virus, such mixing may occur between subtypes or strains that affect different species species. The 1918 pandemic is thought to be caused by a hybrid strain of virus derived from rearrangement between a pig and human influenza A virus. At present, there is a trend concerning the potential emergence of novel influenza strains infective to humans, particularly variants of avian influenza, and more particularly of the H5N1 strain, when mixed in humans exposed concurrently to human influenza viruses and avian. The close contact between farming birds and their familiar human breeders? Most Asian societies have convinced experts that there is no question of whether, but when, such a mixed strain can emerge. A worldwide pandemic could occur quickly, with even more serious consequences than in 1918. Despite the intense efforts, there is still no effective therapy for influenza virus infection and the existence of vaccines is limited in value in part to the properties of change and antigenic flow described above. For these reasons, global surveillance of the influenza A virus has been done for many years, and the National Institutes of Health designate it as one of the top priority pathogens for biodefense. Although current vaccines based on inactivated viruses are capable of preventing the disease in approximately 70-80% of healthy individuals under 65 years of age, this percentage is much lower in older or immunocompromised patients. further, the expense and potential side effects associated with the administration of vaccines make this approach less than optimal. Although antiviral drugs currently approved in the United States of America for influenza treatment and / or prophylaxis are useful, their use is limited due to the collateral effects, compliance, and possible emergence of resistant strains. The patent application E.U.A. 20040242518 and corresponding WO 04/028471, both filed on September 29, 2003, propose a limited number of RNAi agents for the treatment of influenza. Its efficacy in humans is not described. Therefore, there remains a need for the development of effective therapies for the treatment and prevention of influenza infection in humans and animals, and particularly for therapy with high efficiency that allows the management of a wide range of influenza subtypes. A prerequisite for high efficiency is that the active ingredient does not degrade rapidly in a physiological environment.

BRIEF DESCRIPTION OF THE INVENTION The present invention is based on the in vitro and in vivo demonstration that influenza virus infection can be inhibited through intranasal administration of RNAi agents, as well as by parenteral administration of such agents and identification of agents. of potent RNAi from the MP, NP, PBl, PB2, or PA gene of influenza viruses that can reduce RNA levels of various subtypes of influenza virus. Based on these findings, the present invention provides specific compositions and methods that are useful in reducing mRNA levels of influenza virus, influenza virus protein levels, and viral concentrations of influenza virus in a subject, e.g., a mammal, such as a human. The present invention specifically provides RNAi agents consisting of, consist essentially of or comprise at least 15 or more contiguous nucleotides of one of the influenza virus genes, particularly the MP, NP, PB1, PB2 and PA genes of influenza virus. , and more particularly agents comprising 15 or more contiguous nucleotides of one of the sequences provided in Tables 1A-1H. The RNAi agent preferably comprises less than 30 nucleotides per strand, eg, 21-23 nucleotides, such as those provided in Tables 1A-1H. The double-stranded RNAi agent can either have blunt tips or more preferably have coatings of 1-4 nucleotides from either or both 3 'ends of the agent. In addition, the RNAi agent can either contain only naturally occurring ribonucleotide subunits, or it can be synthesized so as to contain one or more modifications to the sugar or base of one or more of the ribonucleotide subunits that is included in the agent. The RNAi agent can be further modified so that it binds to a ligand that is selected to improve the stability, distribution or cellular absorption of the agent, for example cholesterol. The RNAi agents may also be in isolated form or may be part of a pharmaceutical composition used for the methods described herein, particularly as a pharmaceutical composition formulated for administration to the lungs or nasal passage or formulated for parenteral administration. The pharmaceutical compositions may contain one or more RNAi agents, and in some embodiments, will contain two or more RNAi agents, each directed to a different segment of an influenza virus gene or a different influenza virus gene. One aspect of the present invention relates to a double-stranded oligonucleotide comprising at least one unnatural nucleobase. In certain embodiments, the non-natural nucleobase is difluorotolyl, nitroindolyl, nitropyrrolyl, or nitroimidazolyl. In a preferred embodiment, the non-natural nucleobase is difluorotolyl. In certain embodiments, only one of the two oligonucleotide strands comprises the double-stranded oligonucleotide containing an unnatural nucleobase. In certain embodiments, both of the oligonucleotide strands comprising the double-stranded oligonucleotide independently contain an unnatural nucleobase.

The present invention further provides methods for reducing the level of viral RNA of influenza virus in a cell. Such methods comprise the step of administering one of the RNAi agents of the present invention to a subject as further described below. Current methods utilize the cellular mechanisms involved in RNA interference to selectively degrade viral RNA in a cell and are comprised of the step of contacting a cell with one of the antiviral RNAi agents of the present invention. Such methods can be performed directly in a cell or can be performed in a mammalian subject by administering to a subject one of the RNAi pharmaceutical agents / compositions of the present invention. The reduction of viral RNA in cells results in a reduction in the amount of viral protein produced, and in an organism, which results in a decrease in replicated viral concentration (as shown in the Examples). The methods and compositions of the invention, for example, the methods and compositions of the RNAi agent can be used with any dose and / or formulation described herein, as well as with any route of administration described herein. Particularly important is what is shown in the present intranasal administration of an RNAi agent and its ability to inhibit viral replication in respiratory tissues. The details of one or more embodiments of the invention are set forth in the accompanying figures and the description below. Other features, objectives, and advantages of the invention will be appreciated from this description, the drawings, and the claims. This application incorporates all cited references, patents, and patent applications for reference in its entirety for all purposes.

BRIEF DESCRIPTION OF THE FIGURES Figures 1A-1I: Dose response curves for the inhibition of the expression of the target gene for the selected RNAi agents. The respective target gene was recombinantly cloned into Cos-7 cells in a plasmid resulting in the expression of an mRNA encoding the Renilla luciferase target gene, the cells treated with the RNAi agent, and Renilla luciferase was quantified. The cells were treated with the RNAi agent at concentrations of 100 nM, 25 nM, 6.3 nM, 1.6 nM, 400 pM, 100 pM, 24 pM, 6 pM, 1.5 pM, and 380 fM, and the IC50 values determined by the parametrized curve of adjustment using the XLfit program.

DETAILED DESCRIPTION OF THE INVENTION The term "influenza virus" is used herein to refer to any strain of influenza virus that is capable of causing a disease in an animal or human subject, or that is an interesting candidate for experimental analysis. Influenza viruses are described in Fields, B., et al., Fields Virology, 4th ed. 2001, Lippincott Williams and Wilkins; Philadelphia, ISBN: 0781718325. In particular, the term encompasses any strain of influenza A virus that is capable of causing disease in an animal or human subject, or that is an interesting candidate for experimental analysis. A large number of influenza A isolates have been processed partially or completely by sequence. Table 6 presents merely a partial list of complete sequences for the influenza A genome segments that have been deposited in a public database (the influenza sequence database (ISD), see Macken, C, Lu, H ., Goodman, J., &Boykin, L., "The valuation of a database in surveillance and vaccine selection." In Options for the Control of Influenza IV ADME Osterhaus, N. Cox &AW Hampson (Eds.) 2001, Elsevier Science, Amsterdam, pp. 103-106). This database also contains complete sequences for the genome segments of influenza B and C. The database is available on the World Wide Web and includes a convenient search engine that allows the user to search the genome segment, for species infected by the virus, and per year of isolated. Influenza sequences are also available at Genbank. The influenza gene sequences are therefore readily available to, or determinedly by, those of ordinary experience in the art. For ease of disclosure 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 use of the term "ribonucleotide" or "nucleotide" herein may, in the case of a modified RNA or substitute nucleotide, also refer to a modified nucleotide, or substitute replacement portion, as further described below, in one or more positions. An "RNA agent" as used herein, is an unmodified RNA, modified RNA, or substitute nucleoside, each of which is described herein or is well known in the art of synthetic RNA. Although numerous modified RNA and nucleoside substitutes are disclosed, preferred examples include those that have greater resistance to nuclease degradation than unmodified RNAs. Preferred examples include those that have a sugar modification 2 a modification in a single-strand drape, preferably a single-strand drape 3 ', or, particularly if the single strand has a 5' modification which includes one or more groups of phosphate or one or more analogues of a phosphate group. An "RNAi agent" (abbreviation for "RNA interference agent") as used herein, is an RNA agent, which can completely regulate the expression of a target gene, for example, influenza virus. Although it is not desired to be bound by theory, an RNAi agent can act by one or more of a number of mechanisms, including post-transcriptional unfolding of an objective mRNA sometimes referred to in the art as RNAi, or pre-transcriptional or pre-translational mechanisms. An RNAi agent can be a double-stranded RNAi agent. An "RNAi agent" (abbreviation for "double-stranded RNAi agent"), as used herein, is an RNAi agent which includes more than one, and preferably two, strands in which interheat hybridization can form a region of double structure. A "strand" herein refers to a contiguous sequence of nucleotides (including modified or non-naturally occurring nucleotides). The two or more strands can be, or each forms a part of, separate molecules, or they can be covalently interconnected, for example, by a ligation, eg, a polyethylene glycol ligation, to form a molecule. At least one strand may include a region which is sufficiently complementary to a target RNA. Such a thread is called the "antisense strand." A second strand of the dsRNA agent, which comprises a region complementary to the antisense strand, is called the "sense strand". However, an RNAi agent can also be formed from a single RNA molecule which is at least partially self-complementary, forming, for example, a skimmer or pan handle structure, including a double region. The latter is referred to herein as short fork RNA or shRNA. In such a 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. However, in mammals, the agents of ds long RNAi can induce the interferon response which is frequently detrimental, short dni RNA agents do not trigger the interferon response, at least not for an extension that is detrimental to the cell and / or host (Manche et al, Mol Cell. Biol. 12: 5238, 1992; Lee et al, Virology 199: 491, 1994; Castelli et al, J. Exp. Med. 186: 967, 1997; Zheng et al, RNA 10: 1934, 2004; Heidel et al, "Lack of interferon response in animáis to naked sARNis" Natwe Biotechn. advance online publication doi: 10.1038 / nbtl038, Nov. 21, 2004). The RNAi agents of the present invention include molecules that are sufficiently short that they do not trigger a detrimental non-specific interferon response in normal mammalian cells. Thus, administration of a composition that includes an RNAi agent (eg, formulated as described herein) to a subject can be used to decrease the expression of the influenza virus genes expressing the cells in the subject, while surrounding an interferon response. Molecules that are short enough so that they do not trigger a harmful interferon response are named RNAi or sRNAi agents herein, "sRNAi agent" or "sRNAi" as used herein, refers to an RNAi agent. , for example, an RNAi ds agent, which is sufficiently short that it does not induce a detrimental interferon response in a mammalian cell, and particularly a human, for example, has a double region of less than 60 but preferably less than 50. , 40, or 30 nucleotide pairs. The isolated RNAi agents described herein, including dsRNA agents and sRNAs, can mediate the decreased expression of an influenza virus nucleic acid, for example, by RNA degradation. For convenience, such RNA is also referred to herein as the RNA to be silenced. Such nucleic acid is also referred to as a target gene. Preferably, the RNA to be silenced is a product of the gene of an influenza virus gene that is part of a strain of influenza virus that is pathogenic to humans. As used herein, the phrase "mediated RNAi" refers to the ability of an agent to silence, in a specific sequence manner, a target gene. "Mute an objective gene" means the process by which a cell that contains and / or expresses a certain product of the target gene when it is not contacted with the agent, will contain and / or express at least 10%, 20%, 30 %, 40%, 50%, 60%, 70%, 80%, or 90% less of such gene product than when contacted with the agent, as compared to a similar cell which has not been placed in contact with the agent. Such a product of the target gene can, for example, be a messenger RNA (mRNA), a protein, or a regulatory element. As used herein, the term "complementary" is used to indicate a sufficient degree of complementarity such that the stable and specific binding occurs between a compound of the invention and a target RNA molecule, e.g. influenza virus. The 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 the specific binding is desired (that is, 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 Non-target sequences typically differ from the target sequences by at least 2, 3, or 4 nucleotides.

As used herein, an RNAi agent is "sufficiently complementary" to a target RNA, e.g., a target mRNA (e.g., a mRNA of the target influenza virus) if the RNAi agent reduces the production of a protein encoded by the target RNA in the cell. The RNAi agent can also be "exactly complementary" to the target RNA, for example, the target RNA and the RNAi agent combined in their base pairs preferably to form a hybrid made exclusively of Watson-Crick base pairs in the region of exact complementarity . A "sufficiently complementary" RNAi agent can include an internal region (eg, of at least 10 nucleotides) that is exactly complementary to an RNA of the target influenza virus. Therefore, in some embodiments, the RNAi agent specifically discriminates a single nucleotide difference. In this case, the RNAi agent mediates only the RNAi if the exact complementarity is found in the region (e.g., within 7 nucleotides of) of the single nucleotide difference. Preferred RNAi agents are based on or consist of or comprise the sense and antisense sequences provided in Table 1A-1H. As used herein, "essentially identical" when used with reference to a first nucleotide sequence as compared 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 (for example, adenosine replaced by uracil). "Essentially maintaining the ability to inhibit the expression of influenza virus in cultured human influenza virus expressing cells", as used herein refers to an RNAi agent not identical to but derived from one of the RNAi agents. of Tables 1A-1H by deletion, addition or substitution of nucleotides, means that the derivatized RNAi agent possesses an inhibitory activity of not less than 20% of the inhibitory activity of the RNAi agent of Tables 1A-1H of which derived. For example, an RNAi agent derived from an RNAi agent of Tables 1A-1H which decreases the amount of influenza virus mRNA present in cultured human cells infected with the influenza virus by 70% may itself decrease the amount of influenza virus mRNA present in human cultured cells infected with the influenza virus by at least 50% in order to be considered as essentially maintaining the ability to inhibit the replication of influenza virus in cultured human cells infected with the influenza virus. Optionally, an RNAi agent of the invention can decrease the amount of influenza virus mRNA present in cultured human cells infected with the influenza virus by at least 50%. As used herein, a "subject" refers to a mammalian organism undergoing treatment for a disease mediated by infection with an influenza virus. The subject can be any mammal, such as a cow, horse, mouse, rat, dog, pig, goat, or primate. In a preferred embodiment, the subject is a human.

Viral Characteristics of Influenza Influenza viruses are enveloped, negative-strand RNA viruses of the Orthomyxoviridae family. They are classified as types of influenza A, B, and C, of which influenza A is the most pathogenic and is believed to be the only type capable of undergoing redistribution with animal strains. The types of influenza A, B, and C can be distinguished by differences in their nucleoprotein and matrix proteins. As discussed further below, influenza A subtypes are defined by the variation in their hemagglutinin (HA) and neuraminidase (NA) genes and are usually distinguished by antibodies that bind to the corresponding proteins. The viral genome of influenza A consists of ten genes distributed in eight segments of RNA. Genes encode 10 proteins: the glycoproteins enveloped in hemagglutinin (HA) and neuraminidase (NA); matrix protein (referred to as Ml or MP herein); nucleoprotein (NP); three polymerases (PBl, PB2, and PA) which are components of an RNA-dependent RNA transcriptase also referred to as a polymerase or polymerase complex herein; the protein of the ion channel (M2), and nonstructural proteins (NS1 and NS2). See Julkunen, I., et al., Cytokine and Growth Factor Reviews, 12: 171-180, 2001 for additional details regarding influenza A virus and its molecular pathogenesis. See also Fields, B., et al., Fields Virology, 4.sup.th. ed., Philadelphia: Lippincott Williams and Wilkins; ISBN: 0781718325, 2001. The organization of the viral genome of influenza B is extremely similar to that of influenza A while the viral genome of influenza C contains seven RNA segments and lacks the NA gene. The classification of influenza A virus is based on the genes of hemagglutinin (H1-H15) and neuraminidase (Nl-N9). The nomenclature of the World Health Organization (WHO, for its acronym in English) defines each strain of the virus by its animal host of origin (human unless specified), geographical origin, strain number, year of isolation, and antigenic description of HA and NA. For example, A / Puerto Rico / 8/34 (H1N1) designates strain A, isolated 8, which emerged in humans in Puerto Rico in 1934 and has antigenic subtypes 1 of HA and NA. As another example, A / chicken / Hong Kong / 258/97 (H5N1) designates strain A, isolate 258, which emerged in chickens in Hong Kong in 1997 and has an antigenic subtype 5 HA and 1 NA. Human epidemics have been caused by viruses with HA types Hl, H2, and H3 and NA types NI and N2. As mentioned above, genetic variation occurs by two primary mechanisms in influenza A virus. An antigenic flow occurs by means of point mutations, which often occur in antigenically important positions due to the selective pressure of host immune responses, and antigenic change (also referred to as redistribution), which involves the replacement of a segment of the entire viral genome from one subtype with another. Many different types of animal species including humans, pigs, birds, horses, aquatic mammals, and others, can become infected with influenza A viruses. Some influenza A viruses are restricted to a particular species and do not normally infect different species. However, some influenza A viruses can infect several different animal species, mainly birds (particularly migrating ducks), pigs, and humans. This ability is considered to be responsible for major antigenic changes in the influenza A virus. For example, a pig is assumed to be infected with an influenza A virus from a human and at the same time infected with an influenza virus. A different from a duck. When the two different viruses reproduce in the cells of the pig, the genes of the human strain and the duck strain can be "mixed", resulting in a new virus with a unique combination of RNA segments. This process is called genetic redistribution (Note that this type of genetic redistribution is different from the exchange of genetic information that occurs between chromosomes during meiosis). Like other viruses and certain bacterial species, the influenza virus replicates intracellularly. Influenza A virus replicates in epithelial cells of the upper respiratory tract. However, monoliths / macrophages and other white blood cells can also be infected. Numerous other cell types with cell surface glycoproteins containing sialic acid are susceptible to in vitro infection since the virus uses these molecules as a receptor.

Design and selection of RNAi agents As used herein, "disorders associated with the expression of the influenza virus" refers to any biological or pathological state that (1) is mediated at least in part by the presence of a virus of influenza and (2) whose results may be affected by reducing the level of influenza virus present. The specific disorders associated with the expression of the influenza virus are noted below. The present invention is based on the design, synthesis and generation of RNAi agents, such viral genes target of the influenza virus, and the demonstration of silencing of a viral gene in vitro in cultured cells after incubation with an RNAi agent, and the resulting protective effect towards viral infection. An RNAi agent can be rationally designed based on the sequence information and desired characteristics. For example, an RNAi agent can be designed according to the relative melting temperature of the double candidate. Generally, the double should have a lower melting temperature at the 5 'end of the antisense strand than at the 3' end of the antisense strand. The present invention provides compositions containing sARNiA and / or shRNA that target one or more transcripts of the influenza virus. As the description of the replication cycle of the influenza virus presented above demonstrates, several types of viral RNA transcripts (primary and secondary vRNA, primary and secondary viral mRNA, and viral cRNA) are present within the cells infected with the influenza virus and play an important role in the viral life cycle. Any of these transcripts are the appropriate targets for sARNi mediating inhibition by either a direct mechanism or an indirect one in accordance with the present invention. SRNAs and shRNAs that target any viral mRNA transcription will specifically reduce the level of transcription itself in a direct manner, that is, by causing transcription degradation. In addition, as discussed below, sRNAs and shRNAs that target certain viral transcripts (eg, MP, PA, PB1) will indirectly cause the reduction in levels of viral transcripts for which they are not specifically targeted. In situations where alternative splicing is possible, such as for the mRNA encoding MP and M2 and the mRNA encoding NS1 and NS2, transcription without splicing or splicing transcription can serve as an objective transcript. The potential viral transcripts that can serve as a target for RNAi based on therapy according to the present invention include, for example, 1) any genomic segment of the influenza virus.; 2) transcripts encoding any of the viral proteins including transcripts encoding the proteins PB1, PB2, PA, NP, NS1, NS2, MP, M2, HA, or NA. As will be appreciated, the transcripts can be directed in their vRNA, cRNA, and / or mRNA forms by a single siRNA or shRNA. However, it may be that the viral mRNA is the primary or only RNAi target as suggested by Ge et al., WO 04/028471. For any particular target gene that is selected, the design of sRNA or shRNA for use in accordance with the present invention will preferably follow certain guidelines. In general, it is desirable for target sequences that are specific for the virus (as compared to the host), and that, preferably, are important or essential for viral function. Although certain viral genes, particularly those encoding HA and NA, are characterized by a high mutation ratio and are capable of tolerating mutations, certain regions and / or sequences tend to be conserved. According to certain embodiments of the invention such sequences can be particularly appropriate objectives. As further described below, such conserved regions can be identified, for example, through review of the literature and / or comparisons of the influenza gene sequences, a large number of which are publicly available. Also, in many cases, the agent that is administered to a cell according to the present invention may undergo one or more process steps before becoming an active suppressive agent (see below for further discussion); in such cases, those of ordinary skill in the art will appreciate that the relevant agent is preferably designed to include sequences that may be necessary for processing. One aspect of the present invention is the recognition that when multiple strains, subtypes, etc. (referred to collectively as variants), of an existing infectious agent, whose genomes vary in sequence, will often be desirable to select and / or design sRNAs and shRNAs that target regions that are highly conservative among the different variants. In particular, by comparing a sufficient number of sequences and selecting highly conservative regions, it will be possible to direct multiple variants with a single siRNA whose double portion includes such a highly conservative region. Generally such regions should be of sufficient lengths to include the entire double portion of the sRNA (for example, 19 nucleotides) and, optionally, one or more 3 'drapes, through regions shorter than the full length of the double can also be' use (for example, 15, 16, 17, or 18 nucleotides). According to certain embodiments of the invention, a region is highly conservative between multiple variants if it is identical between the variants. According to certain embodiments of the invention, a region (of the length that is to be included in the double portion of the sRNA, for example, 15, 16, 17, 18, or, preferably, 19 nucleotides) is highly conservative if it differs by minus one nucleotide (that is, 0 or 1 nucleotide) between the variants. According to certain embodiments of the invention such a region is highly conservative between multiple variants if it differs by at least two nucleotides (ie, 0, 1, or 2 nucleotides) between the variants. According to certain embodiments of the invention, a region is highly conservative between multiple variants if it differs by at least three nucleotides or (i.e., 0, 1, 2, or 3 nucleotides) between the variants. According to certain embodiments of the invention, a siRNA includes a double portion that is directed to a region that is highly conserved between at least 5 variants, at least variants, at least 15 variants, at least 20 variants, at least 25 variants, less 30 variants, at least 40 variants, or at least 50 or more variants. In order to determine if a region is highly conservative among a set of multiple variants, the following procedure can be used. A member of the set of sequences is selected as the base sequence, that is, the sequence for which other sequences are compared. Typically, the length of the base sequence will be the desired length for the double portion of the sRNA, for example, 15, 16, 17, 18, or, preferably, 19 nucleotides. According to different embodiments of the invention, the base sequence can be either one of the sequences in the set to be compared or it can be a consensus sequence derived, for example, by determining for each position the nucleotide most frequently found in such position between the sequences in the set.

Having selected a base sequence, the sequence of each member of the set of multiple variants is compared with the base sequence. The number of differences between the base sequence and any member of the set of multiple variants on a region of the sequence is used to determine whether the base sequence and such a member are highly conservative on the particular region of interest. As noted above, in various embodiments of the invention if the number of sequence differences between two regions is either 0; 0 or 1, 0, 1, or 2; or 0, 1, 2, or 3, the regions are considered highly conservative. In the positions where the differences occur, the sARNi sequence can be selected to be identical to the base sequence or to one of the other sequences. Generally the nucleotide present in the base sequence will be selected. However in certain embodiments of the invention, particularly if a nucleotide is present in the particular position in a second sequence in the set to be compared, it is found in more of the sequences to be compared than with the nucleotide in the base sequence, then the sequence sARNi it can be selected to be identical to the second sequence. In addition, according to certain embodiments of the invention, if the consensus nucleotide (nucleotide that occurs most commonly) at the position where the difference occurs is different from that found in the base sequence, the consensus nucleotide can be used. It is noted that this may result in a 'sequence that is not identical to any of the sequences to be compared (which may be the use of a consensus sequence as the base sequence). The inventors have found that a significant proportion of the sequences selected using the design parameters described below (see Example 1) prove to be efficient in suppressing viral replication when included in a sRNA or shRNA and tested as described below . Based on the results shown herein, the present invention provides RNAi agents that reduce the replication of influenza virus in cultured cells infected with the influenza virus and in a subject, for example, a mammal, for example a human. Tables 1A-1H provide exemplary RNAi agents directed to influenza viruses. Table IA, C, D, and E list the sRNAs that do not comprise nucleotide modifications except for a phosphorothioate linkage between the 3 'terminal and the penultimate thymidines. Table IB and H list sRNAs where all nucleotides comprising pyrimidine bases are 2 '-O-methyl modified nucleotides in the sense strand, and all uridines in a 5'-ua-3 sequence context 'as all cytidines in a sequence context of or 5'-ca-3' are TO-methyl modified nucleotides in the antisense strand, except for the double-identified RNAi agents AL-DP-2295, AL-DP -2301, and AL-DP-2302, in which all the uridines which are in a sequence context of 5'-ug-3 'are nucleotides modified by 2'-0-methyl in the antisense strand. The latter sRNAs do not have occurrences of the 5'-ua-3 'or 5'-ca-3' sequence portions, and an analysis of degradation fragments after incubation of these agents in mouse serum reveals that the portion of the 5'-ug-3 'sequence was the primary point of endonucleolytic attack. Based on these results, the research specifically provides an RNAi agent that includes a sense strand having at least 15 contiguous nucleotides of the sense strand sequences of the agents provided in Tables 1A-1H, and an antisense strand having at least 15 contiguous nucleotides of the antisense sequences of the agents provided in Tables 1A-1H. The RNAi agents shown in Tables 1A-1H are composed of two strands of 19 nucleotides in length which are complementary or identical to the target sequence, plus a 3'-TT hanging. The present invention provides agents comprising at least 15, or at least 16, 17, or 18, or 19 contiguous nucleotides of these sequences. However, although these lengths may potentially be optimal, RNAi agents are not a means to limit themselves to these lengths. The skilled person is well aware that longer or shorter RNAi agents can be similarly effective, since, within certain length ranges, the efficacy is on the contrary a function of the nucleotide sequence rather than the strand length. For example, Yang, et al., PNAS 9_9: 9942-9947 (2002), demonstrates similar efficiencies for RNAi agents of lengths between 21 and 30 base pairs. Others have shown effective silencing of genes by RNAi agents reduced to a length of about 15 base pairs (Byrom, et al, "Inducing RNAi with sRNAi Cocktails Generated by RNase III" Tech Notes 10 (1), Ambion, Inc., Austin , TX). Therefore, it is possible and contemplated by the present invention to select from the sequences provided in Tables 1A-1H a partial sequence of between 15 to 19 nucleotides for the generation of an RNAi agent derived from one of the sequences provided in Tables 1A-1H. Alternatively, one or more nucleotides may be added for one of the sequences provided in Tables 1A-1H, or an agent comprising 15 contiguous nucleotides of one of these agents, preferably, but not necessarily, in such a way that the aggregated nucleotides are complementary to the respective sequence of the target gene, for example, an influenza virus gene. For example, the first 15 nucleotides of one of the agents can be combined with the 8 nucleotides found 5 'for this sequence in the mRNA of the influenza virus to obtain an agent with 23 nucleotides in the sense and antisense strands. All derived RNAi agents are included in the RNAi agents of the present invention, with the proviso that they essentially maintain the ability to inhibit the replication of the influenza virus in cultured human cells infected with the influenza virus.

Table IA: Exemplary RNAi agents for the target influenza virus that has 80% objective coverage (criterion 1, see example 1) and 79. 9% objective efficiency (criterion 2, see example 1), and has an objective record complete of less than 16.8 (see example 1) Idßntifi ier Sequence of sense strand SEQ SSQ% ELISA ELISA Double expression. { 5 '-3') Influenza Inf infinity (cells (plasmid cells, NO: remaining target1 MDCK), * from Vero),% of iinnhWibition * A -DP-22 1 uggaagcaauggcuuuccu T 1 aggaaagccauugcuuccaTT 2 PBl 3 -31 AL-DP-2242 ggcaccaaacgaucuuaugTT 3 cauaagaueguuuggugccTT NP -10 28 63 AL-DP-2243 aggcaccaaacgaucuuauT 5 auaagaucuguuggugccuTT NP -34 ÍS 51 A -DP- 2 4 caccaaacgaucuuaugaTT 7 ucauaagaucguugugugTT 8 NP -26 74 76 AL-DP-22 5 cuucuaaccgaggucgaaa T 9 u cgaccucgg agaagTT 10 MP -20 -72 AL-DP-2246 gucgaaacguacguucucuT 11 agagaacguacguuucgac T 12 MP -2 -70 AL-DP-2247 cucaaagccgagaucgcscTT 13 gcgcgaucucggcuu-ugagTT 14 MP -4 -95 AL -DP-224B u cuaaccgaggucgaaacTT IB gu cgaccucgguuagaaT le MP -23 -37 AL-DP-2249 ucuaaccgaggiicgaaacgTT 17 cguu cgaccucgguuagaT 18 MP -1 18 AL-DP-2250 ucgaaacguacguucucucTT 19 gagagaacguacguuucga 20 MP -27 15 A -DP-2251 cgaaacguacgu? CucucuTT 21 agagagaacguacg? U cgT 22 MP -16 12 AL-DP-2252 aaacguacguucucucuauTT 23 auagagagaacg accuuuTT 24 MP -21 -24 AL-DP- 253 cccccucaaagccgagaucTT 25 ga cucggtruuugagggggT 26 MP -14 6 AL -DP- 2254 cccucaaagccgagaucgcTT 27 gcgaucucggcuuugagggT 28 MP - 22 -24 AL -DP-2255 ccucaaagccgagaucgcgT 29 cgcgauc cggcuuugaggTT 30 MP -11 -14 AL -DP-2256 acaagaccaauccugucacT 31 g gacaggauuggucuuguTT 32 MP 17 -22 AL -DP-2257 agcgaggacugcagcguagTT 33 c acgcugcagucc cgcuT 34 MP 1 A -DP- 2258 cgaggacugcagcguagacT 35 gc acgcugcag ccucgT 36 MP 26 -37 AL -DP-2259 uugcacuugauauuguggaTT 37 uccacaauaucaagugcaaTT 38 MP 12 -18 AL-DP-2260 gcacuugaua uguggauTT 39 auccacaauaucaagugcaT 40 MP -5 -76 AL-DP-2261 a-uacgguuugaaaagagggTT 41 cccucuuuucaaaccgua-aTT 42 MP -1 5 AL-DP-2262 uacgguuugaaaagagggcTT 43 gcccucu uucaaaccguaT 44 MP -6 -6 Identifier Sequence of sense strand SEQ Sequence of strand SEQ Gene of% ELISA ELISA Double expression (5 '-3') antisense ID. { 5'-3 ') ID influenza infectivity (cells (deplásmirin cells, remaining1 SO: NO: MDCK target), »de Vero),% inhibition2 inhibition3 inhibition4 AL-DP-2263 acgguuugaaaagagggccTT ggcccucuuuucaaaccguTT 46 MP 3 45 -22 A 47 -DP-2264 cgguuugaaaagagggccuTT aggcccucuuuucaaaccgTT MP 48 January 4 AL-DP-2265 cuaaccgaggucgaaacguTT acguuucgaccucgguuagTT 49 50 MP 13 -52 AL-DP-2266 uaaccgaggucgaaacguaTT uacguuucgaccucgguuaTT 51 52 MP 27 - 107 A -DP-2267 aaccgaggucgaaacguacTT 53 guacguuucgaccucgguuTT 54 MP < 25% 42 -73 A -DP-2268 accgaggucgaaacguacgTT SS cguacguuucgaccucggu 56 MP -16 -18 AL-DP-2269 ccgaggucgaaacguacguTT 57 acguacguuucgaccucggTT 58 MP -21 -43 AL-DP-2270 cgaggucgaaacguacguuTT 59 aacguacguuucgaccucgTT 60 MP -6 -25 A -DP -2271 gaggucgaaacguacguucTT 61 gaacguacguuucgaccucTT 62 MP -29 -29 AL-DP-2272 aggucgaaacguacguucuTT 63 agaacguacguuucgaccuT 64 MP -23 -59 AL-DP-2273 ggucgaaacguacguucucTT 65 gagaacguacguuucgaccTT 66 MP -9 -36 AL-DP-2274 gcuaaagacaagaccaaucTT 67 gauuggucuugucuuuagcTT 68 MP - 24 -17 ÍI-DP-2275 aauccugucaccucugacuTT 69 agucagagugaoaggauuT 70 MP -33 -36 A -DP-2276 uccugucaccucugacuaaTT 71 uuagucagaggugacaggaTT 72 MP 30% -20 -10 A -DP-2277 cacgcucaccgugcccaguTT 73 acugggcacggugagcgugTT 74 MP -38 -32 AL-DP -2278 acgcucaccgugcccagugTT 75 aacugggcacggugagcguTT 76 MP -26 -17 A -DP-2279 cgcucaccgugcccagugaTT 77 ucacugggcacggugagcgTT 78 MP -36 -7 AL-DP-2280 gcucaccgugcccagugagTT 79 acacugggcacggugagcTT 80 MP -37 -34 AL-DP-2281 caccgugcccagugagcgaTT 81 ucgcucacug ggcacggugTT 82 MP -46 -52 A -DP-2282 gagcgaggacugcagcguaTT 83 uacgcugcaguccucgcucTT 84 MP -31 -62 AL-DP-2283 uauuguggauucuugaucg T 85 cgaucaagaauccacaauaTT 86 MP 45% -52 -26 AL-DP-2284 uuguggauucuugaucgucTT 87 gacgaucaagaauccacaaTT 88 MP 61% 39 -60 AL-DP-2285 uguggauucugaucgucuTT 89 agacgaucaagaauccacaT 90 MP 41% 3 -49 AL-DP-2286 guggauucugaucgucuuTT 91 aagacgaucaagaauccacTT 92 MP 36% 9 -50 AL-DP-2287 ucaaaugcauuuaucgucgT 93 cgacgauaaaugcauuugaTT 94 MP 38% -17 -11 AL -DP-2288 caaaugoauuuaucgucgcTT 95 gcgacgauaaaugcauuugTT 96 MP 39% 23 -58 1 in vitro plate-forming assay in MCDK cells as described in Example 3.1; 2 in vitro ELISA assay in MCDK cells as described in Example 3.2: 3 in vitro ELISA assay in MCDK cells as described in Example 3.2; 4 in vitro ELISA assay in MCDK cells as described in Example 3.2; negative values indicate that the expression of the target gene was increased in 'treated cells compared to controls Table IB: Exemplary RNAi agents for influenza virus target derived from agents listed in Table IA by stabilization towards nucleolytic degradation by nucleotide modifications Double Identifier no Sense thread sequence. { 5 '- 3') SEQ Sequence of anti-sense strand SEO Gene of double modified ID (S '-3') Influence corresponding ID 'NO: NO: target AL-DP-2289 AL-DP-2241 umggaagsnaaumggcmvim m mcmcp? UmTI 97 aggaaagccmauugcuuccmaTT 98 PBl AL-DP-2290 A -DP-2242 ggcmacmcmaaacmgaumcmumumaumgTT 99 cmaumaagaucguuuggugccTT 100 NP AL-DP-2291 AL-DP-2243 aggcmacmcmaaacmgaumcmuimjmaumTT 101 aumaagaucguuuggugccuTT 102 NP AL-DP-2292 A -DP-2244 gcmacmcmaaacmgauracmurauraaumgaTT 103 ucmaumaagaucguuuggugcTT 104 NP A -DP-2293 AL-DP-2245 cmumumcmumaacmcmgaggumcmgaaaTT 105 uuucgaccucgguumagaagTT 106 MP A -DP-2294 A -DP-2246 gum ngaaacmguraacmgu umcpiuracpiuraTT 107 agagaacgumacguu cgacTT 108 MP AL-DP-2295 A -DP-2247 cmumcmaaagcmcmgagaumcmgcmgcmTT 109 gcgcgaucucggcuuumgagTT 110 MP AL-DP-2296 AL-DP-2248 uptumcmuraaacmcmgaggumcmgaaac TT 111 guuucgaccucgguumagaaTT 112 MP AL-DP-2297 A -DP-2249 uracmumaacmcmgaggumcitigaaacmgT 113 cguuucgaccucgguumagaTT 114 MP AL-DP-2298 A -DP-2250 umcmgaaacmgumacmg? Tm? McmumcmumcmTT 115 gagagaacgumacguuucgaTT 116 MP AL-DP-2299 AL-DP-2251 cmgaaacmgumaanguraumcmu cmuracmumT 117 agagagaacgumacguuucgTT 118 MP AL-DP-2300 AL-DP-2252 aaacmgumacmgupiumcmumcmuracmumaumTr 119 aumagagagaacguraacguuuTT 120 MP AL-DP-2301 AL-DP-2254 cmcmcmumsnaaagcmcmgagaumcitgcmTr 121 gcgaucucggcuuumgagggTT 122 MP A -DP-2302 AL-DP-2255 cmcmumcmaaagcmcmgagaumcmgcmgTT 123 cgcgaucucggcuuumgaggTT 124 MP AL-DP-2303 AL-DP-2256 acmaagacmcmaaumcmcmumg mcmacpiTT 125 gugacmaggauuggucuuguTT 126 MP AL-DP-2304 A -DP-2257 agcmgaggac u gcmagcmgíjinagTT 127 cumacgcugcmaguccucgcuTT 128 MP AL-DP-2305 A -DP-2258 cmgaggacmumgc agcmgumagacraT 129 gucumacgcugcmaguccucgTT 130 MP AL-DP-2306 AL-DP-2259 umumgcmacmumumga'umauriiumg mggaTT 131 uccmacmaauraaucmaagugcmaaT 132 MP AL-DP-2307 AL-DP-2260 umgcmacmum mgaumaumumguraggaum T 133 auccmacmaaumaucmaagugcmaTT 134 MP A -DP-2308 AL-DP-2265 ctnumaacmcmgaggumcmgaaacmguraTT 135 acguuucgaccucgguumagTT 136 MP AL-DP-2309 A -DP-2266 umaacmcmgagguracmgaaacmgumaTT 137 umacguuucgaccucgguumaTT 138 MP AL-DP-2310 AL-DP-2267 aacmcmgaggutncmgaaacmgumacmT 139 gumacguxmcgaccucgguuTT 140 MP A -DP-2311 A -DP-2268 acmcmgaggumcmgaaacraguinaomgTT 141 cgumacguuucgaccucgguTT 142 KP A -DP-2312 A -DP-2269 cracmgaggumcmgaaacmgumacmgumTT 143 acgumacguuucgaccucggTT 144 MP Double srNi agent identifier of Table IA having an identical nucleotide sequence when the nucleotide modifications are unattended Table 1C: The additional RNAi agents for empirical information are not listed in Table A At least 50% objective coverage (criterion 1, see Example 1) and at least 80% objective efficiency (criterion 2, see Example 1), and have a complete objective record of less than 16. 8 ( see Example 1) Identifier Sense strand sequence SEQ Sequence sequence Double SEQ (5 '-3') Antisense ID (5'-3 ') ID NO- NO. AL-DP-2313 augagucuucuaaccgaggT? 145 ccgugguuagaagacucaaTT 146 MP -29 AL-DP-2314 uc cuaaccgagguc a TT 147 uucgaccucgguuagaagaTT 148 KP -51 AL-DP-231 g cuucuaaccgaggucgaTT 149 ucgaccucgguuagaagacTT 150 KP -39 AL-DP-231C c? Ucagaucgaacggucua T 151 uagaccguucgaucugaagTT 152 PBl -63 AL -DP-2317 cagaucgaacggucuaacaTT 153 uguuagaccgu? CgaucugTT 154 PBl -50 AL-DP-2318 agaucgaacgg cuaacag T 155 cuguuagaccguucgaucuTT 156 PBl -43 AL-DP-2319 caaaauacuauaaguaccaTT 157 ugguacuuauagcauuuugTT 158 PBl -42 A -DP-2320 uucagaucgaacggucuaaTT 159 uuagaccguucgauc gaaTT 160 PBl -50 AL-DP-2321 uaccacauucccuuauacuTT 161 aguauaagggaaugugguaTT 162 PBl -35 AL-DP-2322 ucuuacauaaaucggacagTT 163 cuguccgauuuauguaagaT? 164 PBl 12 AL-DP-2323 gucuuacauaaaucggaca T 165 ug ccgauuuauguaagacTT 166 PBl 21 AL-DP-2324 agucuuacauaaaucggacTT 167 guccgauu? Auguaagacu T 168 PBl 20? -DP-2325 ccucugaugauuucgcucuTT 169 agagcgaaaucaucagaggTT 170 PBl 35 AL-DP-2326 ggaugucaauccgacuuuaTT 171 uaaagucggauugacauccTT 172 PBl «0 AL-DP-2327 uuugagagagaaggguacuTT 173 aguacccuucucucucaaaTT 174 SP 38 33 AL-DP-2328 aggcaacgaacccgaucguTT 175 acga cggguucguugcculT 176 NP 36 65 A -DP-2329 ggcaacgaacccgaucgugTT 177 cacgaucggguucguugccTT 178 NP 31 58 A -DP-2330 caacgaacccgaucgugccTT 179 ggcacgaucggguucguugTT 180 NP 33 56 AL-DP-2331 gcaacgaacccgaucgugcTT 181 gcacgaucggguucg ugcTT 182 NP 24 67 AL-DP-2332 gaaaaggcaacgaacccgaTT 183 ucggguucguugccuuuucTT 184 NP 32 78 A -DP-2333 ucgagcuc ^ cggacgaaaaT 185 u uucguccgagagcucgaTT 186 NP < S0 18 69 AL-DP-2334 aacgaacccgaucgugccuT 187 aggcacgaucggg ucguuTT 188 NP 35 30 AI ^ DP-2335 uauuucuucggagacaaugTT 189 cauugucuccagaagaaauaTT 190 NP 2 41 AL-DP-2348 ugcaugauaaaggcaguccTT 191 ggacugccuuuaucaugcaTT 192 PB2 -45 4 AL-DP-2349 augggga gaucggaauauTT 193 auauuccgaucaucccca TT 194 PB2 0 SS AI.-DP-2350 ugggga gaucggaauauuTI 195 aauauuccgaucauccccaTT 196 PB2 -41 52 AL-DP-2351 gaaacgggacucuagcaua T 197 uaugcuagagucccguuucTT 198 PB2 «25 -33 76 AL-DP-2356 agacimuguggagaaugcT 199 gcauuguccacacaaagucuTT 200 PA 19 77 AL-DP-2357 gacuuugugcgacaaugcuTT 201 agcauuguccacaaagucTT 202 PA -84 86 A -DP-2358 uc augggauuccuuucguT 203 acgaaaggaaucccßuagaTT 204 PA -33 30 AL-DP-2359 cuaugggauuccu ucguc T 205 gacgaaaggaaucccauag-TT 206 PA -59 80 A -DP-2360 auguggauggau.ucgaa.ccTT 207 gguucgaauccauccacauTT 208 PA 1 16 AL-DP-2361 uguggauggauucgaaccgTT 209 cgguucgaauccauccacaTT 210 PA -10 -7 AL-DP-2362 guggaugga icgaaccgaTT 211 ucgguucgaauccauccacTT 212 PA < 25 -28 88 AL-DP-2363 uggauggauucgaaccgaaTT 213 uucgguucgaauccauccaTT 214 PA < 25 -7 89 A -DP-2364 ggauggauucgaaccgaacTT 215 guucgguucgaaiiccauccTT 216 PA < 25 55 89 A -DP-2365 gauggauucgaaccgaacgTT 217 cguucgguucgaauccaucTT 218 PA -3 60 AL-DP-2366 auggauucgaaccgaacgg T 219 ccguucgguucgaauccauTT 220 PA 32 31 A -DP-2367 uggauucgaaccgaacggcTT 221 gccguucgguucgaauccaTT 222 PA 0 14 AL-DP-2368 aucuccacaacucgaggggTT 223 ccccucgag ug ggagauTT 224 PA 22 20 1 in vitro plate forming assay in MCDK cells as described in Example 3. 1; 2 in vitro ELISA assay in MCDK cells as described in Example 3. 2: 3 in vitro ELISA assay in MCDK cells as described in Example 3. 2; in ELI SA assay in vitro in MCDK cells as described in Example 3. 2; negative values indicate that expression of the obj ective gene was increased in treated cells compared to controls.

Table ID: Additional empirical RNAi agents for the target influenza virus not li in Table IA or C, and have at least 80% objective coverage (criterion 1, see example 1) and at least 80% of objective efficiency (criterion 2, see example 1) Identifier Sequence sequence SEO sense Sequence of SEO strand Gen of * ELISA ELISA Double expression (5 '-3') Antlense ID (5'-3 ') Influenza ID uifectivity (cells (plasmid cells, js0: NO: target remaining1 MDCK), Vero),% of inhibition1 inhibition1 inhibition4 AL-DP-7614 uaacaauagagagaaugguTT accauucucucuauuguuaTT 225 -80 17 226 KP-7635 AL-DP gaaacguacguucucucuaTT uagagagaacguacguuucTT 227 228 MP July 19 A-DP-7636 aacguacguueucucuaucTT gauagagagaacguacguuTT 225 230 MP 24 January 7637 uggcuaaagacaagaccaaTT -DP-A 231 232 uuggucuugucmiuagccaTT MP < 25 42 8 A-DP-7638 ggcuaaagacaagaccaauTT 233 auuggucuugucuuuagccTT 234 MP May 19 AL-DP-7639 cuaaagacaagaccaauccTT 235 ggauuggucuugucuuuagTT 236 MP 22 24 DPEA-7640 uaaagacaagaccaauccuTT 237 aggauuggucuugucuuuaTT 238 MP November 43 AL-DP-7641 aaagacaagaccaauccugTT 239 caggauugguomgucuuTT 240 MP 13 33 AL aagacaagaccaauccuguTT -DP-7642 241 242 acaggauuggucuugucuuT MP -12 39 A-DP-7643 agacaagaccaauccugucTT gacaggauuggucuugucuTT 244 MP 243 4 5 A-DP-7644 gacaagaccaauccugucaTT ugacaggauuggucuugucTT 245 246 MP March 26 AL-DP-7645 caagaccaauccugucaccTT ggugacaggauuggucuugTr 248 MP 247 2 2 AL- DP-7646 aagaccaauccugucacairr 249 aggugacaggauuggucuuTT 250 MP 12 9 AL-DP-7647 agaccaauccugucaccucTT 251 gaggugacaggauuggucurr 252 MP 8 -5? -DP-7648 MP gaccaauccugucaccucTT 253 254 -27 2 agaggugacaggauuggucTT AL-DP-7649 accaauccugucaccucugTT cagaggugacaggauugguTT 256 MP 255 8 0 AL-DP-7650 ccaauccugucacscugaTT ucagaggugacaggauuggTT 258 MP 257 -1 11 AL-DP-7651 caauccug caccucugacTT 259 MP 260 <gucagaggugacaggauugTT; 50 30 16 AL-DP-7652 auccugucaccucugacuaTT 261 uagucagaggugacaggauTT 262 MP < 50 69 9 AL-DP-7653 uucacgcucaccgugcccaTT 263 ugggcacggugagcgugaaTT 264 MP < 75 31 6 AL-DP-7654 ucacgcucaccgugcccagT 265 cugggcacggugagcgugaTT 266 MP < 75 57 12 AL-DP-7655 cucaccgugcccagugagcTT 267 gcucacugggcacggugagT 268 MP 22 1 in typifier Sense strand sequence Sequence sequence SEQ Gene of% ELISA ELISA Double expression (S '-3') antisense (5 '-3') ID Influenza infectivity (cells (plasmid cells, target res e MDCK), Vero t),% inhibition% inhibition1 inhibition * AL-DP-7656 ucaccgugcccagugagcgTT 269 270 MP < 7S 69 10 AL-DP-7657 accgugccca ugagcgagTT 271 272 MP 1 22 AL-DP-7 58 ccgugcccagugagcgaggTT 273 274 MP < 75 34 20 AL-DP-7659 cgugcccagugagcgaggaTT 275 276 MP 4 35 A -DP-7660 gugcccagugagcgaggacT 277 278 MP < 75 33 49 AL-DP-7661 ugcccagugagcgaggacuTT 279 28C MP < 50 -10 58 AI r-DP-7662 gcccagugag gaggacugT 281 282 MP -16 -44 A -DP-7663 cccagugagcgaggacugcT 283 284 MP 11 -8 AL-DP-7664 ccagugagcgaggacugcaT 285 286 MP 24 -20 AL-DP-7665 cagugagcgaggaeugcagTT 287 288 MP 7 -24 AL-DP-7666 agugagcgaggacugcagcTT 289 290 MP < 50 42 -22 AL-DP-7667 gugagcgaggacugcagcgTT 291 292 MP 20 -17 AL- DP- 7668 ugagcgaggacugcagcg T 293 294 MP 50 51 -54 AL-DP-7669 gcgaggacugcagcguagaT 295 296 MP < 25 32 37 AL-DP-7Ó70 gaggacugcagcguagacgTT 297 298 MP < 75 35 20 AL-DP-7671 gca cuugaua ugug gauu 299 300 MP -19 4 AL-DP-7672 cacuugauauuguguuucTT 301 302 MP 12 -10 AL-DP-7673 acuugauauuguggauucuTT 303 304 vrp 0 -1 AL-DP-7674 cuugauauuguggauucuuTT 305 306 MP -8 -36 AL-DP-7675 uuga.uauuguggauucuugT 307 308 MP t75 2 -27 AL-DP-7676 ugauauuguggauucuuga T 309 310 MP -29 -40 AL-0P-7677 gauauuguggauucuugauTT 311 312 MP -14 -24 AL-DP- 7678 auauuguggauucuugaucTT 313 314 MP 24 -22 AL-DP-7679 ggauucuugaucgucuuuuTT 315 316 MP 3 -34 AL-DP-7684 ccgucaggcccccucaaagTT 317 318 MP -1 23 AL-pp-7685 cgucaggcccccucaaagcTT 319 320 MP -12 36? L-DP-7686 gucaggcccccucaaagccTT 321 322 MP -4 14 AL-DP-7687 ucaggcccccucaaagccgTT 323 324 MP < 75 32 -11 AL-DP-7688 caggcccccucaaagccga T 325 326 MP < 25 56 -14 AL-DP-7689 aggcccccucaaagccgagTT 327 328 MP < 50 83 -21 AL-DP-7690 ggcccccucaaagccgagaTT 329 330 MP < 50 89 -29 AL -DP-7691 gcccccucaaagccgagauTT 331 332 MP 8 -21 AL -DP-7692 ccccucaaagccgagaucgTT 333 MP 5 -86 1 in vitro plate forming assay in MCDK cells as described in Example 3. 1; 2 in ELI SA assay in vitro in MCDK cells as described in Example 3. 2: 3 in ELI SA assay in vitro in MCDK cells as described in Example 3. 2; in vitro ELISA assay in MCDK cells as described in Example 3. 2; negative values indicate that expression of the obj ective gene was increased in treated cells compared to controls Table 1E: Additional empirical RNAi agents for the target influenza virus not listed in Table IA, C or D, and have at least 50% objective coverage (criterion 1, see example 1) and at least 80 Obj ective efficiency% (criterion 2, see example 1) AL-DP-756S cgagagaggcgaagagacaTT 335 ugucueuucgucucucucgTT 336 PA 50 AL -D -7566 gaagagacaauugaagaaaTT 337 uuuc? Ucaa ugucucuucTT 338 PA < 75 AL.DP-7567 uuuagagccuauguggaugTT 339 cauccacauaggcucuaaaTT 340 PA 75 AL-DP-7568 uuagagccuauguggauggT 341 ccauccacauaggc? CuaaT 342 PA 1 60 AL-DP-7569 uagagccuauguggauggaTT 343 uccauccacauaggcuc? ATT 344 PA 7 67 AL-DP-7570 agagccuauguggauggauTT 345 auccacauaggcucuTT 346 PA < 50 -23 87 AL-DP-757J gagccuau uggaugga? UTT 347 aauccauccacauaggcucTT 348 PA < 25 2 94 AL-DP-7572 agccuauguggauggauucTT 349 gaauccauccacauauaggcuTT 350 PA «25 -14 82 AL-DP-7573 ua gaagcaauugaggaguTT 351 acuccucaauugcuucaua T 352 PA < 75 -58 48 AL-DP-7574 augaagcaauugaggagugTT 353 cacuccucaauugcu? CauT 354 PA -69 16 AL-DP-7575 ugaagcaauugaggagugcTT 355 gcacucc? CaauugcuucaTT 356 PA -65 99 AL-DP-7576 gaagcaauugaggagugccTT 357 ggcacuccucaauugcuucTT 358 PA 2S AL-DP-7577 aagcaau? jgaggagugccuTT 359 aggcacuccucsauugcuuTT 360 PA < 25 AL-DP-7578 gaucscuggguuuugcuuaTT uaagcaaaacscagggaucTT 362 PA < 50 AL-DP-7579 aucccugguuuuuuuuuuTT 363 uuaagcaaaacccagggauTT 364 PA < 25 -51 98 87 AL-DP-7580 ucccuggguuuuuuuuuuu TT 365 au? AagcaaaacccagggaTT 366 P? < 75 15 95 60 AL-DP-7S8I ccsaggguuuugcuuaaugT uaagcaaaacccagggTT ca 367 368 PA 55100 75 AL-DP-7582 ccuggguuuugcuuaaugcTT gcauuaagcaaaacccaggTT 369 370 PA "25 AL-DP-7583 ucuugguucaacuccuuccTT ggaaggaguugaaccaagaTT GA 372" 75 A -DP-7584 cuugguucaacuccuuccuTT aggaaggaguugaaccaagTT 374 l'A AL-DP-7585 aaacgggac cuagcauacTT 375 guaugcuagaucucguguuuTT 376 PB2? L-DP-7586 aacgggacucuagcauacuTT 377 aguaugcuagagucccg? uTT 378 PB2 <; 25 AI.-DP-7587 acgggacucuagcauacuu T 379 aaguaugcuagagucccguTT 380 PB2 < 25 14 52 71 A -DP-7588 cgggacucuagcauacuuaTT 381 uaaguaugcuagagucccgT 382 PB2 < 25 34 36 72? L-DP-7589 gggacucuagcauacuuacTT 383 guaaguaugcuagagucecTT 384 PB2 -28 32 69 AL-DP-7590 ggacucuagcauacuuacuTT 385 aguaaguaugcuagaguccTT 386 PB2 -10 36 75 AL-DP-7591 gacucuaguauacuuacugTT 387 caguaaguaugcuagagucTT 388 PB2 -20 22 61 A -DP -7592 acr cuagcauacuuacugaTT 389 ucaguaaguaugcuagaguTT 390 PB2 -25 48 77 AL-DP-7593 cucuagcauacuuacugacTT 391 gucagaaaguaugcuagagTT 392 PB2 -14 50 64 AL-DP-7594 ucuagcauacuuacugacaTT 393 ugucaguaaguaugcuagaTT 394 PB2 -40 9 44 AL-DP-7595 cuacacacubacugacagTT 395 cugucaguaaguaugcuagTT 396 PB2 59 48 66 AL-DP-7596 uagcauacuuacugacagcTT 397 gcugucaguaaguauscuarr 398 PB2 -33 -14 44 AL-DP-7597 agcauacuuacugacagccTT 399 ggcugucaguaaguaugcuTT 400 PB2 -13 -27 29? L-DP-7598 gcauacuuacugacacaccaTT 401 uggcugucaguaaguaugcTT 402 PB2 < 25 8 65 73 AL-DP-7599 cauacuuacugacagccagTT 403 cusgcugucaguaaguaugTT 404 PB2 < 25 -39 43 69 AL-DP-7600 auacuuacugacagccagaTT 405 ucuggcugucaguaaguauTT 406 PB2 < 25 -33 48 74 AL-DP-7601 uacuuacugacagccagacTT 407 gucuggcugucaguaaguarr 408 PB2 -28 -40 35 AI -DP-7602 acu-aacugacagccagacaTT 409 ugucuggcugucaguaaguTT 410 PB2 6 17 60 AL-DP-7603 cuuacugacagccagacagTT 411 cugucuggcugucaguaagTT 412 PB2 16 73 77 AL- DP-7604 uuacugacaccaccacacacTT 413 gcugucuggcugucaguaaTT 414 PB2 18 -26 37 AL-DP-7605 uacugacagccagacagcgTT 415 cgcugucuggcugucaguaTT 416 PB2 20 -133 41 ALRDP-7606 acugacagccagacagcgaTT 417 ucgcugucuggcugucag-aTT 418 PB2 < 25 34 0 80? L-DP-7607 cugacagccagacagcgacTT 419 gucgcugucuggcugucagTT 420 PB2 < 25 38 51 74 AL-DP-7608 ugacagccagacagcgaccTT 421 ggucgcugucuggcugucaTT 422 PB2 < 25 64 -155 34 AL-DP-7609 gacagccagacagcgaccaTT 423 uggucgcugucuggcugucTT 424 PB2 < 25 86 -16 71 AL-BP-7610 acagccagacagcgaccaaTT 425 uuggucgcugucuggcuguTT 426 PB2 «25 55 29 72 AL-DP-7611 cagccagacagcgaccaaaTT 427 uuuagucgcugucuggcugTT 428 PB2 c25 33 88 78 AL-DP-7612 agccagacagcgaccaaaaTT 429 uuuuggucgoigucuggcuTT 430 PB2 < 25 37 73 74 AL-DP-7613 gccagacagcgaccaaaagTT 431 cuuuuggucgcugucuggcTT 432 PB2 < 25 57 -4 79 AL-DP-7615 cccgaucguccucucuuuTT 433 aaaggaaggcacgaucgggTT 434 NP 17 -80 35 A -DP-7616 ccgaucugucu ccuuugTT 435 caaaggaaggcacgaucggTT 436 KP 11 -40 47 AL-DP-7617 cgaucugucucucuuugaTT 437 ucaaaggaaggcacgaucgTT 438 W 22 -81 47 AL- DP-7618 gaucguccucucucu? GacTT 439 g-acaaaggaaggcacgaucTT 440 NP 87 86 73 Identifier Sense strand sequence SEQ Sequence sequence Seq ELISA gene ELISA Double expression (5 '-3') antisense ID (5'-3'J Influenza infectivity ID (cells (p <p <1> Hp cells, NO-target remaining1 MDCK), »from Vero),» e »and inhibition2 inhibition 'inhibition4 AL-DP-7619 aucgugcucucuuugacaTT 441 ugucaaaggaaggcacgauTT 442 NP < 25 86 82 50 AL-DP-7620 ucgugccuuccuuugacauTT 443 augucaaaggaaggcacgaTT 444 NP < 25 3 43 53 AL-DP-7621 cgugccuuccuuugacaugTT 445 caugucaaaggaaggcacgTT 446 NP -22 7 47 AL-DP-7622 gugccuuccuuugacaugaTT 447 ucau ucaaaggaaggcacTT 448 NP < 25 17 7ß 53 AL-DP-7623 ggaucauauuucuucggagTT 449 cuccgaagaaauaagauccTT 450 NP 25 66 95 58 AL-DP-7624 gaucuuauuucuucggagaTT 451 ucuccgaagaaauaagaucTT 452 NP < 25 95 96 75 AL-DP-7625 aucuuauuucuucg agacTT 453 gucuccgaagaaauaagauTT 454 NP < 25 33 78 77 AL-DP-7626 ucuuauuucuucggagacaTT 455 ugucuccagaagaaauaagaTT 456 NP 17 7 AL-DP-7627 cuuauuuuuuuuuuuuuuTT 457 uugucuccagaagaaauaagTT 458 NP < 25 32 66 54 AL-DP-7628 uuauuucuucggagacaauTT 459 auugucuccagaagaaauaaTT 460 NP < 25 24 81 72 AL-DP-7629 auuucuucggagacaaugcTT 461 gcauugucuccgaagaaauTT 462 NP < 50 11 44 61 AL-DP-7630 gggcggggagucuucgagcTT 463 gcucgaagacuccccgcccTT 464 NP 15 24 9 J.-DP-7631 ggcggggagucuucgagcuTT 465 agcucgaagacuccccgccTT 4 * 6 NP 5 33 30 AL-DP-7632 gcggggagucuucgagcucTT 467 gagcucgaagacuccccgcTT 468 NP 25 16 41 33 AL- DP-7633 cggggagucuucgagcucuTT 469 agagcucgaagacuccccgTT 470 NP < 25 33 55 50 AL-DP-7634 ggggagucuucgagcucucTT 471 gagagcucgaagacuccccTT 472 NP < 25 41 82 44 AL-DP-7680 ugacgauggucauuuugucTT 473 gacaaaaugaccaucgucaTT 474 MP < 25 58 72 49 AL-DP-76S1 gacgauggucauuuugucaTT 475 ugacaaaaugaucucucTT 476 MP -1 23 AL-DP-7682 ucccgucaggcccccucaaTT 477 uugagggggccugacgggaTT 478 MP -12 36 AL-DP-7683 cccgucaggcccccucaaaTT 479 uuugagggggccugacgggTT 480 MP -4 14 AL-DP-8102 ugagucuucuaaccgagguTT 481 accucgguuagaagacucaTT MP 482 AL-DP-8103 gagucuucuaaccgaggucTT gaccucgguuagaagacucTT 484 MP 483 A -DP-8104 agucuucuaaccgaggucgTT cgaccucgguuagaagacuTT 486 MP 485 A DP-8107 auaguggauucuugaucguTT acgaucaagaauccacaauTT 487 MP 488? L-DP-8108 uggauucuugaucgucuuuTT aaagacgaucaagaauccaTT 490 MP 489 A -DP-8109 491 gauucuugaucgucuuuucTT gaaaagacgaucaagaaucTT 492 MP AL-DP-8110 auucuugaucgucuuuucuTT 493 agaaaagacgaucaagaauTT 494 MP AL-DP-8111 uucuugaucgucuuuucuuTT 495 aagaaaagacgaucaagaaTT 496 MP AL-DP-8112 ucuugaucgusauuucuucTT 497 gaagaaaagacgaucaagaTT 498 MP AL-DP-8113 cuugaucgucuuuucuucaTT 499 ugaagaaaagacgaucaagTT 500 MP At-DP-8114 uuga cguc ? uuucuucaaTT 501 uugaagaaaagacgaucaaTT 502 MP AL-DP-S115 ugaucgucuuuucuucaaaTT MP 504 503 uuugaagaaaagacgaucaTT? L-DP-8116 gaucgucuuuucuucaaauTT auuugaagaaaagacgaucTT 506 MP 505 AL-DP-8117 aucgucuuuucuucaaaugTT cauuugaagaaaagacgauTT 508 MP 507 AL-DP-8118 ucgucuuuucuucaaaugcTT gcauuugaagaaaagacgaTT 510 MP 509 A -DP-8119 cgucuuuucuucaaaugcaTT ugcauuugaagaaaagacgTT 511 MP 512 AL-DP-8120 gucuuuucuucaaaugcauTT 513 augcauuugaagaaaagacTT 514 MP AL-DP-8121 ucuuuucuucaaaugcauuTT 515 aaugcauuugaagaaaagaTT 516 MP AL-DP-8122 cuuuucuucaaaugcauuuTT 517 aaaugcauuugaagaaaagTT 518 MP AL-DP-8123 uuuucuucaaaugcauuuaTT 519 uaaaugcauuugaagaaaaTT 520 MP AL-DP-8124 umicuucaaaugcauuuauTT 521 auaaaugcauuugaagaaaTT 522 MP AL-DP-812J uucuucaaaugcauuuaucTT 523 524 MP gauaaaugcauuugaagaaTT AL-DP-8126 ucuucaaaugcauuuaucgTT cgauaaaugcauuugaagaTT 525 526 MP A -DP-S127 cuucaaaugcauuuaucguTT acgauaaaugcauuugaagTT 527 528 MP? L-DP-8128 uucaaaugcauuuaucgucTT 529 530 MP gacgauaaaugcauuugaaTT AL-DP-8129 uuaaauacgguuugaaaagTT cuuuucaaacc uauuuaaTT 531 532 MP AL-DP -8130 uaaauacgguuugaaa agaTT 533 ucuuuucaaaccguauuuaTT 534 MP A DP-8131 aaauacgguuugaaaagagTT 535 cucuuuucaaaccguauuuTT 536 MP Identif icator Sequence of strand sense SEO Sequence of strand SEO. ELISA gene Ex Double expression (5 '-3') Antisense ID (5 '-3") Influenza ID mfectivity (céllllai (Raseinide cells, NO: NO target remaining1 MDCK), > Vero),« of «inhibition2 inhibition1 inhibition4 AL-DP-8132 aauacgguuugaaaagaggTT 537 ccucu? UucaaaccguauuTT 538 MP AL-DP-8133 uugaaaagagggccuucuaTT 539 540 MP uagaaggcccucuuuucaaTT AL-DP-8134 ugaaaagagggccuucuacTT guagaaggcccucuuuucaTT 541 542 MP AL-DP-8135 gaaaagagggccuucuacgTT 543 guagaaggcccucuuuucTT A 544 MP 545 -DP-8136 ccugagucuaugagggaagTT cuucccucauagacucaggTT MP 546 AL-DP-8137 cugagucuaugagggaagaTT ucuucccucauagacucagTT 547 548 MP AI.-DP-8138 ugcuguggauguugacgauTT aucgucaacauccacagcaTT 549 550 MP AL-DP-8139 gcuguggauguugacgaugTT caucgucaacauccacagcTT 551 552 MP A1.-DP-8140 cuguggauguugacgauggTT ccaucgucaacauccacagTT 553 554 MP AL-DP-8141 uguggauguugacgaugguTT accaucgucaacauccacaTT 555 556 MP AL-DP-8142 guggauguugacgauggucTT gaccaucgucaacauccacTT 557 558 MP AL-DP-8143 uggau guugacgau GGU CATT ugaccaucgucaacauccaTT 559 560 MP A -DP-8144 ggauguugacgauggucauTT augaccaucgucaacauccTT 561 562 MP AL-DP -8145 gauguugacgauggucauuTT aaugaccaucgucaacaucTT 563 564 MP DP-8146 AI ^ auguugacgauggucauuuTT aaaugaccaucgucaacauTT 565 566 MP A -DP-8147 uguugacgauggucauuuuTT aaaaugaccaucgucaacaTT 567 568 MP AL-DP-8148 guugacgauggucauuu? GTT 569 570 MP caaaaugaccaucgucaacTT? L-DP-8149 uugacgauggucauuuuguTT acaaaaugaccaucgucaaTT 571 572 MP A -DP-8152 acgauggucauuuugucaaTT 573 uugacaaaauga ccaucguTT 574 MP AL-DP-8153 cgauggucauuuugucaacTT 575 guugacaaaaugaccaucgTT 576 MP AL-DP-8154 gauggucauuuugucacacaTT 577 uguugacaaaaugaccaucTT 578 MP! AL-DP-8155 auggucauuuugucaacauTT auguugacaaaaugaccauTT 579 580 MP? L-DP-8156 uggucauuuugucaacauaTT 581 582 MP uauguugacaaaaugaccaTT AL-DP-8157 ggucauuuugucaacauagTT cuauguugacaaaaugaccTT 583 584 MP A -DP-8158 gucauuuugucaacauagaTT ucuauguugacaaaaugacTT 585 586 MP AL-DP-8159 ucaaggcaccaaacgaucuTT agaucguuuggugecuugaTT 587 588 A -DP NP-8160 NP caaggcaccaaacgaucuuTT 589 590 aagaucguuuggugccuugTT AL-DP-8161 aaggcaccaaacgaucuuaTT uaagaucguuuggugccuuTT 591 592 NP AL-DP-8162 aacagcauaacaauagagaTT ucucuauuguuaugcuguuTT 593 594 NP AL-DP-8163 acagcauaacaauagagagTT cucucuauuguuaugcuguTT 595 596 NP AL-DP-8164 cagcauaacaauagagagaTT ucucucuauuguuaugcugTT 597 598 NP AL-DP-8165 agcauaacaauagagagaaTT uucucucuauuguuaugcuTT 599 600 NP-8166 A -DP gcauaacaauagagagaauTT auucucucuauuguuaugcTT 601 NP 602 81 -DP-A 7 603 cauucucucuauuguuaugTT cauaacaauagagagaaugTT NP 604 AL-DP-8168 605 au gcauaugagagaauguTT acauucucucauaugcaauTT NP 606 AL-DP-8169 607 uugcauaugagagaaugugTT cacauucucucauaugcaaTT 608 NP A -DP-8 170 gcauaugagagaaugugcaTT 609 ugcacauucucucauaugcTT 610 NP AL-DP-8171 cauaugagagaaugugcaaTT 611 uugcacauucucucauaugTT 612 NP AU3P-8177 gggagucuucgagcucucgTT 613 cgagagcucgaagacucccTT 614 NP AL-DF-8178 ggagucuucgagcucucggTT 615 ccgagagcucgaagacuccTT 616 NP AL-DP-8179 gagucuucgagcucucggaTT 617 uccgagagcucgaagacucTT 618 NP AL-DP-8180 agucuucgagcucucggacTT guccgagagcucgaagacuTT 619 620 NP-8181 A -DP gucuucgagcucucggacgTT cguccgagagcucgaagacTT 621 622 NP-8182 A -DP ucuucgagcucucggacgaTT ucguccgagagcucgaagaTT 623 624 NP-8183 A -DP cuucgagcucucggacgaaTT uucguccgagagcucgaagTT 625 626 NP-8184 A -DP uucgagcucucggacgaaaTT uuucguccgagagcucgaaTT 627 628 NP AL-DP-8185 cgagcucucggacgaaaagTT 629 cuuuucguccgagagcucgTT 630 NP AL-DP-8186 gagcucucggacgaaaaggTT 631 ccuuuucggagagagcucTT 632 NP Identifier Sense strand sequence SEQ Sequence sequence SEQ Gene of ELISA ELISA Express: double (5 '-3') antisense (5 '-3') (cells (cells of p'¿ * Influenza KDCK infectivity), From Vero), »from« from NO: fjO. target remaining1 inhibition1 inhibition3 inhltai AL-DP-8187 633 agcucucggacgaaaaggcTT gccuuuucguccgagagcuTT [NP 634 AL-DP-8188 gcucucggacgaaaaggcaTT ugccuuuucguccgagagcTT 635 r 636 NP-8189 A -DP cucucggacgaaaaggcaaTT uugccuuuucguccgagagTT 637 [NP 638 AL-DP-8190 ucucggacgaaaaggcaacTT guugccuuuucguccgagaTT 639 l NP 640 AL-DP-8191 cucggacgaaaaggcaacgTT 641 cguugccuuuucguccgagTT; 642 NP AL-DP-8192 ucggacgaaaaggcaacgaTT 643 ucguugccuuuucguccgaTT 644 NP AL-DP-8193 cggacgaaaaggcaacgaaTT 645 uucguugccuuuucguccgTT [646 NP AL-DP-8194 ggacgaaaaggcaacgaacTT 647 guucguugccuuuucguccTT l 648 NP AL-DP-8195 gacgaaaaggcaacgaaccTT 649 gguucguugccuuuucgucTT 650 NP AL-DP-816 acgaaaaggcaacgaacccTT 651 ggguucugcucuuuucguTT: 652 NP AI ^ DP-8197 cgaaaaggcaacgaacccgTT 653 cggguucguugccuuuucgTT 654 NP AL-DP-8198 aaaaggcaacgaacccgauTT 655 aucggguucguugccuuuuTT 656 NP AL-DP-8199 aaaggcaacgaacccgaucTT 657 gaucggguucguusccuuuTT; 658 NP AL-DP-8200 aaggcaacgaacccgaucgTT 659 cgaucggguucguugccuuTT l 660 NP AL-DP-8201 acgaacccgaucgugccuuTT 661 aaggcacgaucggguucguTT [662 NP AL-DP-8202 cgaacccgaucgugccuucTT 663 gaaggcacgaucggguucgTT; 664 NP A-DP-8203 gaacccgaucgugccuuccTT 665 ggaaggcacgaucggguucTT; 666 NP AL-DP-8204 aacccgaucgugccuuccuTT 667 aggaaggcacgaucggguuTT 668 NP AL-DP-8205 acccgaucgugccuuccuuTT 669 aaggaaggcacgaucggguTT; 670 NP AL-DP-8221 auggaugucaauccgacuuTT 671 aagucggauugacauccauTT; 672 PBl AL-DP-8222 uggaugucaauccgacuuuTT 673 aaagucggauugacauccaTT; 674 PBl A -DP-8223 gaugucaauccgacuuuacTT 675 guaaagucggauugacaucTT • 676 PBl A -DP-8224 augucaauccgacuuuacucuTT 677 aguaaagucggauugacauTT; 678 PBl AL-DP-8225 ugucaauccgacuuuacuuTT 679 aaguaaagucggauugacaTT • 680 PBL-DP-8226 ccauacagccauggaacagTT 681 682 cuguuccauggcuguauggTT PBl AI.-DP-8227 cauacagccauggaacaggTT 683 684 ccuguuccauggcuguaugTT PBl AL-DP-8228 acaggauacaccauggacaTT uguccaugguguauccuguTT 685 686 PBl AL-DP-8229 caggauacaccauggacacTT guguccaugguguauccugTT 687 688 PBl AL-DP-8230 uuggaagcaauggcuuuccTT ggaaagccauugcuuccaaTT 690 689 PBl? -DP-S231 ggaagcaauggcuuuccuuT aaggaaagccauugcuuccTT 691 692 PBl AI.-DP-8232 agcaauggcuuuccuugaaTT uucaaggaaagccauugcuTT 693 694 PBl AL-DP-8233 augaugacuaacucacaagTT cuugugaguuagucaucauTT 695 696 PBl AL-DP-8234 ugaugacuaacucacaagaT? 697 ucuugugaguuagucaucaTT 698 PBl A-DP-8235 accaaauggaaugagaaucTT 699 gauucucauuccauuugguTT 700 PBl A-DP-8236 ccaaauggaaugagaaucaTT 701 ugauucucauuccauuuggTT 702 PBl A-DP-8237 ggaaugaugaugggcauguTT 703 acaugcccaucaucauuccTT 704 PBl A-DP-8238 gaaugaugaugggcauguuTT 705 aacaugcccaucaucauucTT 706 PBl A-DP-8239 cuccaauccucugaugauuTT 707 aaucaucagaggauuggagTT 708 PBl AL-DP-8240 uccaauccucugaugauuuTT 709 aaaucaucagaggauuggaTT 710 PBl AL-DP-8241 aucaugagggaauacaagcTT 711 gcuuguauucccucaugauTT 712 PBl AL-DP-8242 uuugugcgacaaugcuucaTT 713 ugaagcauugucgcacaaaTT 714 PA AL-DP-8243 uauggga iccuuucgucaTT 715 ugacgaaaggaaucccauaTT 716 PA AL-DP-8244 uccgagagaggcgaagagaTT 717 ucucuucgccucucucggaTT 718 PA AL-0P-8245 ccgagagaggcgaagagacTT 719 gucucuucgccucucucggTT 720 PA AL-DP-8247 gagagaggcgaagagacaaTT 721 uugucucuucgccucucucTT 722 PA AL-DP-8248 agagaggcgaagagacaauTT 723 auugucucuucgccucucuTT 724 PA AL-DP-8249 gagaggcgaagagacaauuTT 725 aauugucucuucgccucucTT 726 PA A-DP-8250 agaggcgaagagaca auugTT 727 caauugucucuucgccucuTT 728 PA Identified! Sequence of sense strand SEQ Sequence of strand SEQ Gene of E1"* ELISA Double expression (5 '-3' J ID antisense (5'-3 '! ID Influenza infectivity (cells (plasmid cells, NO : remaining objective1 MDCK), «from Vero),« from «from NO: inhibition1 inhibition5 inhibition * AL-DP-8251 gaggcgaagagacaauugaTT 729 ucaauugucucuucgccucTT 730 PA AL-DP-8252 aggcgaagagacaauugaaTT 731 uucaauugucucu cgccuTT 732 PA AL-DP-8253 ggcgaagagacaauugaagTT 733 cuucaauugucucuucgccTT 734 PA AL-DP-8254 gcgaagagacaauugaagaTT 735 ucuucaauugucucuucgcTT 736 PA AL-DP-8255 cgaagagacaauugaagaaTT 737 uucuucaauugucucuucgTT 738 PA AL-DP-8257 uucuccagccuugaaaacuTT 739 aguuuucaaggcuggagaaTT 740 PA AL-DP-8258 ucuccagccuugaaaacuuTT 741 aaguuuucaaggcuggagaTT 742 PA AL-DP-8259 cuccagccuugaaaacuuuTT 743 aaaguuuucaaggcuggagTT 744 PA A-DP-8260 uccagccuugaaaacuuuaTT 745 uaaaguuuucaaggcuggaTT 746 PA AL-DP-8261 ccagccuugaaaacuuuagTT 747 cuaaaguuuucaaggcuggTT 748 PA AL-DP-8262 cagccuugaaaacuuuagaTT 749 ucuaaaguuuucaaggcugTT 750 PA A-DP-8263 agccuugaaaacuuuagagTT 751 cucaaaaguuuucaaggcuTT 752 PA AL-DP-8264 gccuugaaaacuuuagagcTT 753 gcucuaaaguuuucaaggcTT 754 PA A-DP-8265 ccuugaaaacuuuagagccTT 755 ggcucuaaaguuuucaaggTT 756 PA AL-DP-8266 cuugaaaacuuuagagccuTT 757 aggcucuaaaguuuucaagTT 758 PA AL-DP-8267 uugaaaacuuuagagccuaTT 759 uaggcucuaaaguuuucaaTT 760 PA AL-DP-8268 ugaaaacuuuagagccuauTT 761 auaggcucuaaaguuuucaTT 762 PA AL-DP-8269 gaaaacuuuagagccuaugTT 763 cauaggcucuaaaguuuucTT 764 PA AI? 5P-8270 aaaacuuuagagccuauguTT 765 acauaggcucuaaaguuuuTT 766 PA AL-DP-8271 aaacuuuagagccuaugugTT 767 cacauaggcucuaaaguuuTT 768 PA Ai-DP-8272 aacuuuagagccuauguggTT 769 ccacauaggcucuaaaguuTT 770 PA AL-DP-8273 acuuuagasccuauguggaTT 771 uccacauaggcucuaaaguT T 772 PA AL-DP-8274 cuuuagagccuauguggauTT 773 auccacauaggcucuaaagTT 774 PA AL-DP-8281 aaccgaacggcugcauugaTT 775 ucaaugcagccguucgguuTT 776 PA AL-DP-8282 accgaacggcugcauugagTT 777 cucaaugcagccguucgguTT 778 PA A-DP-8283 ccgaacggcugcauugaggTT 779 ccucaaugcagccguucggTT 780 PA AL-DP-8284 cgaacggcugcauugagggTT 781 cccucaaugcagccguuegTT 782 PA AL-DP-8285 gaacggcugcauugagggcTT 783 gcccucaaugcagccguucTT 784 PA AL-DP-8286 aacggcugcauugagggcaTT 785 ugcccucaaugcagccguuTT 786 PA AL-DP-8287 acggcugcauugagggcaaTT 787 uugcccucaaugcagccguTT 788 PA AL-DP-8288 cggcugcauugagggcaagTT 789 cuugcccucaaugcagccgTT 790 PA AL-DP-8289 ggcugcauugagggcaagcTT 791 gcuugcccucaaugcagccTT 792 PA AL-DP-8290 gcugcauugagggcaagcuTT 793 agcuugcccucaaugcagcTT 794 PA AL-DP-8291 cugcauugagggcaagcuuTT 795 aagcuugcccucaaugcagTT 796 PA AL-DP-8292 ugcauugagggcaagcuuuTT 797 aaagcuugcccucaaugcaTT 798 PA A-DP-8293 gcauugagggcaagcuuucTT 799 gaaagcuugcccucaaugcTT 800 PA AL-DP-8294 cauugagggcaagcuuucuTT 801 agaaagcuugcccucaa UGTT 802 PA AL-DP-8295 auugagggcaagcuuucucTT 803 gagaaagcuugcccucaauTT 804 PA AL-DP-8296 uugagggcaagcuuucucaTT 805 ugagaaagcuugcccucaaTT 806 PA AL-DP-8297 ugagggcaagcuuucucaaTT 807 uugagaaagcuugcccucaTT 808 PA AM3P-8298 gagggcaagcuuucucaaaTT 809 uuugagaaagcuugcccucTT 810 PA AL-DP-8299 agggcaagcuuucucaaauTT 811 auuugagaaagcuugcccuTT 812 PA AL-DP-8300 gggcaagcuuucucaaaugTT 813 cauuugagaaagcuugcccTT 814 PA AL-DP-8301 ggcaagcuuucucaaauguTT 815 acauuugagaaagcuugccTT 816 PA AL-DP-8302 gcaagcuuucucaaaugucTT 817 gacauuugagaaagcuugcTT 818 PA AL-DP-8303 augauaagcaaaugcagaaTT 819 uucugcauuugcuuaucauTT 820 PA AL-DP-8304 ugauaagcaaaugcagaacTT 821 guucugcauuugcuuaucaTT 822 PA AL-DP-8305 cuuagggacaaccuggaacTT 823 guuccagguugucccuaagTT 824 PA Identifier Sequence of sense strand SEQ Sequence of strand SEQ Gene of% ELISA ELISA Double expression (5'-3 ') antisense ID' 5'-3") Influenza ID nfectivity (cells (pLasmid cells, NO- NO: remaining objective1 MDCK), ida Vero), «of» and inhibition1 inhibition1 inhibition4 A -DP-8306 uuagggacaaccuggaaccTT gguuccagguugucccuaaTT 825 826 AL-DP-PA S307 uagggacaaccuggaaccuTT agguuccagguugucccuaTT 827 828 PA AL-DP-8308 830 PA cagguuccagguugucccuTT agggacaaccuggaaccugTT 829 AL-DP-8309 832 PA ccagguuccagguugucccTT gggacaaccuggaaccuggTT 831 AL-DP-8315 TT S34 agcaauugaggagugccugTT 833 caggcacuccucaauugc PA AL-DP-8316 gcaauugaggagugccugaTT 835 ucaggcacucsacaauugcTT 836 PA AL-DP-8317 caauugaggagugccugauTT 837 aucaggcacuccucaauugTT 838 PA AL-DP-8318 aauugaggagugccugauuTT 839 aaucaggcacuccucaauuTT 840 PA AL-DP-8319 auugaggagugccugauuaTT 841 uaaucaggcacuccucaaup 842 PA AL-DP-8320 uugaggagugccugauuaaTT 843 uuaaucaggcacuccucaaTT 844 P? ? L-DP-8328 uugguucaacuccuuccucTT 84S gaggaaggaguugaaccaaTT 846 PA L-DP-8329 gaaugaaauggaugauggcTT 847 848 gccaucauccauuucauucTT PB2 AL-DP-8330 ugguaaugaaacggaaacgTT 849 850 cguuuccguuucauuaccaTT PB2 AL-DP-8331 augaaacggaaacgggacuTT 851 852 agucccguuuccguuucauTT PB2 A -DP-8332 ugaaacggaaacgggacucTT 853 gagucccguuuccguuucaTT PB2 854 AL-DP-8333 PB2 856 agagucccguuuccguuucTT gaaacggaaacgggacucuTT 855 AL-DP-8334 PB2 858 uagagucccguuuccsuuuTT aaacggaaacgggacucuaTT 857 AL-DP-8335 PB2 860 cuagagucccguuuccguuTT aacggaaacgggacucuagTT 859 AL-DP-8336 PB2 862 acggaaacgggacucuagcTT 861 gcuagagucccguuuccguTT AI.-DP-8337 863 cggaaacgggacucuagcaTT ugcuagagucccguuuccsTT 864 PB2 AL-DP-8338 ggaaacgggacucuagcauTT 865 augcuagagucccguuuccTT 866 PB2 1 in vitro plate-forming assay in MCDK cells as described in Example 3.1; 2 in vitro ELISA assay in MCDK cells as described in Example 3.2: 3 in vitro ELISA assay in MCDK cells as described in Example 3.2; 4 in vitro ELISA assay in MCDK cells as described in Example 3.2; negative values indicate that expression of the target gene was increased in treated cells compared to controls Table 1F: Exemplary RNAi agents for the target influenza virus, and have 100% objective coverage (criterion 1, see example 1) and 100% objective efficiency (criterion 2, see example 1) but allow for up to 3 universal bases in the unseeded region of the RNAi agent; x is established for the position of a universal base Identifier Sequence of sense strand SEQ Sequence of strand SEQ Gene of double (5'-3 ') ID antisense (5 -3') Influenza NO: NO: objective AL-DP-8368 ucxgcxgaxaugagcauugTT 867 caaugcucauxucxgcxgaTT 868 PBl AL-DP-8369 cxgcxgaxaugagcauggT 869 ccaaugcucauxucxgcxgTT 870 PBl AL-DP-8370 xaagaucugxuccaccauuTT 871 aaugguggaxcagaucuuxTT 872 PBl AL-DP-8371 aagaucugxuccaccauugTT 873 caaugguggaxcagaucuuTT 874 PBl AL-DP-8372 agaucugxuccaccauugxTT 875 xcaaugguggaxcagaucuTT 876 PBl AL-DP-8373 xugaauuxxcuuguccuuTT 877 aaggacaagxxaaauucaxTT 878 PBl AL-DP-8374 ugaauuxxcuuguccuucT 879 gaaggacaagxxaaauucaTT 880 PBl AL-DP-8375 gaauuuxxcuuguccuucxTT 881 xgaaggacaagxxaaauucTT 882 PBl AL-DP-8376 uuguccuuuuuuuuuuuuu 883 auuuucaxgaaggacaaTT 884 PBl AL-DP-8377 uguccuucxugaaaaaa? IgTT 885 cauuuuuucaxgaaggacaTT 886 PBl AL-DP-8378 guccucxugaaaaaaugcTT 887 gcauuuuuucaxgaaggacTT 888 PBl AL-DP-8379 uccuucxugaaaaaaugcxTT 889 xgcauuuuuucaxgaaggaTT 890 PBl ALtDP-8380 aaxggxugxauugagggcaTT 891 ugcccucaauxcaxccxuuTT 892 PA AL-DP-8381 axggxugxau? GagggcaaTT 893 uugcccucaauxcaxccxuTT 894 PA AL-DP-8382 xggxugxauugagggcaagTT 895 cuugcccucaauxcaxccxTT 896 PA AL-DP-8383 ggxugxauugagggcaagcTT 897 gcuugcccucaauxcaxccTT 898 PA AL-DP-8384 gxugxauugagggcaagcuTT 899 agcuugcccucaauxcaxcTT 900 PA AL-DP-8385 xugxauugagggcaagcuwTT 901 wagcuugcccucaauxcaxTT 902 PA AL-DP-8386 aaxgcuacuxuuugcuaucTT 903 gaagcaaaxaguagcxuTT 904 PA AL-DP-8387 axgcuacuxuuugcuauccTT 905 ggauagcaaaxaguagcxuTT 906 PA AL-DP-8388 xgcuacuxuuugcuauccaTT 907 uggauagcaaaxaguagcxTT 908 PA AL-DP-8389 gcuacuxuuugcuauccauTT 909 auggauagcaaaxaguagcTT 910 PA Identifier Sense strand sequence SEQ Sequence sequence SEQ Gene double (5 '-3') antisense ID (5"-3") influenza ID NO: NO: target AL-DP-8390 cuacuxuuugcuauccauaTT 911 uauggauagcaaaxaguagTT 912 PA AL-DP-8391 uacuxuuugcuauccauacTT 913 guauggauagcaaaxaguaTT 914 PA AL-DP-8392 acuxuuugcuauccauacuTTT 915 aguauggauagcaaaxaguTT 916 PA AL-DP-8393 cuxuuugcuauccauacugTT 917 caguauggauagcaaaxagTT 918 PA AL-DP-8394 uxuuugcuauccauacuguTT 919 acaguauggauagcaaaxaTT 920 PA AL-DP-8395 xuuugcuauccauacugucTT 921 gacaguauggauagcaaaxTT 922 PA AL-DP-8396 uuugcuauccauacugucxTT 923 xgacagua ggauagcaaaTT 924 PA AL-DP-8397 ucggccxxcxaaagcagguTT 925 accugcuuuxgxxggccgaTT 926 PB2 AL-DP-8398 cggccxxcxaaagcaggucTT 927 gacc gcuuuxgxxggccg T 928 PB2 AL-DP-8399 ggccxxcxaaagcaggucaTT 929 ugaccugcuuuxgxxggccTT 930 PB2 AL-DP-8400 gccxxcxaaagcaggucaaTT 931 ugaccugcuuuxgxxggcTT 932 PB2 AL-DP-8401 gacagxcagxcagcgaccaTT 933 uggucgcugxcugxcug cTT 934 PB2 AL-DP-8402 acagxcagxcagcgaccaxTT 935 x ggucgcugxcugxc guTT 936 PB2 AL-DP-8403 xuxuhgaauxguuuaaaaaTT 937 uuuuuaaacxauuchaxaxTT 938 PB2 AL-DP- &404 uxgaa-uxgu uaaaaacTT 939 guuuuuaaacxau cxacaTT 940 PB2 AL-DP-8405 guxgaauxguuuaaaaacsTT 941 sguuuuuaaacxauucxacTT 942 PB2 AL-DP-8406 uguuucuxxxauauggcgcTT 943 gcgccauauxxxagaaacaTT 944 PB2 AL-DP-8407 guuucuxxxauauggcgcaTT 945 ugcgccauauxxxagaaacTT 946 PB2 AL-DP-8408 uuucuxxxauauggcgcauTT 947 augcgccauauxxxagaaaTT 948 PB2 AL-DP-84Q9 uucuxxxauauggcgcauaTT 949 ua gcgccauauxxxagaaTT 950 PB2 AL-DP-84I0 ucuxxxauauggcgcauacTT 951 guaugcgccauauxxxagaTT 952 PB2 A -DP-8411 cuxxxauauggcgcauacuTT 953 aguaugcgccauauxxxagTT 954 PB2 AL-DP-8412 uxxxauauggcgca ac cTT 955 gaguaugcgccauauxxxaTT 956 PB2 AL-DP-8413 xxxuauggcgcauacucgTT 957 cgaguaugcgccauaxxxTT 958 PB2 AL-DP-84I4 xxauauggcgcauacucggTT 959 ccgaguaugcgccauauxxTT 960 PB2 AL-DP-8415 xauauggcgca acucgggTT 961 cccgaguaugcgccauauxTT 962 PB2 AL-DP-8416 auauggcgcauacucgggcTT 963 gcccgaguaugcgccauauTT 964 PB2 AL-DP-8417 uauggcgcauacucgggcaTT 965 ugcccgag augcgccauaTT 966 PB2 AL-DP-8418 auggcgcauacucgggcauTT 967 augcccgaguaugcgcca TT 968 PB2 AL-DP-8419 uggcgcauac cgggcaugTT 969 ca gcccgaguaugcgccaT 970 PB2 A -DP-8420 ggcgcauacucgggcauguTT 971 acaugcccgaguaugcgccTT 972 PB2 AL-DP-8421 xxggcccccxcaaagccgaTT 973 ucggcuu gxgggggccxxTT 974 MP AL-DP-8422 xggcccccxcaaagccgaxTT 975 xucggcu ugxgggggccxTT 976 MP AL-DP-8423 xuuxacgcuxaccgugcccTT 977 gggcacgguxagcguxaaxTT 978 MP A -DP-8424 uuxacgcuxaccgugcccaTT 979 ugggcacgguxagcguxaaTT 980 MP A -DP-8425 uxacgcuxaccgugcccagTT 981 cugggcacggruxagcguxaTT 982 MP AL-DP-8426 xacgcuxaccgugcccagxTT 983 xcugggcacgguxagcguxTT 984 MP 1 in in vitro plaque-forming assay in MCDK cells as described in Example 3.1 Table 1G: Exemplary RNAi agents for the target influenza virus, and have 80% objective coverage (criterion 1, see example 1) and 80% target efficiency (criterion 2, see example 1) but allows for up to 1 universal basis in the unseeded region of the RNAi agent; x is established for the position of a universal base Identifier Sense strand sequence SEQ Sequence sequence SEQ Gene double (5 '-3") antisense ID (5' -3") influenza ID NO: NO: target AL-DP-8427 acguacguucucucucucxTT 985 xgauagagagaacguacguT 986 MP A -DP-8428 cucucuaucxucccgucagTT 987 cugacgggaxgauagagagTT 988 MP AL-DP-8429 ucuc aucxucccgucaggTT 989 ccugacgggaxgauagagaTT 990 MP AL-DP-8430 cucuaucxucccgucaggcTT 991 gccugacgggaxgauagagTT 992 MP AL-DP-8431 ucuaucxucccgucaggccTT 993 ggccugacgggaxgauagaTT 994 MP AL-DP-8432 c aucxucccgucaggcccTT 995 gggccugacgggaxgauagTT 996 MP AL-DP-8433 uaucxucccgucaggccccTT 997 ggggccugacgggaxgauaTT 998 MP AL-DP-8434 aucxucccgucaggcccccTT 999 gggggccugacgggaxgauTT 1000 MP AL-DP-8435 ucxucccgucaggcccccuTT 1001 agggggccugacgggaxgaTT 1002 MP AL-DP-8436 cxucccgucaggcccccucTT 1003 gagggggccugacgggaxgTT 1004 MP AL-DP-8437 xucccgucaggcccccucaTT 1005 ugagggggcc gacgggaxTT 1006 MP AI ^ DP-8438 aagccgagaucgcgcagaxTT 1007? UcgcgaucucggcuTT 1008 MP AL-DP-8439 gaucuxgaggcucucauggTT 1009 ccaugagagccucxagaucTT 1010 MP AL-DP-8440 aucuxgaggcucucauggaTT 1011 uccaugagagccucxagauTT 1012 MP AL-DP-8441 ucucauggaxuggcuaaagTT 1013 cuuuagccax ccaugagaTT 1014 MP AL-DP-8442 cucauggaxuggcuaaagaTT 1015 ucuuagccaxuccaugagTT 1016 MP AL-DP-8443 ucauggaxuggcuaaagacTT 1017 gucuuuagccaxuccaugaTT 1018 MP AL-DP-8444 cauggaxuggcuaaagacaTT 1019 uguc iuagccax ccaugTT 1020 MP AL-DP-8445 to ggaxuggcuaaagacaaTT 1021 uug cuuuagccaxuccauTT 1022 MP AL-DP-8446 uggaxuggcuaaagacaagTT 1023 cuugucuuuagccaxuccaTT 1024 MP AL-DP-8447 ggaxuggcuaaagacaagaTT 1025 ucuugucuuuagccaxuccTT 1026 MP AL-DP-8448 gaxuggcuaaagacaagacTT 1027 gucuuguc agccaxucTT 1028 MP AL-DP-8449 axuggcuaaagacaagaccTT 1029 ggucuugucuuuagccaxuTT 1030 MP AL-DP-8450 xuggcuaaagacaagaccaTT 1031 uggucug? CuuuagccaxTT 1032 MP AL-DP-8451 ccugucaccucugacuaaxTT 1033 xuuagucagaggugacaggTT 1034 MP AL-DP-8452 uuug x ucacgcucaccgTT 1035 cggugagcgugaaxacaaaTT 1036 MP AL-DP-8453 uuguxuucacgcucaccguTT 1037 acggugagcgugaaxacaaTT 1038 MP AL-DP-8454 guxuucacgcucaccgugTT 1039 cacggugagcgugaaxacaTT 1040 MP Identifier Sense strand sequence SEQ Sequence sequence SEQ Double gene (S '-3'.}. Antisense ID (5 '-3') Influenza NO: NO: target AL-DP-8455 guxuucacgcucaccgugcTT 1041 gcacggugagcg gaaxacTT 1042 MP AL-DP-8456 uxuucacgcucaccgugccTT 1043 ggcacggugagcgugaaxaTT 1044 MP A -DP-8457 xuucacgcucaccgugcccTT 1045 gggcacggugagcgugaaxTT 1046 MP A -DP-8458 aggacugcagcguagacgxTT 1047 xcgucuacgcugcag ccuTT 1048 MP A -DP-8459 ugxauggg cucauauácaTT 1049 uguauaugagacccauxcaTT 1050 MP AL-DP-8460 gxaugggucucauauacaaTT 1051 uuguauaugagacccauxcTT 1052 MP AL-DP-8461 xaugggucucauauacaacTT 1053 guuguauaugagacccauxTT 1054 MP AL-DP-8462 auggguc cauauacaacxTT 1055 xguuguauaugagacccauTT 1056 MP AL-DP-8463 ugugccacxugugagcagaTT 1057 ucugcucacaxguggcacaTT 1058 MP AL-DP-8464 gugccacxugugagcagauTT 1059 aucugcucacaxguggcacTT 1060 MP AL-DP-8465 gccacxugugagcagauugTT 1061 caaucugcucacaxguggcrr 1062 MP A -DP-8466 ccacxugugagcagauugcTT 1063 gcaaucugcucacaxguggTT 1064 MP A -DP-8467 cuaggcaxauggugcaggcTT 1065 gccugcaccauxugccuagTT 1066 MP AL-DP-8468 augagxacaauugggacucTT 1067 gagucccaauuguxcucauTT 1068 MP AL-DP-8469 ugagxacaau gggacucaTT 1069 ugagucccaauuguxcucaTT 1070 MP A -DP-8470 uuugcaggcxuaccagaaaTT 1071 uuucugguaxgccugcaaaTT 1072 MP AL-DP-8471 uugcaggcxuaccagaaacTT 1073 guuucugguaxgccugcaaTT 1074 MP A -DP-8472 ugcaggcxuaccagaaacgTT 1075 cguuucugguaxgccugcaTT 1076 MP AI ^ DP-8473 augcagcgxuucaagugauTT 1077 aucacuugaaxcgcugcauTT 1078 MP A -DP-8474 ugcagcgxuucaagugaucTT 1079 gaucacuugaaxcgcugcaTT 1080 MP AL ^ DP-8475 gcagcgxuucaagugauccTT 1081 ggaucacuugaaxcgcugcTT 1082 MP AL-DP-8476 cagcgxuucaagugauccuTT 1083 aggaucacuugaaxcgcugTT 1084 MP A -DP-8477 agcgxuucaagugauccucTT 1085 gaggaucacuugaaxcgcuTT 1086 MP A -DP-8478 gcgxuucaagugauccucuTT 1087 agaggaucacuugaaxcgcTT 1088 MP A1 DP-8479 cauugggauxuugcacuugTT 1089 caagugcaaxaucccaaugTT 1090 MP A -DP-8480 auugggauxuugcacuugaTT 1091 ucaagugcaaxaucccaauTT 1092 MP AL-DP-8481 uugggauxuugcacuugauTT 1093 aucaagugcaaxaucccaaTT 1094 MP A -DP-8482 ugggauxuugcacuugauaTT 1095 uaucaagugcaaxaucccaTT 1096 MP AL ^ DP-8483 gggauxuugcacuugauauTT 1097 auaucaagugcaaxaucccTT 1098 MP AL-DP-8484 ggauxuugcacuugauauuTT 1099 aauaucaagugcaaxauccTT UOO MP A -DP-8485 gauxuugcacuugauau gTT 1101 caauaucaagugcaaxaucTT 1102 MP AL-DP-8486 auxuugcacuugauauuguTT 1103 acaauaucaagugcaaxauTT 1104 MP A -DP-8487 uxuugcacuugauauugugTT 1105 cacaauaucaagugcaaxaTT 1106 MP A -DP-8488 xuugcacuugauauuguggTT 1107 ccacaauaucaagugcaaxTT 1108 MP AL-DP-8489 aaaugcauuuaucgucccxTT 1109 xgcgacgauaaaugcauuuTT 1110 MP AL-DP-8490 uaucgucgcxuuaaauacgTT 1111 cuauuuaaxgcgacgauaTT 1112 MP AL-DP-8491 aucgucgcxuuaaauacggTT 1113 ccguauuuaaxgcgacgauTT 1114 MP AL-DP-8492 ucgucgcxuuaaauacgguTT 1115 accguauuuaaxgcgacgaTT 1116 MP AL-DP-8493 cgucgcxuuaaauacgguuTT 1117 aaccguauuuaaxgcgacgTT 1118 MP A -DP-8494 gucgcxuuaaauacgguuuTT 1119 aaaccguauuuaaxgcgacTT 1120 MP AI ^ DP-8495 ucgcxuuaaauacgguuugTT 1121 caaaccguauuuaaxgcgaTT 1122 MP AL-DP-8496 cgcxuuaaauacgguuugaTT 1123 ucaaaccguauuuaaxgcgTT 1124 MP AL-DP-8497 gcxuuaaauacgguuugaaTT 1125 uucaaaccguauuuaaxgcTT 1126 MP AL-DP-8498 cxuuaaauacgguuugaaaTT 1127 uuucaaaccguauuuaaxgTT 1128 MP AL-DP-8499 xuuaaauacgguuugaaaaTT 1129 uuuucaaaccguauuuaaxTT 1130 MP AL-DP-8500 gguu gaaaagagggccuxTT 1131 xaggcccucuuuucaaaccTT 1132 MP A -DP-8501 xuugaaaagagggccuucuTT 1133 agaaggcccucuuuucaaxTT 1134 MP AL-DP-8502 aaaaxagggcc uc acggTT 1135 ccguagaagcucccuxuuuuTT 1136 MP AL-DP-8503 aaagagggccuucuacggxTT 1137 xccguagaaggcccucuuuTT 1138 MP AL-DP-8504 guxcc gagucuaugagggTT 1139 cccucauagacucaggxacTT 1140 MP Identifier Signal strand sequence SEQ Sequence sequence SEQ Double gene (5 '-3') Anti-sense ID (5 '-3') Influenza ID NO: NO : objective A DP-8505 uxccugagucuaugagggaTT 1141 ucccucauagacucaggxaTT 1142 MP AL-DP-8506 xccugagucuaugagggaaTT 1143 uucccucauagacucaggxTT 1144 MP AL-DP-8507 ugagucuaugagggaagaxTT 1145 xucuucccucauagacucaTT 1146 MP AL-DP-8508 cagaxugcuguggauguugTT 1147 caacauccacagcaxucugTT 1148 MP A -DP-8509 agaxugcuguggauguugaTT 1149 ucaacauccacagcaxucuTT 1150 MP A -DP-8510 gaxugcuguggauguugacTT 1151 gucaacauccacagcaxucTT 1152 MP A -DP-8511 axugcuguggauguugacgTT 1153 cgucaacauccacagcaxuTT 1154 MP AL-DP-8512 xugcuguggauguugacgaTT 1155 ucgucaacauccacagcaxTT 1156 MP A -DP-8513 xucaaggcaccaaacgaucTT 1157 gaucguuuggugccuugaxTT 1158 NP AL-DP-8514 aggcaccaaacgaucuuaxTT 1159 xuaagaucguuuggugccu T 1160 NP A -DP-8515 uaugaxcagauggaaacugTT 1161 caguuuccaucugxucauaTT 1162 NP AL-DP-8516 augaxcagauggaaacuggTT 1163 ccaguuuccaucugxucauTT 1164 NP AL-DP-8517 ugaxcagauggaaacugguTT 1165 accaguuuccaucugxucaTT 1166 NP A -DP-8518 gaxcagauggaaacuggugTT 1167 caccaguuuccaucugxucTT 1168 NP AX-DP-8519 axcagauggaaacugguggTT 1169 ccaccaguuuccaucugxuTT 1 170 NP A -DP-8520 aacugguggxgaacgccagTT 1171 cuggcguucxccaccaguuTT 1172 NP AL-DP-852I acugguggxgaacgccagaTT 1173 ucuggcguucxccaccaguTT 1174 NP AL-DP-8522 cugguggxgaacgccagaaTT 1175 uucuggcguucxccaccagTT 1176 NP AL-DP-8523 ugguggxgaacgccagaauTT 1177 auucuggcguucxccaccaTT 1178 NP AL-DP-8524 gguggxgaacgccagaaugTT 1179 cauucuggcguucxccaccTT 1180 NP AL-DP-8525 guggxgaacgccagaaugcTT 1181 gcauucuggcguucxccacTT 1182 NP AL-DP-8526 ccagaaugcxacugagaucTT 1183 gaucucaguxgcauucuggTT 1184 NP AL-DP-8527 cagaaugcxacugagaucaTT 1185 ugaucucaguxgcauucugTT 1186 NP A -DP-8528 agaaugcxacugagaucagTT 1187 cugaucucaguxgcauucuTT 1188 NP AL-DP-8529 gaugugcacxgaacucaaaTT 1189 uuugaguucxgugcacaucTT 1190 NP AL-DP-8530 augugcacxgaacucaaacTT 1191 guuugaguucxgugcacauTT 1192 NP AL-DP-8531 ugugcacxgaacucaaacuTT 1193 aguuugaguucxgugcacaTT 1194 NP AL-DP-8532 gugcacxgaacucaaacucTT 1195 gaguuugaguucxgugcacTT 1196 NP AL-DP-8533 ugcacxgaacucaaacucaTT 1197 ugaguuugaguucxgugcaTT 1198 NP AL-DP-8534 gcacxgaacucaaacucagTT 1199 cugaguuugaguucxgugcTT 1200 NP AL-DP-8535 caxaacagcauaacaauagTT 1201 cuauuguuaugcuguuxugTT 1202 NP AL-DP-8536 axaacagcauaacaauagaTT 1203 ucuauuguuaugcuguuxuTT 1204 NP A -DP-8537 xaacagcauaacaauagagTT 1205 cucuauuguuaugcuguuxTT 1206 NP AL-DP-8538 aacaauagagagaaugguxTT 1207 xaccauucucucuauuguuTT 1208 NP AL-DP-8539 ugaugauxuggcauuccaaTT 1209 uuggaaugccaxaucaucaTT 1210 NP A -DP-8540 augugxucucugaugcaagTT 1211 cuugcaucagagaxcacauTT 1212 NP AI ^ DP-8541 ugugxucucugaugcaaggTT 1213 ccuugcaucagagaxcacaTT 1214 NP A -DP-8542 agxauugcauaugagagaaTT 1215 uucucucauaugcaauxcuTT 1216 NP AL-DP-8543 gxauugcauaugagagaauTT 1217 auucucucauaugcaauxcTT 1218 NP AL-DP-8544 xauugcauaugagagaaugTT 1219 cauucucucauaugcaauxTT 1220 NP A -DP-8545 ugcxuaugagagaaugugcTT 1221 gcacauucucucauaxgcaTT 1222 NP A -DP-8546 auaugagagaaugugcaaxTT 1223 xuugcacauucucucauauTT 1224 NP A -DP-8547 uaugaxagaaugugcaacaTT 1225 uguugcacauucuxucauaTT 1226 NP A -DP-8548 augaxagaaugugcaacauTT 1227 auguugcacauucuxucauTT 1228 N? AL-DP-8549 aaugugcaaxauccucaaaTT 1229 uuugaggauxuugcacauuTT 1230 NP A -DP-8550 augugcaaxauccucaaagTT 1231 cuuugaggauxuugcacauTT 1232 NP Al ^ DP-8551 ugugcaaxauccucaaaggTT 1233 ccuuugaggauxuugcacaTT 1234 NP AL-DP-8552 agggaaauuxcaaacagcaTT 1235 ugcuguuugxaauuucccuTT 1236 NP AL-DP-8553 gggaaauuxcaaacagcagTT 1237 cugcuguuugxaauuucccTT 1238 NP A -DP-8554 ggaaauuxcaaacagcagcTT 1239 gcugcuguuugxaauuuccTT 1240 NP Identifier Sense strand sequence SEQ Sequence sequence SEQ Double gene (5 '-3' J antisense ID (S "-3 ') influenza ID NO: NO: target AL-DP-8555 gaaauuxcaaacagcagcaTT 1241 ugcugcuguuugxaauuucTT 1242 NP AL-DP-8556 aaauuxcaaacagcagcacTT 1243 gugcugcuguuugxaauuuTT 1244 NP A -DP-8557 aauuxcaaacagcagcacaTT 1245 ugugcugcuguuugxaauuTT 1246 NP AL-DP-8558 auuxcaaacagcagcacaaTT 1247 uugugcugcuguuugxaauTT 1248 NP AL-DP-8559 gcacaaxgagcaaugauggTT 1249 ccaucauugcucxuugugcTT 1250 NP AL-DP-8560 cacaaxgagcaaugauggaTT 1251 uccaucauugcucxuugugTT 1252 NP AL-DP-8561 acauucccxuauacuggagTT 1253 cuccaguauaxgggaauguTT 1254 PBl AL-DP-8562 cauucccxuauacuggagaTT 1255 ucuccaguauaxgggaaugTT 1256 PBl AL-DP-8563 ggagaxccuccauacagccTT 1257 ggcuguauggaggxucuccTT 1258 PBl AL-DP-8564 gagaxccuccauacagccaTT 1259 uggcuguauggaggxucucTT 1260 PBl AL-DP-8565 agaxccuccauacagccauTT 1261 auggcuguauggaggxucuTT 1262 PBl A -DP-8566 gaxccuccauacagccaugTT 1263 cauggcuguauggaggxucTT 1264 PBl A -DP-8567 ccxccauacagccauggaaTT 1265 uuccauggcuguauggxggTT 1266 PBl AL-DP-8568 cxccauacagccauggaacTT 1267 guuccauggcuguauggxgTT 1268 PBl AL-DP-8569 xccauacacacacacacacaTT 1269 uguuccauggcuguauggxTT 1270 PBl AL-DP-8570 auacagccauggaacaggxTT 1271 xccuguuccauggcuguauTT 1272 PBl AL-DP-8571 ggaacaggxacaggauacTT 1273 guauccuguxccuguuccaTT 1274 PBl A -DP-8572 ggaacaggxacaggauacaTT 1275 uguauccuguxccuguuccTT 1276 PBl AL-DP-8573 gaacaggxacaggauacacTT 1277 guguauccuguxccuguucTT 1278 PBl A -DP-8574 aacaggxacaggauacaccTT 1279 gguguauccuguxccuguuT 1280 PBl AL-DP-8575 acaggxacaggauacaccaTT 1281 ugguguauccuguxccuguTT 1282 PBl A -DP-8576 caggxacaggauacaccauTT 1283 augguguauccuguxccugTT 1284 PBl A -DP-8577 aggxacaggauacaccaugTT 1285 caugguguauccuguxccuTT 1286 PBl A -DP-8578 ggxacaggauacaccauggTT 1287 ccaugguguauccuguxccTT 1288 PBl AL-DP-8579 gxacaggauacaccauggaTT 1289 uccaugguguauccuguxcTT 1290 PBl A -DP-8580 xacaggauacaccauggacTT 1291 guccaugguguauccuguxTT 1292 PBl AL-DP-8581 aggauacaccauggacacxTT 1293 xguguccaugguguauccuTT 1294 PBl AL-DP-8582 acacxgucaasagacacaTT 1295 uguguucuguugacxguguTT 1296 PBl A -DP-8583 guxuuggaagcaauggcuuTT 1297 aagccauugcuuccaaxacTT 1298 PBl AL-DP-8584 uxuuggaagcaauggcuuuTT 1299 aaagccauugcuuccaaxaTT 1300 PBl AL-DP-8585 xuuggaagcaauggcuuucTT 1301 gaaagccauugcuuccaaxTT 1302 PBl AL-DP-8586 gcaauggcuuuccuugaaxTT 1303 xuucaaggaaagccauugcTT 1304 PBl AL-DP-8587 caauggcxuuccuugaagaTT 1305 ucuucaaggaaxgccauugTT 1306 PBl AL-DP-8588 ugaaaacucxugucuugaaTT 1307 uucaagacaxgaguuuucaTT 1308 PBl A -DP-8589 gaaaacucxugucuugaaaTT 1309 uuucaagacaxgaguuuucTT 1310 PBl AL-DP-8590 aaaacucxugucuugaaacTT 1311 guuucaagacaxgaguuuuTT 1312 PBl AL-DP-8591 cgccagacxuaugacuggaTT 1313 uccagucauaxgucuggcgTT 1314 PBl AL-DP-8592 gccagacxuaugacuggacTT 1315 guccagucauaxgucuggcTT 1316 PBl AL-DP-8593 ccagacxuaugacuggacaTT 1317 uguccagucauaxgucuggTT 1318 PBl AL-DP-8594 caugaccaaxaaaauggucTT 1319 gaccauuuuxuuggucaugTT 1320 PBl AL-DP-8595 augaccaaxaaaauggucaTT 1321 ugaccauuuuxuuggucauTT 1322 PBl AL-DP-8596 ugaccaaxaaaauggucacTT 1323 gugaccauuuuxuuggucaTT 1324 PBl AL-DP-8597 gaccaaxaaaauggucacaTT 1325 ugugaccauuuuxuuggucTT 1326 PBl AWJP-8598 accaaxaaaauggucacacTT 1327 gugugaccauuuuxuugguTT 1328 PBl AL-DP-8599 ccaaxaaaauggucacacaTT 1329 ugugugaccauuuuxuuggTT 1330 PBl AL-DP-8600 caaxaaaauggucacacaaTT 1331 uugugugaccauuuuxuugTT 1332 PBl A -DP-8601 axaaaauggucacacaaagTT 1333 cuuugugugaccauuuuxuTT 1334 PBl A -DP-8602 ugacaxugaacacaaugacTT 1335 gucauuguguucaxugucaTT 1336 PBl A -DP-8603 aaxaugaugacuaacucacTT 1337 gugaguuagucaucauxuuTT 1338 PBl AL-DP-8604 axaugaugacuaacucacaTT 1339 ugugaguuagucaucauxuTT 1340 PBl Identifier Sense strand sequence SEQ Strand sequence b & U Double gene (5X3 ') antisense ID (5'-3') influenza ID NO: NO: target AL-DP-8605 xaugaugacuaacucacaaTT 1341 uugugaguuagucaucauxTT 1342 PBl AL-DP-8606 gaugacuaacucacaagaxTT 1343 xucuugugaguuagucauc? T 1344 PBl AL-DP-8607 gacaaxaccaaauggaaugTT 1345 cauuccauuugguxuugucTT 1346 PBl AL-DP-8608 acaaxaccaaauggaa gaTT 1347 ucauuccauuugguxuuguTT 1348 PBl AL-DP-8609 caaxaccaaauggaaugagTT 1349 1350 PBl AL-DP-8610 aaxaccaaauggaaugagaTT 1351 ucucauuccauuugguxuuTT 1352 PBl AL-DP-8611 axaccaaauggaaugagaaTT 1353 uucucauuccauuugguxuTT 1354 PBl AL-DP-8612 xaccaaauggaaugagaauTT 1355 auucucauuccauuugguxTT 1356 PBl AL-DP-8613 caaauggaaugagaaucaxTT 1357 xugauucucauuccauuugTT 1358 PBl AL-DP-8614 auugcxccua aauguucuTT 1359 agaacauuauaggxgcaauTT 1360 PBl AL-DP-8615 uugcxccuauaauguucucTT 1361 gagaacauuauaggxgcaaTT 1362 PBl AL-DP-8616 gcxccuauaauguucucaaTT 1363 uugagaacauuauaggxgcTT 1364 PBl AL-DP-8617 cxccuauaauguucucaaaTT 1365 umigagaacauuauaggxgTT 1366 PBl AL-DP-8618 uacgxacacaaa accagcTT 1367 gcugguauuuguguxcguaTT 1368 PBl AL-DP-8619 cgxacacaaauaccagcagTT 1369 cugcugguauuuguguxcgTT 1370 PBl AL-DP-8620 gxacacaaauaccagcagaTT 1371 ucugcugguauuuguguxcTT 1372 PBl AL-DP-8621 acacaxauaccagcagaaaTT 1373 uuucugcugguauxuguguTT 1374 PBl AL-DP-8622 cacaxauaccagcagaaauTT 1375 auuucugcugguauxugugTT 1376 PBl A -DP-8623 acaaauaccxgcagaaaugTT 1377 cauuucugcxgguauuuguTT 1378 PBl AL-DP-8624 caaauaccxgcagaaaugcTT 1379 gcauuucugcxgguauuugTT 1380 PBl AL-DP-8625 aaauaccxgcagaaaugcuTT 1381 agcauuucugcxgguauuuTT 1382 PBl AL-DP-8626 aauaccagcxgaaaugcuuTT 1383 aagcauuucxgcugguauuTT 1384 PBl AL-DP-8627 auaccagcxgaaaugcuugTT 1385 caagcauuucxgcugguauTT 1386 PBl AL-DP-8628 uaccagcxgaaaugcuugcTT 1387 gcaagcauuucxgcugguaTT 1388 PBl AL-DP-8629 accagexgaaaugcuugcaTT 1389 ugcaagcauuucxgcugguTT 1390 PBl AL-DP-8630 ccagcxgaaaugcuugcaaTT 1391 uugcaagcauuucxgcuggTT 1392 PBl AL-DP-8631 agaaaauxgagaaaauaagTT 1393 cuuauuuucucxauuuucuTT 1394 PBl Table 1H: RNAi ej emplares agents for the objective influenza virus derived from agents listed in Table 1C by stabilization towards nucleolytic degradation by nucleotide modifications Double Identifier no Sequence of strand sense SEQ Sequence of strand SEO. Modified double gene (5'-3 ') Anti-sense ID (5' -3 ') Corresponding influenza ID NO: NO: target AL-DP-2336 AL-DP-2316 amimumcmagaumcmgaacmggumcmumaTT 1395 umagaccguucgaucugaagTT 1396 PB2 AL-DP-2337 A -DP-2317 cmaga \? Mcp? Gaacmggumc? NuroaacmaTT 1397 uguumagaccguucgaucugTT 1398 P32 A -DP-2338 AL.-DP- 2318 agaumcmgaacmggumcmu aactnagTT cug umagaccguucgaucuTT 1399 AL-DP- 1400 PB2 2339 AL-DP- 2319 cmaaaaumgcmumauraaagumac croaTT uggupacuumauínagcpiauuuugTT 1401 1402 2340 PB2 A -DP- AL - DP- 2320 or 1403 umcraagaunicmgaacmggjmciiiumaaTT uumagaccguucgaucugaaTT 1404 AL-DP- 2341 PB2 al.-DP- 2321 umacmcmacmaumumcmcmapumumaupiacmumTT 1405 agumaumaagggaauguggumalT PB2 AL-DP- 1406 AL-DP- 2342 2327 1407 umupnimgagagagaagggumac umTT agumacccuucucucuanaaaTT NP AL-DP- 1408 AL-DP- 2343 2328 1409 aggcmaac gaacmcmcmgaumcmguraTT acgaucggguucguumgccuTT NP AL-DP- 1410 AL-DP- 2344 2329 1411 ggcmaacmgaacmcracragaum nigumgTT cmacgaucggguucguugccTT 1412 NP AL-DP-2345 AD-DP-2330 cmaacrogaacmcmcmgaumcmgumgsncpiTT 1413 ggcmacgaucggguucguugTT 1414 NP AL-DP-2346 Al-DP-2331 gcmaacmgaacmcmcmgaumcmguirg cpiTT 1415 gcmacgaucggguucguugcTT 1416 NP AL-DP-2347 AL-DP-2332 gaaaagscptaacmgaacracmcmgaTT 1417 ucggguucguumgccuuuucTT 1418 NP AL-DP-2352 AL-DP-2348 umgcmaumgaumaaaggcpragumcracmTT 1419 ggacugccuuumaucmaugcmaTT 1420 PB2 Mi-DP-2353 AL-DP-2349 aup > ggggaumgaumcmggaau, t? aumTT 1421 aumauuccgaucmaucccsnauTT 1422 PB2 AL-DP-2354 AL-DP-2350 umgggga mgautncmggaauraaumumTT 1423 aaumauuccgaucmauccccmaTT 1424 PB2 AL-DP-2355 AL-DP-2351 gaaacmgggacimimcmumagcmaumaTT 1425 umaugcumagagucccguuucTT 1426 PB2 AL-DP-2369 AL-DP-2356 agacmuraumuraguragcmgaanaauragcmTT 1427 gctnauuguccmacmaaagucuTT 1428 PA AL-DP-2370 AL-DP-2357 gac mumumgumgcmgacmaaumgcmuinTT 1429 agcmauugucgsnacmaaagucTT 1430 PA A -DP-2371 AL-DP-2358 urocimimaumgggaup mcmctmiipurauíncrogumTT acgaaaggaauccc aumagaTT 1431 1432 PA AL-DP-2372 DP-2359 AL-1433 cmimaumgggaumumcmc mUQumangumcmTT gacgaaaggaaucccmaumagTT PA 1434 AL-DP-2373 AL-DP-2360 aumgumggaumggaumumcmgaaciTic? IITT 1435 gguucgaauccmauccmacmauTT PA 1436 AL-DP-2374 A-DP-2361 umgumggaumggauuiumcmgaacmcmgTT 1437 cgguucgaauccmauccmacraaTT 1438 PA AL-DP-2375 AL P-2362 gumggaupiggaumumcingaacmcmgaTT 1439 ucggu cgaauccmauccmacTT 1440 PA AL-DP-2376 AL-DP-2363 umggaumggaumumcitgaacracmgaaTT 1441 uvLcgguucgaauccmauccmaT 1442 PA AL-DP-2377 AL-DP-2364 ggaumggaupnmcmgaacmcmgaacmTT 1443 guucgguucgaauccmauccTT 1444 PA AL-DP-2378 DP-2365 AL-1445 gaupiggauí imcmgaacrccmgaacmgTT cguucgguucgaauccpiaucTT PA 1446 AL-DP-2379 DP-2366 AL-1447 aumggaupraraangaaancmgaacmggTT ccguucgguucgaaucanauTT PA 1448 AL-DP-2380 DP-2367 AL-1449 umggaumumcmgaasticmgaacraggcmTT gccguucggmicgaauccmaTT PA 1450 AL-DP- 2381 AL-DP-2368 aumcmumcmcmacmaacmumcmgaggggTT 1451 ccccucgaguumgumggagauTT 1452 PA The double siRNA agent identifier of Table 1C having an identical nucleotide sequence when the nucleotide modifications are unattended Table II: Activity of the modified RNAi agents listed in Table IB and H towards the inhibition of the expression of the Influenza in the assays described in Example 3 ELISA ELISA Expression dentifier% gene (cells (plasmid cells, double influenza infectivity MDCK),% of Vero),% of target% s te1 inhibition2 inhibition5 inhibition1 AL-DP-2289 PBl 104% 17 -31 AL-DP-2290 NP 29% -8 -36 61 AL-DP-2291 NP 34% -28 -30 5 AL-DP-2292 NP 34% -25 -14 36 AL-DP-2293 MP 40% -7 -74 AL-DP-2294 MP 78% -19 -53 AL-DP-2295 MP 67% -39 -85 A ALL - DDPP - 22229966 M MPP 6 611 %% -21 AL-DP-2297 MP -15 -27 AL-DP-2298 MP -21 11 AL-DP -2299 MP -23 12 AL-DP-2300 MP -37 -62 AL-DP-2301 MP -13 -62 AL-DP-2302 MP -30 -51 AL-DP-2303 MP 1 -44 A ALL - DDPP - 22330044 M MPP -16 -38 AL-DP-2305 MP 45% 28 -42 AL-DP-2306 MP 46% -1 -46 AL-DP-2307 MP 39% 11 -18 AL-DP-2308 MP - 5 15 AL-DP-2309 MP 19 -42 AL-DP-2310 MP -1 -29 ftL-DP-2311 MP -46 -45 A ALL - DDPP - 22331122 M MPP -66 -31 / AL-DP- 2336 PB2 11 -15 AL-DP-2337 PB2 6 -23 AL-DP-2338 PB2 5 5 AL-DP-2339 PB2 33 -38 AL-DP-2340 PB2 19 -46 Identifier% ELISA gene (ELISA cells (cells Expression of plasmid, double influenza infectivity MDCK),% of Vero),% of% inhibition * target remaining1 inhibition2 inhibition3 AL-DP-2341 PB2 14 -5 AL-DP-2342 NP 9 3 42 AL-DP-2343 NP -32 -20 29 AL-DP-2344 NP -27 -10 22 AL-DP-234 5 NP 15 -29 39 AL-DP-2346 NP -22 -32 29 AL-DP-2347 NP -9 -24 65 AL-DP-2352 PB2 3 17 5 AL-DP-2353 PB2 -44 9 28 A -DP -2354 PB2 -54 - 9 27 A -DP-2355 PB2 < 25 13 45 59 AL-DP-2369 PA < 75 40 3 2 AL-DP-2370 PA 28 27 67 AL-DP-2371 PA 15 -24 12 AL-DP-2372 PA 18 -29 73 AL-DP-2373 PA < 25 37 27 71 AL-DP-2374 PA < 75 27 -48 9 AL-DP-2375 PA < 25 44 53 87 AL-PP-2376 PA 4 -40 38 AL-DP-2377 PA < 25 21 39 65 AL-DP-2378 PA -50 -75 11 AL-DP-2379 PA -39 -20 19 AL-DP-2380 PA 0 -27 31 AL-DP-2381 PA -52 -54 43 1 in vitro plate-forming assay in MCDK cells as described in Example 3.1; 2 in vitro ELISA assay in MCDK cells as described in Example 3.2: 3 in vitro ELISA assay in MCDK cells as described in Example 3.2; 4 in vitro ELISA assay in MCDK cells as described in Example 3.2; negative values indicate that expression of the target gene was increased in treated cells compared to controls Table 2: Concentration in 50% inhibition (IC50) for selected RNAi agents from Table 1 The antisense strand of an RNAi agent must be equal to or at least 14, 15, 16, 17, 18, 19, 25, 29, 40, or 50 nucleotides in length. It must be equal to or less than 60, 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. The sense strand of an RNAi agent must be equal to or at least 14, 15, 16 17, 18, 19, 25, 29, 40, or 50 nucleotides in length. It must be equal to or less than 60, 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. The double-stranded portion of an RNAi agent must 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 must be equal to or less than 60, 50, 40, or 30 nucleotide pairs in length. Preferred ranges are 15-30, 17 to 25, 19 to 23, and 19 to 21 nucleotide pairs in length. Generally, the RNAi agents of the present invention include a region of sufficient complementarity for the respective influenza virus gene, and have a sufficient length in terms of nucleotides, in which the RNAi agent, or a fragment thereof, can mediate the down regulation of the influenza virus gene. It is not necessary that there is a perfect complementarity between the RNAi agent and the target gene, but the correspondence must be sufficient to allow the RNAi agent, or a cleavage product thereof, to direct the sequence-specific silencing, for example, by cleavage of RNAi from an influenza virus RNA. Accordingly, the RNAi agents of the present invention include agents comprising a sense strand and antisense strand each comprising a sequence of at least 16, 17 or 18 nucleotides that are essentially identical, as defined below, for one of the sequences of Tables 1 A-IH, except that no more than 1, 2 or 3 nucleotides per strand, respectively, have been replaced by other nucleotides (e.g., adenosine replaced by uracil), while retaining essentially the ability to inhibit replication of the influenza virus in human cultured cells infected with the influenza virus, respectively. These agents will therefore possess at least 15 nucleotides identical to one of the sequences of Tables 1A-1H, but 1, 2 or 3 base incompatibilities with respect to either the RNA sequence of the target influenza virus or between the strand. sense and antisense. Inequalities for the RNA sequence of the target influenza virus, particularly in the antisense strand, is more tolerated in the terminal regions and if it is present preferentially in a terminal region or regions, for example, within 6, 5, 4, or 3 nucleotides of a 5 'and / or 3' term, more preferably within 6, 5, 4, or 3 nucleotides of the 5 'terminus of the sense strand or the 3' terminus of the antisense strand. The sense strand only needs to be sufficiently complementary to the antisense strand to maintain the overall double stranded character of the molecule. It is preferred that the sense and antisense strands are chosen in such a way that the RNAi agent includes a single strand or a non-peer region at one or both ends of the molecule. , an RNAi agent contains sense and antisense strands, preferably paired to contain a drapery, for example, one or two 5 'or 3' draperies but preferably a 3 'drapery of 2-3 nucleotides. Most modalities will have a 3 'drapery. Preferred sRNAi agents will have single-stranded coatings, preferably 3 'draperies, from 1 to 4, or preferably 2 or 3 nucleotides, in length, at one or both ends of the RNAi agent. The hangings can be the result of a thread that is longer than another, or the result of two strands of the same length that alternate. The unpaired nucleotides forming the curtain can be ribonucleotides, or they can be deoxyribonucleotides, preferably thymidine. The 5 'ends are preferably phosphorylated, or may be non-phosphorylated. Preferred lengths for the double region are between 15 and 30, more preferably 18, 19, 20, 21, 22, and 23 nucleotides in length, for example, in the range of sARNi agent discussed above. The sARNi agents can be similar in length and can structure the natural Dicer products of long dsRNA. The modalities in which the two strands of the sARNi agent are linked, for example, are covalently linked, are also included. The fork, or other single-strand structures provide the required double-strand region, and preferably a 3 'drapery is also found within the invention.

Evaluation of the Candidate Agent for RNAi As noted above, the present invention provides a system that identifies sRNAs that are useful as inhibitors of influenza virus infection and / or replication. Therefore, as noted above, the shRNAs are processed intracellularly to produce sRNAs having double portions with the same sequence as the mother structure of the shRNA, the system is equally useful for identifying shRNAs that are useful as inhibitors of the shRNA infection. influenza virus. For the purposes of the description of this section, it will refer to sRNA, although the system also includes the corresponding sshsh. Specifically, the present invention demonstrates the successful preparation of sRNAs targeted to viral genes to block or inhibit viral infection and / or replication. The techniques and reagents described herein can be easily applied to design new potential sRNAs, directed to other genes or regions of the gene, and can be tested for their activity by inhibiting influenza virus infection and / or replication as discussed in I presented. It is expected that influenza viruses will continue to mutate and undergo regrouping that may be desirable to continue to develop and test new sRNAs directed differently. In various embodiments of the invention, potential influenza virus inhibitors can be tested by introducing sRNAi candidates into the cells (eg, by exogenous administration or by introducing a vector or construct directing the endogenous synthesis of sRNA in the cell), or laboratory animals, prior to, concurrent with, or after transfection with an influenza genome or portion thereof (eg, within minutes, hours, or at most a few days). or before a, simultaneously with, or after infection with the influenza virus. In turn, potential influenza virus inhibitors can be tested by introducing sARNi candidates into cells or laboratory animals that are productively infected with the influenza virus (ie, cells that produce the progeny virus). The ability of the candidate sRNAs to reduce the levels of transcription directed and / or inhibit or suppress one or more aspects or characteristics of the viral life cycle such as viral replication, pathogenicity, and / or infectivity is then assessed. For example, the production of viral particles and / or production of viral proteins, etc., can be evaluated using either directly or indirectly methods known in the art. The cells or laboratory animals which have been supplied with inventive siRNA compositions (cell / animal assays) can be compared with similar or comparable cells or laboratory animals that have not received the inventive composition (cell / animal control, example, cells / animals that have not received any sRNA or sRNA control such as a sRNAi directed to a non-viral transcript such as GFP). The susceptibility of the cell / animal assay for infection of the influenza virus can be compared with the susceptibility of the cell / animal control for infection. The production of viral proteins and / or offspring viruses can be compared in the cell / animal assay relative to cell / animal control. Another indication of viral infectivity, replication, pathogenicity, etc., can be similarly compared. Standard in vitro antiviral assays can utilize inhibition of viral plaques, viral cytopathic effect (CPE), and viral hemagglutinin or other protein, inhibition of viral performance, etc., CPE can be determined visually by dye absorption. For example, see Sidwell, R., W. and Smee, D., F, "In vitro and in vivo assay systems for the study of influenza virus inhibitors" Antiviral Res 2000, 48: 1. Usually, the cell / animal assay and cell / animal control could be of the same species and, for the cells, of similar or identical cell type. For example, cells from the same cell line could be compared. When the test cell is a primary cell, typically the control cell would also be a primary cell. Typically, the same strain of influenza virus will be used to compare the cell / animal assay and the cell / animal control. For example, the ability of a candidate sARNi to inhibit influenza virus production can be conveniently determined by (i) supplying the candidate sARNi to the cells (either before, at the same time as, or after exposure to the virus). influenza virus); (ii) evaluating the production of viral hemagglutinin using a haemagglutinin assay; and (iii) comparing the amount of haemagglutinin produced in the presence of sRNA with the amount produced in the absence of sRNA. (The test need not include a control in which the sRNA is absent but may make use of prior information regarding the amount of hemagglutinin produced in the absence of an inhibition.) A reduction in the amount of hemagglutinin strongly suggests a reduction in the virus production. This assay can be used to test sRNAs that target any viral transcription and is not limited to sRNAs that target the transcript encoding viral hemagglutinin. The ability of a candidate sRNAi to reduce the level of targeted transcription can also be assessed by measuring the amount of target transcription, using for example, Northern immunoassay, nuclease protection assays, reverse transcription (RT) -PCR, RT-PCR in time real, microconfiguration analysis, etc. The ability of a candidate sRNA to inhibit the production of a polypeptide encoded by the target transcript (either at a transcriptional or post-transcriptional level) can be measured using a variety of antibody-based methodologies which include but are not limited to, Western immunoassay, immunoassays, ELISA, flow cytometry, protein microconfigurations, etc. In general, any method can be used to measure the amount of either the target transcript or a polypeptide encoded by the target transcript. In general, certain preferred influenza virus inhibitors reduce the target transcript level by at least about 2 times, preferably at least about 4 times, more preferably, at least about 8 times, at least about 16 times, by at least about 64 times or to an even greater degree relative to the level that would be present in the absence of the inhibitor (eg, in a comparable control cell lacking the inhibitor). In general, certain preferred influenza virus inhibitors inhibit viral replication, so that the level of replication is lower in a cell containing the inhibitor in place of a control cell that does not contain the inhibitor by at least about 2 times, preferably at least about 4 times, more preferably at least about 8 times, at least about 16 times, at least about 64 times, at least about 100 times, at least about 200 times, or at least even higher grade. Certain preferred influenza virus inhibitors inhibit viral replication so that the development of the detectable viral titre is prevented for at least 24 hours, at least 36 hours, at least 48 hours, or at least 60 hours following the administration of sRNA and infection of the cells. Certain preferred influenza virus inhibitors prevent (ie, reduce undetectable levels) or significantly reduce viral replication for at least 24 hours, at least 36 hours, at least 48 hours, or at least 60 hours following the administration of sARNi. According to several embodiments of the invention, a significant reduction in viral replication is a reduction of less than about 90% of the level that would occur in the absence of sRNA, a reduction of less than about 75% of the level that would occur in the absence of sRNA. , a reduction of less than approximately 50% of the level that would occur in the absence of sRNA, a reduction in less than approximately 25% of the level that would occur in the absence of sRNA, or a reduction in less than approximately 10% of the level that would occur in the absence of the sARNi. The reduction in viral replication can be measured using any method that includes, but is not limited to the measurement of HA titration.

Stability of the test, modification, and retesting of the RNAi agents A candidate RNAi agent can be evaluated for stability, for example, its susceptibility to cleavage by an endonuclease or exonuclease, such as when the RNAi agent is introduced into the RNAi agent. the body of a matter. Methods can be employed to identify sites that are susceptible to modification, particularly cleavage, for example, cleavage by a component found in the body of a subject. Such methods may include the isolation and identification of most of the abundant fragments formed by the degradation of the candidate RNAi agent after incubation with the biological media isolated in vitro, for example, serum, plasma, sputum, cerebrospinal fluid, or cells. tissue homogenates, or after contacting a subject with the candidate RNAi agent in vivo, identifying the prone sites for cleavage. For example, such methods are without limitation, in the co-owned International Application No. PCT / US2005 / 018931, filed on May 27, 2005. When sites susceptible to splitting are identified, an additional RNAi agent can be designed and / or it can be synthesized, wherein the site of the potential splitting becomes resistant to cleavage, for example, by introducing a modification 2 'at the cleavage site, for example a 2'-O-methyl group. This additional RNAi agent can be tested again for stability, and this process can be iterative until it is found that an RNAi agent exhibits desired stability.

In vivo Test An RNAi agent that is identified as having the ability to inhibit the expression of the influenza virus can be tested for in vivo functionality in an animal model (eg, in a mammal, such as in a mouse or rat). For example, the RNAi agent can be administered to an animal, and the RNAi agent evaluate it for its biodistribution, stability, and its ability to inhibit the replication of the influenza virus or reduce a biological or pathological process mediated at least in part for the influenza virus. The RNAi agent can be administered directly to the target tissue, such as by injection, or the RNAi agent can be administered to the animal model in the same manner as it is administered to a human. Preferably, the RNAi agent is delivered to the subject's airways, as intranasally. The RNAi agent can also be evaluated for intracellular distribution. The evaluation may include determining whether the RNAi agent met in the cell. The evaluation may also include determining the stability (e.g., half-life) of the RNAi agent. Evaluation of an RNAi agent in vivo can be facilitated by the use of an RNAi agent conjugated to an identifiable marker (eg, a fluorescent label such as fluorescein, a radioactive label, such as 35S, 32p, 33P, or 3H;; or antigen particles for immunohistochemistry). The RNAi agent can be evaluated with respect to its ability to down-regulate the replication of the influenza virus. The expression levels of the influenza virus gene can be measured in vivo, for example, by in situ hybridization, or by isolation of the RNA from the tissue before and after exposure to the RNAi agent. When the animals need to be sacrificed to harvest the tissue, an untreated control animal will be used for comparison. The RNA of the influenza virus can be detected by any desired method, including but not limited to RT-PCR, Northern immunoassay, branched DNA assay, or RNase protection assay. Alternatively, or additionally, the expression of the influenza virus can be monitored by performing a Western immunoassay analysis or plaque-forming assays on tissue extracts with the RNAi agent. Potential influenza virus inhibitors can be tested using any of a variety of animal models that have been developed. The compositions comprising the sARNi candidate, constructs or vectors capable of directing the synthesis of such sRNAs within a host cell, or cells designed or manipulated to contain candidate sRNAs can be administered to an animal prior to, concurrent with, or following infection with an influenza virus. . The ability of the composition to prevent viral infection and / or delay or prevent the appearance of influenza-related symptoms and / or decrease its relative severity to animals infected with influenza that have not received the potential influenza inhibitor is evaluated. . Such models include, but are not limited to, murine, chicken, ferret, and non-human primate models for influenza infection, all known in the art and used to test the efficacy of potential influenza vaccines and therapeutics. See, for example, Sidwell, R., W. and Smee, D., F, referenced above. Such models may involve the use of naturally occurring strains of influenza virus and / or strains that have been modified or adapted to the existence in a particular host (for example, the strains WSN or PR8, which are adapted for replication in mice). The above animal models can also be used to establish the concentration necessary to achieve a certain desired effect (for example, EC50).

RNAi chemistry. Isolated RNAi agents, for example, RNA agents that mediate RNAi to inhibit the expression of an influenza virus gene are described herein. The RNA agents discussed herein include otherwise unmodified RNA as well as RNA that has been modified, for example, to improve efficiency, and polymers of nucleoside substitutes. The unmodified RNA refers to a molecule in which the components of the nucleic acid, mainly the sugars, bases, and portions of phosphate, are the same or essentially the same as occurs in nature, preferably as occurring naturally in the body human. The art has referred to rare or unusual RNAs, but they occur naturally, as modified RNAs, see for example, Limbach et al. Nucleic Acids Res. 22: 2183-2196, 1994. As used herein, such rare or unusual RNAs, often called modified RNAs (apparently because they are typically the result of a post-transcriptional modification) are found within the term RNA not modified. Modified RNA as used herein refers to a molecule in which one or more of the components of the nucleic acid, namely the sugars, bases, and portions of phosphate, are different from those occurring in nature, preferably different. to those that occur in the human body. Even when they are called modified "RNA", it will be clear that due to the modification, they include molecules that are not RNA. Nucleoside substitutes are molecules in which the structure of the ribophosphate is replaced with a non-ribophosphate construct that allows the bases to present the correct spatial relationship in such a way that the hybridization is substantially similar to what is observed in the ribofosphate structure , for example, uncharged imitations of the ribofosphate structure. Examples of the above are discussed in the present. The modifications described herein can be incorporated into any of the molecules such as RNA and double-stranded RNA described herein, for example, an RNAi agent. It may be desirable to modify one or both of the sense and antisense strands of an RNAi agent. When the nucleic acids are polymers of subunits or monomers, many of the modifications described below occur in a position that is repeated within a nucleic acid, for example, a modification of a base, or a phosphate moiety, or the O-bond of a portion of phosphate. In some cases, the modification will occur in all the target positions in the nucleic acid but in many, and in fact in most cases it does not occur. By way of example, a modification can only occur in a terminal 3 'or 5' position, it can only occur in a terminal region, for example to a position in a terminal nucleotide or in the last 2, 3, 4, 5, or 10 nucleotides of a strand. A modification can occur in a double-stranded region, a single-stranded region, or both. For example, a modification of the phosphorothioate to a position without 0 bond can occur only in one or both terms, it can occur only in terminal regions, for example, in a position in a terminal nucleotide or in the last 2, 3, 4, 5, or 10 nucleotides of a strand, or it can occur in regions of a double strand and single strand, particularly in the term. Similarly, a modification in the sense strand, the antisense strand, or both may occur. In some cases, the sense and antisense strand will have the same modifications or the same kind of modifications, but in other cases, the sense strand and antisense strand will have different modifications, for example, in some cases it may be desirable to modify only one strand, example, the sense thread. The two primary objectives for the introduction of modifications in RNAi agents are their stabilization towards degradation in biological environments and the improvement of pharmacological properties., for example, pharmacodynamic properties that are discussed further below. Other suitable modifications to a sugar, base, or RNAi agent structure are described in the co-owned PCT Application described No. PCT / US2004 / 01193, filed January 16, 2004. An RNAi agent may include a base that does not occur naturally, such as the bases described in the PCT Application co-owned No. PCT / US2004 / 011822, filed on October 16, 2004. April of 200 An RNAi agent may include a sugar that does not occur naturally, such as a cyclic carrier molecule without carbohydrates. Exemplary characteristics of sugars that do not naturally occur for use in RNAi agents are described in the co-pending PCT Application No. PCT / US2004 / 11829, filed April 16, 2003. An RNAi agent may include an internucleotide link (eg, example, the chiral phosphorothioate linkage) useful for increasing nuclease resistance. In addition, or alternatively, an RNAi agent may include an imitation of the ribose to increase the resistance of the nuclease. Exemplary internucleotide linkages and ribose mimics for increased nuclease resistance are disclosed in co-pending PCT Application No. PCT / US2004 / 07070, filed March 8, 2004. An RNAi agent may include subunits of monomers conjugated to the ligand and monomers for the synthesis of the oligonucleotide. Exemplary monomers are disclosed in U.S. co-owned No. 10 / 916,185, filed August 10, 2004. An RNAi agent may have a ZXY structure, such as described in the co-pending PCT Application No. PCT / US2004 / 07070, filed on 8 March of 2004.

An RNAi agent can be formed into complexes with an amphipathic portion. Exemplary amphipathic portions are described for use with RNAi agents in the co-pending PCT Application No. PCT / US2004 / 07070, filed March 8, 2004. In another embodiment, the RNAi agent can form complexes for a delivery agent It offers a modular complex. The complex may include a carrier agent linked to one or more of (preferably two or more, more preferably all three of): (a) condensing agent (eg, an agent capable of attracting, for example, a bond, an acid nucleic, for example, through ionic or electrostatic interactions); (b) a fusogenic agent (e.g., an agent capable of fusing and / or transporting through a cell membrane); and (c) a targeting group, for example, a cell or agent that targets tissue, for example, a lectin, glycoprotein, lipids or proteins, for example, an antibody that binds to a specified cell type. The RNAi agents that form complexes for a delivery agent are described in the co-pending PCT Application No. PCT / US2004 / 07070, filed March 8, 2004. An RNAi agent can have non-canonical matings, such as between sense and antisense sequences of double RNAi. The exemplary characteristics of non-canonical RNAi agents are described in the PCT Application co-owned No.

PCT / US2004 / 07070, filed on March 8, 2004.

Enhanced Nuclease Resistance An RNAi agent, for example, an RNAi agent that directs the influenza virus, may have improved resistance to the nuclease. One way to increase resistance is to identify the cleavage sites and modify such sites to inhibit cleavage, as described in co-owned US Application No. 60 / 559,917, filed May 4, 2004. For example, the dinucleotide 5'-ua-3 ', 5'-ca-3', 5'-ug-3 ', 5'-uu-3', or 5'-ccp-3 'can serve as cleavage sites. In certain embodiments, all pyrimidines of an RNAi agent carry a 2 'modification either in the sense strand, antisense strand, or both strands, and therefore, the RNAi agent has improved its resistance to endonucleases. Improved nuclease resistance can also be achieved by modifying the 5 'nucleotides, which result for example, in at least one 5'-uridine adenine dinucleotide (5'-ua-3') wherein the uridine is a nucleotide 2 ' modified; at least one 5'-cytidine-adenine-3 '(5'-ca-3') dinucleotide, wherein, the 5'-cytidine nucleotide is a modified T-nucleotide; at least one 5'-uridine-guanine-3 '(5'-ug-3') f dinucleotide wherein the 5'-uridine is a 2'-modified nucleotide; at least one 5'-uridine-uridine-3 'dinucleotide (5'-uu-3'), wherein the 5'-uridine is a 2'-modified nucleotide; or at least one 5'-cytidine-cytidine-3 '(5'-c., p.-3') dinucleotide, wherein the 5'-cytidine is a modified T-nucleotide, as described in the International Application co-proprietary NO.PCT / US2005 / 018931, filed May 27, 2005. The RNAi agent can include at least 2, at least 3, at least 4 or at least 5 such dinucleotides. In a particularly preferred embodiment, the 5 'nucleotides in all occurrences of the portions of the sequence 5'-ua-3' and 5'-ca-3 'either in the sense strand, the antisense strand, or both strands is a modified nucleotide. Preferably, the 5 'nucleotides in all occurrences of the 5' -ua-3 ', 5'-ca-3' and 5'-ug-3 'portions of the sequence, and either the sense strand, the antisense strand , or both strands are a modified nucleotide. More preferably, all the pyrimidine nucleotides in the sense strand are the modified nucleotides, and the 5 'nucleotides in all occurrences of the 5'-ua-3' and 5'-ca-3 'portions of the sequence in the strand. antisense are modified nucleotides, or where the antisense strand does not comprise any of the 5 '-ua-3' and 5'-ca-3 'portions, in all occurrences of the 5'-ug-3' portion of the sequence.

Preferably, the 2'-modified nucleotides include, for example, a modified 2'-ribose unit, eg, the 2'-hydroxyl (OH) group can be modified or can be replaced with a variety of "oxy" or "deoxy" substituents. "different. Examples of modifications of the hydroxyl group "oxy" -2 'include alkoxy or aryloxy (OR, for example, R = H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or sugar); polyethylene glycols (PEG), 0 (CH2CH20) nCH2CH2OR "," blocked "nucleic acids (LNA) where the hydrophilic 2 'is connected, for example, by means of a methylene bridge, to the 4' carbon of the same sugar of the ribose; -AMINE and aminoalkoxy, 0 (CH2) nAMINE, (for example, AMIN = NH2, alkylamino, dialkylamino, heterocyclic amino, arylamino, diaryl amino, heteroaryl amino, or diheteroaryl amino, ethylene diamine, polyamino) It is notable that the oligonucleotides which contain only the methoxyethyl group (MOE), (OCH2CH2OCH3, a PEG derivative), exhibit nuclease stabilities comparable to those modified with solid phosphorothioate modification, "deoxy" modifications include hydrogen (ie, deoxyribose sugars, which are particularly relevant to the portions of partially RNA projection), halo (eg, fluoro), amino (eg, NH2; alkylamino, dialkylamino, heterocyclyl, arylamino, diaryl amino, heteroaryl amino, diheteroaryl amin or, or amino acids); NH (CH2CH2NH) nCH2CH2-AMIN (AMIN = NH2; alkylamino, dialkylamino, heterocyclyl amino, arylamino, diaryl amino, heteroaryl amino, or diheteroaryl amino), - NHC (0) R (R = alkyl, cycloalkyl, aryl, aralkyl, heteroaryl or sugar), cyano; mercapto; alkylthioalkyl; thioalkoxy; and alkyl, cycloalkyl, aryl, alkenyl and alkynyl, which may be optionally substituted with, for example, an amino functionality. Preferred substituents are 2'-methoxyethyl, 2'-OCH3, 2'-0-allyl, 2'-C-allyl, and 2'-fluoro. The inclusion of furanose sugars in the oligonucleotide structure can also decrease the endonucleolytic cleavage. An RNAi agent can be further modified by the inclusion of a 3'-cationic group, or by inverting the nucleoside at the 3'-terminus with a 3'-3'-linkage. In another alternative, the term 3'- can be blocked with an aminoalkyl group, for example, a 3 'dT C5-aminoalkyl. Other 3 'conjugates can inhibit 3'-5' exonucleolytic cleavage. Although not limited in theory, a 3 'conjugate, such as naproxen or ibuprofen, can inhibit exonucleolytic cleavage by steric blockade of the exonuclease from the 3' end link of the oligonucleotide. Even small alkyl chains, aryl groups or heterocyclic conjugates or modified sugars (D-ribose, deoxyribose, glucose etc.) can block the 3'-5'-exonucleases. Nucleolithic cleavage can also be inhibited by the introduction of modifications of the phosphate bond, for example, phosphorothioate linkages. Thus, preferred RNAi agents include enriched or pure nucleotide dimers for a particular chiral form formed of a modified phosphate group that normally contains a heteroatom at a position other than that of an oxygen bridge. The heteroatoms can be S, Se, Nr2, or Br3. When the hetero atom is S, an enriched or chirally pure link Sp is preferred. The enriched media is at least 70, 80, 90, 95, or 99% of the preferred form. Modified phosphate bonds are particularly effective at inhibiting exonucleolytic cleavage when introduced near the 5 - or 3'-terminal positions, and preferably the 5'-terminal positions of an RNAi agent. The 5 'conjugates can also inhibit the 5' -3 'exonucleolytic cleavage. Although not limited in theory, a 5 'conjugate, such as naproxen or ibuprofen, can inhibit exonucleolytic cleavage by spherical blockade of the exonuclease from the 5' end of the oligonucleotide. Even, small alkyl chains, aryl groups or heterocyclic conjugates or modified sugars (D-ribose, deoxyribose, glucose etc.) can block the 3'-5'-exonucleases. An RNAi agent may have increased its resistance to nucleases when a double RNAi agent includes a projection of the single-stranded nucleotide at at least one end. In preferred embodiments, the nucleotide projection includes 1 to 4, preferably 2 to 3, unpaired nucleotides. In a preferred embodiment, the unpaired nucleotide of the single strand projection directly adjacent to the terminal nucleotide pair contains a purine base, and the terminal nucleotide pair is a GC pair, or at least two of the latter Four pairs of complementary nucleotides are GC. In additional embodiments, the nucleotide projection may have 1 or 2 unpaired nucleotides, and in an exemplary embodiment, the projection of the nucleotide is 5'-gc-3 '. In preferred embodiments, the projection of the nucleotide is at the 3 'end of the antisense strand. In one embodiment, the RNAi agent includes the 5'-cgc-3 'portion at the 3' end of the antisense strand, such that a 2-nt 5 '-gc-3' projection is formed. Thus, an RNAi agent may include modifications that inhibit degradation, for example, by nucleases, for example, endonucleases or exonucleases, found in the body of a subject. These monomers are referred to herein as NRM, or Monomers that promote Nuclease Resistance, corresponding modifications such as NRM modifications. In many cases, these modifications will modulate other properties of the RNAi agent also, for example, the ability to interact with a protein, e.g., a transport protein, e.g., serum albumin, or a RISC member, or the ability of the first and second sequences to form a double with one or the other or to form a double with another sequence, for example, a target molecule. One or more different NRM modifications can be introduced into an RNAi agent or a sequence of an RNAi agent. An NRM modification can be used more than once in a sequence or in an RNAi agent. NRM modifications include some that can only be placed at the end and others that can go in any position. Some NRM modifications can inhibit hybridization because they are only preferred for use in terminal regions, and it is preferred to use them at the cleavage site or in the cleavage region of a sequence that targets a target gene or sequence, particularly in the antisense strand. These can be used anywhere in the sense strand, provided sufficient hybridization is maintained between the two strands of the RNAi agent. In some embodiments, it is desirable to place the MRN at the cleavage site or in the region of cleavage of a sense strand, because it can minimize the target silencing. In most cases, NRM modifications will be distributed differently depending on whether they comprise a sense or antisense thread. If in an antisense strand, modifications that interfere with or inhibit the unfolding of the endonuclease should not be inserted into the region that is subject to cleavage mediated by RISC, for example, the cleavage site or the cleavage region (As described in FIG. Elbashir et al, 2001, Genes and Dev. 15: 188, incorporated herein by reference). The cleavage of the target occurs approximately in the middle of 20 or 21 antisense strands nt, or approximately 10 or 11 nucleotides upstream of the first nucleotide in the target mRNA which is complementary to the antisense strand. As used herein, the cleavage site refers to nucleotides either on the side of the cleavage site, on the target or on the strand of the RNAi agent that hybridizes it. The region of unfolding means nucleotides within 1, 2, or 3 nucleotides of the cleavage site in any direction. Such modifications can be introduced in the terminal regions, for example, in the terminal position or with 2, 3, 4, or 5 positions of the term, of a sense strand or antisense strand.

Related Ligands The properties of an RNAi agent, including its pharmacological properties, can be influenced and customized, for example, by the introduction of ligands, for example, related ligands. In addition, the pharmacological properties of an RNAi agent can be improved by incorporating a ligand into an RNAi agent formulation when the RNAi agent has or does not have a related ligand. A wide variety of entities, for example, ligands, can be bound to an RNAi agent or can be used as a conjugate of the formulation or additive, for example, to the carrier of a monomer subunit conjugated to the ligand. Examples are described below in the context of a monomer subunit conjugated to the ligand, although only entities that can be coupled to other sites on an RNAi agent are preferred. Preferred portions are ligands that are preferably covalently coupled, either directly or indirectly by means of an intermediate lateral extension, to the carrier. In preferred embodiments, the ligand is attached to the carrier by means of an intermediate lateral extension. The ligand or ligand made in lateral extension may be present in the monomer that is conjugated to the ligand when the monomer conjugated to the ligand is incorporated into the growth strand. In some embodiments, the ligand can be incorporated into a monomer subunit conjugated to the "precursor" ligand after a monomer subunit conjugated to the "precursor" ligand has been incorporated into the growth strand. For example, a monomer having for example, an amino-terminating lock, for example, TAP- (CH2) nNH2 can be incorporated into a sense strand or antisense strand. In a subsequent operation, that is, after the incorporation of the precursor monomer subunit into the strand, a ligand having an electrophilic group, for example, a pentafluorophenyl ester or aldehyde group, can subsequently be linked to the monomer conjugated to the parent ligand. coupling the electrophilic group of the ligand with the terminal nucleophilic group of the lateral extension of the monomer subunit conjugated to the precursor ligand. In preferred embodiments, a ligand alters the distribution, targeting or life of an RNAi agent in which it is incorporated. In preferred embodiments, a ligand provides improved affinity for a selected target, e.g., molecule, cell or cell type, compartment, e.g., a cell compartment or organ, tissue, organ or body region, as, for example, compared to an absent species such as a ligand. Preferred ligands may improve transport, hybridization, and specificity properties and may also improve the nuclease resistance of the resulting natural or modified oligoribonucleotide, or a polymeric molecule comprising any combination of monomers described herein and / or natural ribonucleotides or modified. Ligands in general may include therapeutic modifiers, for example, to enhance absorption; diagnostic compounds or reporter groups for example, to monitor the distribution; crosslinking agents; portions that confer nuclease resistance; and natural or unusual nucleobases. General examples include lipophilic molecules, lipids, lectins, steroids (e.g., uvaol, hecigenin, diosgenin), terpenes (e.g., triterpenes, e.g., sarsasapogenin, Friedelin, lithocholic acid derived from epifriedelanol), vitamins, carbohydrates (e.g. dextran, swarm, chitin, chitosan, inulin, cyclodextrin or hyaluronic acid), proteins, agents that bind to proteins, molecules that direct integrins, polyication, peptides, polyamines, and peptide imitations. The ligand may be naturally occurring or recombinant or synthetic molecule, such as a synthetic polymer, for example, a synthetic polyamine acid. Examples of polyamino acids include polylysine (PLL), L-aspartic acid, poly L-glutamic acid, styrene maleic anhydride copolymer, poly (L-lactide-co-glycolic) copolymer, divinyl ether-maleic anhydride copolymer, copolymer of N- (2-hydroxypropyl) methacrylamide (HMPA), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyurethane, poly (2-ethylacrylic acid), polymers of N-isopropylacrylamide, or polyphosphazine. Example of polyamines includes: polyethylene imine, polylysine (PLL), spermine, spermidine, polyamine, pseudopeptide-polyamine, polyamine peptidomimetic, polyamine of the dendrimer, arginine, amidine, protamine, cationic portions, for example, cationic lipids, cationic porphyrin, quaternary salt of a polyamine, or a helical alpha peptide. Ligands may also include targeting groups, for example, a cell or tissue targeting agent, for example, a thyrotropin, melanotropin, surfactant protein A, mucin carbohydrate, a glycosylated polyamino acid, transferrin, bisphosphonate, polyglutamate, polyaspartate , or an RGD peptide or imitation of the RGD peptide. The ligands can be proteins, for example, glycoproteins, lipoproteins, for example, low density lipoproteins (LDL), or albumins, for example, human serum albumin (HSA), or peptides, for example, molecules that have a specific affinity for a co-ligand, or antibodies for example, an antibody that binds to a specific cell type such as a cancer cell, endothelial cell or bone cells. The ligands may also include hormones and hormone receptors. They may also include non-peptidic species, such as cofactors, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-galactosamine, multivalent mannose, or multivalent mucosa. The ligand may be, for example, a lipopolysaccharide, a p38 MAP kinase activator, or an NF-? B activator. The ligand can be a substance, for example, a drug that can increase the uptake of the RNAi agent in the cell, for example, by fragmenting the cytoskeleton of the cells, for example, by fragmenting the microtubules of the cell, microfilaments, and / or filaments. intermediate The drug can be for example, taxon, vincristine, vinblastine, cytochalasin, nocodazole, japlaquinolide, latrunculin A, phalloidin, swinholide A, indanocin, or mioservin. In one aspect, the ligand is a lipid or lipid-based molecule. Such a lipid or lipid-based molecule preferabinds to a serum protein, for example, human serum albumin (HSA). A ligand that binds HSA allows distribution of the conjugate to a target tissue, for example, liver tissue, which includes parenchymal cells of the liver. Other molecules that can bind HSA as ligands can also be used. For example, neproxin or aspirin can be used. A lipid or ligand based on lipids can (a) increase the resistance to degradation of the conjugate, (b) increase the targeting or transport in an objective cell or cell membrane, and / or (c) can be used to adjust the link to a whey protein, for example, HSA. A ligand of the lipid can be used to modulate, for example, control the binding of the conjugate to a target tissue. For example, a lipid or lipid-based ligand that binds to HSA will likely be stronger to target the kidney and therefore, likely to be released from the body. A lipid or a ligand based on less strong lipids that bind to HSA can be used to direct the conjugate to the kidney. In a preferred embodiment, lipid-based ligands bind HSA. Prefera the HSA linkage is performed with sufficient affinity that the conjugate will preferabe distributed to a tissue other than the kidney. However, it is preferred that the affinity is not so strong that the binding of the HSA-ligand can not be reversed. In another aspect, the ligand is a portion, for example, a vitamin or nutrient that is absorbed by a target cell, for example, a proliferation cell. These are particularly useful for treating disorders characterized by unwanted cell proliferation, for example, of the malignant or non-malignant type, for example, cancer cells. Exemplary vitamins include vitamin A, E, and K. Other exemplary vitamins include B vitamins, for example, folic acid, B 12, riboflavin, biotin, pyridoxal, or other vitamins or nutrients absorbed by cancer cells. In another aspect, the ligand is an agent that penetrates the cells, preferably an agent that penetrates the helical cells. 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, invertomers, bonds without peptides or pseudo-peptides, and use of D-amino acids. The helical agent is preferably an alpha-helical agent that preferably has a lipophilic phase and a lipophobic phase.

'-Phosphate Modifications In preferred embodiments, RNAi agents are 5'-phosphorylated or include a phosphoryl analogue at the 5'-primary end. The 5'-phosphate modifications of the antisense strand include those that are compatible with RISC mediated by the silencing of the gene. Suitable modifications include: 5 '-monophosphate ((HO) 2 (O) P-O-5); 5'-diphosphate ((H0) 2 (0) P-O-P (HO) (O) -0-5); 5'-triphosphate ((H0) 2 (0) P-0 -. (HO) (0) P-O-P (HO) (0) -0-5); 5'-guanosine cap (7-methylated or non-methylated) (7m-G-0-5 '- (HO) (0) P-0- (H0) (0) P-0- P (H0) (0) -0-5 '); cap 5 '-adenosine (Appp), and any of the cap structure of unmodified nucleotides (N-0-5? - (HO) (O) PO- (HO) (O) POP (HO) (O) -0 -5); 5'-monothiophosphate (phosphorothioate; (H0) 2 (S) P-0-5 '); 5'-monodithiophosphate (phosphorodithioate; (HO) (HS) (S) P-0-5), 5'-phosphorothiolate ((HO) 2 (0) P-S-5); any additional combination of monophosphate replaced with oxygen / sulfur, monophosphate, diphosphate, and triphosphates (eg, 5'-alpha-thiotriphosphate, '-gamma-thiotriphosphate, etc.), 5'-phosphoramidates ((H0) 2 (0) P-NH-5 ', (HO) (NH2) (0) P-0-5), 5'-alkylphosphonates (R = alkyl = methyl, ethyl, isopropyl, propyl, etc., for example RP (OH) (0) -0-5-, (OH) 2 (0) P-5 '-CH2-), 5'- alkyl etherphosphonates (R = alkylether = methoxymethyl (MeOCH2 -), ethoxymethyl, etc., for example RP (OH) (0) -0-5 -). The sense thread can be modified to inactivate the sense thread and prevent the formation of an active RISC, while potentially reducing the effects of addressing. This can be achieved by a modification that prevents 5'-phosphorylation of the sense strand, for example, 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.) Other modifications that prevent phosphorylation can also be used, for example, by simply substituting the 5'-OH by H instead of OMe. Alternatively, a large bulky group can be added to the 5'-phosphate which converts it into a phosphodiester bond.

Unnatural nucleobases Nitropyrrolyl and nitroindolyl are unnatural nucleobases that are members of a class of compounds known as universal bases. The universal bases are those compounds that can be replaced with any of the four bases that occur naturally without substantially affecting the fusion behavior or activity of the double of the oligonucleotide. In contrast to stabilization, the hydrogen-binding interactions, associated with naturally occurring nucleobases, postulate that duplexes of the oligonucleotide containing 3-nitropyrrolyl nucleobases are stabilized only by stacking interactions. The absence of significant hydrogen bonding interactions with the nitropyrrolyl nucleobases obviates the specificity for a specific complementary base. In addition, several records confirm that 4-, 5- and 6-nitroindolyl show very little specificity for the four natural bases. Interestingly, a double of the oligonucleotide containing 5-nitroindolyl was more stable than the corresponding oligonucleotides containing 4-nitroindolyl and 6-nitroindolyl. The procedures for the preparation of 1- (2 '-O-methyl-β-D-ribofuranosyl) -5-nitroindole are described in Gaubert, G .; Wengel, J., Tetrahedron Letters 2004, 45, 5629. Other universal bases which can be tackled for the present invention include hypoxanthinyl, isoinosinyl, 2-aza-inosinyl, 7-deaza-inosinyl, nitroimidazolyl, nitropyrazolyl, nitrobenzimidazolyl, nitroindazolyl, aminoindolyl, pyrrolopyrimidinyl, and structural derivatives thereof. For a more detailed discussion, which includes synthetic, nitropyrrolyl, nitroindolyl, and other universal bases discussed above see Vallone et al., Nucleic Acids Research, 27 (17): 3589-3596 (1999); Loakes et al., J. Mol. Bio., 270: 426-436 (1997); Loakes et al., Nucleic Acids Research, 22 (20): 4039-4043 (1994); Oliver et al., Organic Letters, Vol., 3 (13): 1977-1980 (2001); Amosova et al., Nucleic Acids Research, 25 (10): 1930-1934 (1997); Loakes et al., Nucleic Acids Research, 29 (12): 2437-2447 (2001); Bergstrom et al., J. Am. Chem. Soc, 117: 1201-1209 (1995); Franchetti et al., Biorg. Med. Chem. Lett. 11: 67-69 (2001); and Nair et al., Nucelosides, Nucleotides & Nucleic Acids, 20 (4-7): 735-738 (2001). Difluorotolyl is an unnatural nucleobase that functions as a universal base. Difluorotolyl is a thymine isostere of the natural nucleobase. But unlike thymine, difluorotolyl does not show any appreciable selectivity for any of the natural bases. Other aromatic compounds that function as universal bases and are suitable for the present invention are 4-fluoro-6-methylbenzimidazole and 4-methylbenzimidazole. In addition, the relatively hydrophobic isocarbostyryl derivatives 3-methyl isocarbostyryl, 5-methyl isocarbostyryl, and 3-methyl-7-propynyl isocarbostyryl are universal bases causing only slight destabilization of the oligonucleotide doubles compared to the oligonucleotide sequence containing only natural bases . Other non-natural nucleobases contemplated in the present invention include 7-azaindolyl, 6-methyl-7-azaindolyl, imidizopyridinyl, 9-methyl-imidizopyridinyl, pyrrolopyrizinyl, isocarbostyryl, 7-propynyl isocarbostyryl, propynyl-7-azaindolyl, 2,4,5 trimethylphenyl, 4-methylindolyl, 4,6-dimethylindolyl, phenyl, naphthalenyl, anthracenyl, phenanthracenyl, pyrenyl, stilbenyl, tetracenyl, pentacenyl, and structural derivatives thereof. For a more detailed discussion, including synthetic procedures, of difluorotolyl, 4-fluoro-6-methylbenzimidazole, 4-methylbenzimidazole, and other non-natural bases mentioned above, see: Schweitzer et al., J. Org. Chem., 59: 7238-7242 (1994); Berger et al., Nucleic Acids Research, 28 (15): 2911-2914 (2000); Moran et al., J. Am. Chem. Soc, 119: 2056-2057 (1997); Morales et al., J. Am. Chem. Soc, 121: 2323-2324 (1999); Guckian et al., J. Am. Chem. Soc, 118: 8182-8183 (1996); Morales et al., J. Am. Chem. Soc, 122 (6): 1001-1007 (2000); McMinn et al., J. Am. Chem. Soc, 121: 11585-11586 (1999); Guckian et al., J. Org. Chem., 63: 9652-9656 (1998); Moran et al., Proc Nati. Acad. Sci., 94: 10506-10511 (1997); Das et al., J. Chem. Soc, Perkin Trans., 1: 197-206 (2002); Shibata et al., J. Chem. Soc, Perkin Trans., 1: 1605-1611 (2001); Wu et al., J. Am. Chem. Soc, 122 (32): 7621-7632 (2000); O'Neill et al., J. Org. Chem., 67: 5869-5875 (2002); Chaudhuri et al., J. Am. Chem. Soc, 117: 10434-10442 (1995); and the U.S. Patent. No. 6,218,108. Additional details to the synthesis and use of universal bases are given in PCT / US2005 / 025967 co-pending, and co-owned presented on July 21, 2005, incorporated herein by reference in its entirety. Universal bases can be particularly useful in situations where an attempt is made to direct a gene in an organism that shows variability between the different strains of that organism. This is often true for regions of a viral genome that are considered favorably preserved. The incorporation of a universal base can allow the design of RNAi agents that direct a wide variety of different strains of a virus that differ in one, a few, for example in up to three positions of the nucleotide. Universal bases are best included in a region of an RNAi agent that is sensitive to at least the incompatibilities of the nucleotide with respect to the specificity and activity of the RNAi agent. It has been shown that the 2-9 position of the antisense strand of an RNAi agent is very sensitive to the incompatibilities between the antisense strand and the target mRNA, this region has been called the "sown region" of an RNAi agent. Here, when one or more universal bases or bases are incorporated into an RNAi agent, they are preferably incorporated outside this seeding region. Table 1 F and Table 1G show RNAi agents comprising universal bases in mutually complementary positions in the sense strand and anti sense strand. However, while this is a preferred embodiment of the RNAi agents of the present invention, the effect of the universal base on an RNAi agent is more pronounced when the universal base is present in the antisense strand. It is therefore envisioned that the base in the sense strand in a position in which it will mate with a universal antisense strand base can be either a universal basis, or any other convenient basis, such as a, u, c or g. Preferably, it will be proved that the base in such a position of the sense strand will provide the highest activity and / or selectivity for the RNAi agent. Alternatively, the base may be chosen to be present in this particular position in most variants of the target gene projected to be inhibited in its expression by the RNAi agent in question.

Transport of RNAi agents in cells Not wishing to be limited by any theory, the chemical similarity between the RNAi agents conjugated with cholesterol and certain constituents of lipoproteins. { for example, cholesterol, cholesteryl esters, phospholipids) can lead to an association of RNAi agents with lipoproteins (e.g., LDL, HDL) in the blood and / or the interaction of the RNAi agent with cellular components that have an affinity for the cholesterol, for example, the components of the cholesterol transport path. The lipoproteins as well as their constituents are absorbed and processed by cells by various active and passive transport mechanisms, for example, without limitation, LDL endocytosis that binds to the LDL receptor, oxidized endocytosis or in addition modified LDL through interaction with the receptor A scavenger, absorption mediated by the HDL cholesterol receptor debugger HDL in the liver, pinocytosis, or transport of cholesterol through membranes by proteins carrying ABC (cassette that binds ATP), for example ABC-A1, ABC-G1 or ABC-G. Here, the RNAi conjugates with cholesterol could enjoy the absorption facilitated by cells that possess such transport mechanisms, for example, cells of the liver. As such, the present invention provides evidence and general methods for targeting RNAi agents in cells expressing certain cell surface components, e.g., receptors, by conjugating a natural ligand for such a component (e.g., cholesterol) to the RNAi agent, or by conjugating a chemical moiety (eg, cholesterol) to the RNAi agent with which it associates or binds to a natural ligand for the component (e.g., LDL, HDL).

Other Modalities An RNA, for example, an RNAi agent, can be produced in a cell in vivo, for example, from exogenous DNA templates that are delivered in the cell. For example, DNA templates can be inserted into vectors and can be used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (U.S. Patent No. 5,328,470), or by stereotactic injection (see, for example, Chen et al Proc. Nati. Acad. Sd. USA 91: 3054-3057, 1994). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or it can comprise a sustained release matrix in which the gene delivery vehicle is incorporated. DNA templates can, for example, include two transcription units, one that produces a transcript that includes a higher strand of an RNAi agent and one that produces a transcript that includes the lower strand of an RNAi agent. When the templates are transcribed, the RNAi agent is produced, and processed into fragments of the sRNA agent that mediates the silencing of the gene.

Formulation The present invention also includes pharmaceutical compositions and formulations that include the dsRNA compounds of the invention. The pharmaceutical compositions of the present invention can be administered in a variety of ways depending on whether local or systemic treatment is desired after the area has been treated. Administration can be topical, pulmonary, for example, by inhalation or insufflation of powders or aerosols, including nebulization; intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, hypodermic, intraperitoneal or intramuscular injection or infusion; or intracranial, for example, intrathecal or intraventricular administration. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. The carriers conventional medications, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful. Preferred topical formulations include those in which the dsRNAs of the invention are mixed with a topical delivery agent such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelating agents and surfactants. Preferred lipids and liposomes include neutral (for example, ethanolamine dioleoylphosphatidyl DOPE, dimyristoylphosphatidyl choline = DMPC, distearyl phosphatidyl choline) negative (eg, dimyristoylphosphatidyl glycerol = DMPG) and cationic (eg, dioleoyltetramethylaminopropyl = DOTAP and dioleoylphosphatidyl ethanolamine = DOTMA). The dsRNAs of the invention maybe encapsulated within the liposomes or can form complexes thereof, in particular, cationic liposomes. Alternatively, dsRNAs can form complexes in lipids, in particular, cationic lipids. Preferred fatty acids and esters include but are not limited to arachidonic acid, oleinic acid, eicosanoic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein , dilaurin, glyceryl 1-monocaprate, l-dodecylazacycloheptane-2-one, an acylcarnitine, an acylcholine, or a C 1 - or alkyl ester (eg, IPM isopropylmyristate), monoglycerides, diglycerides or pharmaceutically acceptable salts thereof. Topical formulations are described in detail in U.S. Patent Application No. 09 / 315,298 filed May 20, 1999, which is incorporated herein by reference in its entirety.

Compositions and formulations for oral administration include powders or granules, microparticles, nanoparticles, suspensions or solutions in water or non-aqueous media, capsules, gel capsules, sachets, tablets or mini-tablets. Thickeners, seasoning agents, diluents, emulsifiers, dispersion aids or binders may be desirable. Preferred oral formulations are those in which the dsRNAs of the invention are administered together with one or more penetration enhancers, surfactants and sealants. Preferred surfactants include fatty acids and / or esters or salts thereof, bile acids and / or salts thereof. Preferred bile acids / salts include chenodeoxycholic acid (CDCA) and ursodeoxychnodeoxycholic acid (UDCA), cholic acid, dehydrocholic acid, deoxycholic acid, glycolic acid, glycolic acid, glycodeoxycholic acid, taurocholic acid, tauro-24, 25-dihydro-fusidate, sodium and sodium glycidihydrofusidate. Preferred fatty acids include arachidonic acid, undecanoic acid, oleinic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin, glyceryl 1-monocaprate , l-dodecylazacycloheptane-2-one, an acylcarnitine, an acylcholine, or a monoglyceride, a diglyceride or a pharmaceutically acceptable salt thereof (eg, sodium). Also preferred are combinations of penetration enhancers, for example, fatty acid / salts in combination with acids / salts of bile. A particularly preferred combination is the sodium salt of lauric acid, capric acid and UDCA. Penetration enhancers include polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether. The dsRNA of the invention can be supplied orally, in granular form including dried sprayed particles, or complexes to form micro or nanoparticles. Agents that form dsRNA complexes include poly-amino acids; polyimines; polyacrylates; polyalkyl acrylates, polyoxetanes, polyalkyl cyanoacrylates; cationized gelatins, albumins, starches, acrylates, polyethylene glycols (PEG) and starches; polyalkylcyanoacrylates; polyimines derived from DEAE, polyulans, celluloses and starches. Particularly preferred complexing agents include chitosan, N-trimethylquintosan, poly-L-lysine, polyhistidine, polyornithine, polyspermines, protamine, polyvinylpyridine, polyethyldimethylaminomethylethylene P (TDAE), polyaminestyrene (e.g., p-amino), poly (methylcyanoacrylate) ), poly (ethyanocyanoacrylate), poly (butylcyanoacrylate), poly (isobutylcyanoacrylate), poly (isohexyl-cyanoacrylate), DEAE-methacrylate, DEAE-hexylacrylate, DEAE-acrylamide, DEAE-albumin and DEAE-dextran, polymethylacrylate, polyhexylacrylate, poly (D) acid , L-lactic acid), poly (DL-lactic-co-glycolic acid (PLGA), alginate, and polyethylene glycol (PEG).) Oral formulations for dsRNAs and their preparation are described in detail in the Application EUA Ser. No. 08 / 886,829 (filed July 1, 1997), Ser. No. 09 / 108,673 (filed M. 1, 1998), Ser. No. 09 / 256,515 (filed on February 23, 1999), Ser. No. 09 / 082,624 (filed May 21, 1998) and Ser. No. 09 / 315,298 (present on May 20, 1999) each of which is incorporated herein by reference in its entirety. Compositions and formulations for parenteral, intrathecal or intraventricular administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives, but which are not limited to, enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions of the present invention include, but are not limited to, solutions, emulsions, and formulations containing liposomes. These compositions can be generated from a variety of components including, but not limited to, preformed liquids, self-emulsifying and semi-solid self-emulsifying solids. The pharmaceutical formulations of the present invention, which can be suitably presented in a unit dosage form, can be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the meeting stage in association with the active ingredients with the drug carriers or excipients. In general, the formulations are prepared uniformly and intimately by pooling the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. The compositions of the present invention can be formulated in any of many possible dosage forms such as, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present invention can also be formulated as suspensions in an aqueous, non-aqueous or mixed medium. Aqueous suspensions may contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethyl cellulose, sorbitol and / or dextran. The suspension may also contain stabilizers. In one embodiment of the present invention, the pharmaceutical compositions can be formulated and used as foams. Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies and liposomes. Although these formulations are basically similar in nature, they vary in the components and consistency of the final product. The preparation of such compositions and formulations is generally known to those skilled in the pharmaceutical and formulation arts and can be applied to the formulation of the compositions of the present invention.

Emulsions The compositions of the present invention can be prepared and formulated as emulsions. Emulsions are typically heterogeneous systems from one liquid dispersed in another in the form of droplets that normally exceed 0.1 μm in diameter (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc. , New York, NY, volume 1, p.199; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, NY, Volume 1, p.245; Block in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, NY, volume 2, p.335, Higuchi et al, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, p.301). Emulsions are often biphasic systems comprising two immiscible liquid phases intimately mixed and dispersed together. In general, the emulsions can be either a water-in-oil (water / oil) or oil-in-water (oil / water) variety. When an aqueous phase is finely divided into and dispersed as minute drops in an oily bulk phase, the resulting composition is called water-in-oil (water / oil) emulsion. Alternatively, when an oily phase is finely divided into minute droplets dispersed in a bulk aqueous phase, the resulting composition is called an oil in water (oil / water) emulsion. The emulsions may contain additional components in addition to the dispersed phases, and the active drug which may be present as a solution in either the aqueous phase, oily phase or likewise as a single phase. Medicated excipients such as emulsifiers, stabilizers, dyes, and antioxidants may also be present in emulsions as necessary. The pharmaceutical emulsions can also be multiple emulsions comprising more than two phases, such as, for example, in the case of oil-in-water-in-oil (oil / water / oil) emulsions and water-in-oil-in-water emulsions (water / oil). /Water). Such complex formulations often provide certain advantages that simple binary emulsions do not. Multiple emulsions in which the individual oil droplets of an oil / water emulsion include small water droplets constitute a water / oil / water emulsion. Likewise, a system of oil droplets in the water globules stabilized in an oily continuous phase provides an oil / water / oil emulsion. Emulsions are characterized by having little or no thermodynamic stability. Often, the dispersed discontinuous phase of the emulsion is dispersed either in the external or continuous phase and is maintained in this form through the means of the emulsifiers or the viscosity of the formulation. Both phases of the emulsion can be a semi-solid or a solid, as is the case with ointment bases of the type of an emulsion and creams. Other means for stabilizing the emulsions involve the use of emulsifiers that can be incorporated in any phase of the emulsion. Emulsifiers can be broadly classified into four categories: synthetic surfactants, naturally occurring emulsifiers, absorption bases, naturally occurring emulsifiers, absorption bases (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988). Marcel Dekker, Inc., New York, NY, volume 1, page 199). Synthetic surfactants are also known as surface active agents, broad applicability has been found in the formulation of emulsions and has been reviewed in the literature (Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988). , Marcel Dekker, Inc., New York, NY, volume 1, p.285, Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), Marcel Dekker, Inc., New York, NY, 1988, volume 1, p.199). The surfactants are typically amphiphilic and comprise a hydrophilic portion and hydrophobic portion. The proportion of the hydrophilic to the hydrophobic nature of the surfactant has been called the hydrophilic / lipophilic balance (HLB) and is a valuable tool for the categorization and selection of surfactants in the preparation of the formulations. Surfactants may be classified into different classes based on the nature of the hydrophilic group: non-ionic, anionic, cationic and amphoteric (Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N. Y., volume 1, p.285). The naturally occurring emulsifiers used in formulations for the emulsion include lanolin, beeswax, phosphatides, lecithin and acacia. The absorption bases possess hydrophilic properties such that they can be soaked with water to form water / oil emulsions that still retain their semi-solid consistencies, such as anhydrous lanolin and hydrophilic petrolatum. They have also been used on finely divided solids such as suitable emulsifiers, especially in combination with surfactants and in viscous preparations. These include polar inorganic solids, such as heavy metal hydroxides, non-expansive clays such as bentonite, attapulgite, hectorite, kaolin, montmorillonite, colloidal aluminum silicate and colloidal magnesium silicate, pigments and non-polar solids such as carbon or glyceryl tristearate. A wide variety of non-emulsifying materials are included in the emulsion formulations and contribute to the properties of the emulsions. These include fats, oils, waxes, fatty acids, fatty alcohols, fatty esters, humectants, hydrophilic colloids, preservatives and antioxidants (Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc. , New York, NY, volume 1, p. 335; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Hydrophilic colloids or hydrocolloids include naturally occurring gums and synthetic polymers such as polysaccharides (e.g., acacia, agar, alginic acid, carrageenan, guar gum, Baraya gum and tragacanth), cellulose derivatives (e.g., carboxymethylcellulose and carboxypropylcellulose) ), and synthetic polymers (e.g., carbomers, cellulose ethers, and carboxyvinyl polymers). These are dispersed or expanded in water to form colloidal solutions that stabilize the emulsions that form strong interfacial films around the dispersed phase droplets and increasing the viscosity of the external phase.

Since emulsions often contain a variety of ingredients such as carbohydrates, proteins, sterols and phosphatides that can easily support the growth of microbes, these formulations often incorporate preservatives. Commonly used preservatives included in the emulsion formulations include methyl paraben, propyl paraben, quaternary ammonium salts, benzalkonium chloride, esters of p-hydroxybenzoic acid, and boric acid. Antioxidants are also commonly added to emulsion formulations to prevent deterioration of the formulation. The antioxidants used may be free of radical scavengers such as tocopherols, alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, or reducing agents such as ascorbic acid and sodium metabisulfite, and antioxidant synergists such as citric acid, tartaric acid, and lecithin. . The application of emulsion formulations via the dermatological, oral and parenteral routes and methods for their manufacture in the literature (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, NY, volume 1, page 199). Emulsion formulations for oral delivery have been widely used due to the ease of formulation, as well as efficacy from the point of view of absorption and bioavailability (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds .), 1988, Marcel Dekker, Inc., New York, NY, volume 1, p.245, Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York , NY, volume 1, page 199). Mineral oil base laxatives, oil-soluble vitamins and high-fat nutritional preparations are among the materials that have been orally administered such as oil / water emulsions. In one embodiment of the present invention, dsRNA and nucleic acid compositions are formulated as microemulsions. A microemulsion can be defined as a system of water, oil and an amphiphile that is an optically simple isotropic and a thermodynamically stable liquid solution (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc. ., New York, NY, volume 1, p.245). Typically, microemulsions are systems that are prepared by first dispersing an oil in an aqueous surfactant solution and then adding a sufficient amount of a fourth component, generally an intermediate chain length alcohol to form a transparent system. Accordingly, microemulsions have also been described as thermodynamically stable, isotropically clear dispersions of two immiscible liquids that are stabilized by interfacial films of surface active molecules (Leung and Shah, in: Controlled Relay of Drugs: Polymers and Aggregate Systems, Rosoff, M., Ed., 1989, VCH Publishers, New York, pages 185-215). Normally, microemulsions are prepared via a combination of three to five components including oil, water, surfactants, cosurfactants and electrolytes. Whether the microemulsion is water-in-oil (water / oil) or oil-in-water (oil / water) type depends on the properties of the oil and the surfactants used in the structure and the geometric packing of the polar heads and the ends of the hydrocarbon of the surfactant molecules (Schott, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, p 271). The phenomenological methodology that uses phase diagrams has been studied extensively and has produced a comprehensive knowledge, by an experienced in the art, of how to formulate microemulsions (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N. Y., volume 1, p. 245; Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335). Compared to conventional emulsions, microemulsions offer the advantage of solubilizing water-insoluble drops in a formulation of thermodynamically stable droplets that form spontaneously. Surfactants used in the preparation of microemulsions include, but are not limited to, ionic surfactants, nonionic surfactants, Brij 96, polyoxyethylene oleyl ethers, polyglycerol fatty acid esters, tetraglycerol monolaurate (ML310), tetraglycerol monooleate (MO310) ), hexaglycerol monooleate (PO310), hexaglycerol pentaoleate (PO500), decaglycerol monocaprate (MCA750), decaglycerol monooleate (MO750), decaglycerol sequioleate (SO750), decaglycerol decaoleate (DAO750), alone or in combination with countersurfactants The cosurfactants, normally a short chain alcohol such as ethanol, 1-propanol, and 1-butanol, serve to increase the interfacial fluidity by penetrating the film of the surfactant and consequently creating a disordered film due to the null space generated between the molecules of the surfactant. surfactant. The microemulsions can, however, be prepared without the use of cosurfactants and self-emulsifying alcohol-free microemulsion systems are known in the art. The aqueous phase may typically be, but not limited to, water, an aqueous solution of the drug, glycerol, PEG300, PEG400, polyglycerols, propylene glycols, and ethylene glycol derivatives. The oily phase may include, but is not limited to, materials such as Captex 300, Captex 355, Capmul MCM, fatty acid esters, half chain (C8-C12) mono, di, and triglycerides, esters of polyoxyethylated fatty acids, fatty alcohols , polyglycolized glycerides, saturated Cß-C? or polyglycolized glycerides, vegetable oils and silicone oil. Microemulsions are of particular interest from the viewpoint of drug solubilization and improved drug absorption. Lipid-based microemulsions (both oil / water and water / oil) have been proposed to improve the oral bioavailability of the drugs, which include the peptides (Constantinides et al., Pharmaceutical Research, 1994, 11, 1385-1390; Ritschel, Meth. Find. Exp. Clin. Pharmacol., 1993, 13, 205). The microemulsions offer improved drug solubilization advantages, protection of the drug from enzymatic hydrolysis, possible improvement of drug absorption due to the alterations induced by the surfactant in the membrane fluidity and permeability, ease of preparation, ease of administration discussion of solid dosage forms, improved clinical potency, and decreased toxicity (Constantinides et al., Pharmaceutical Research, 1994, 11, 1385; Ho et al., J. Pharm. Sci., 1996, 85, 138-143)). Often, microemulsions can form spontaneously when their components congregate at room temperature. This can be particularly advantageous when thermolabile drugs, peptides or dsRNAs are formulated. Microemulsions have also been effective in the transdermal delivery of active components in both cosmetic applications and pharmaceutical applications. It is expected that the microemulsion compositions and formulations of the present invention will facilitate the increased systemic absorption of dsRNA and nucleic acids from the gastrointestinal tract, as well as improve the local cellular uptake of dsRNA and nucleic acids within the gastrointestinal tract, vagina, oral cavity and other areas of administration. The microemulsions of the present invention may also contain additional components and additives such as sorbitan monostearate (Grill 3), Labrasol, and penetration enhancers to improve the properties of the formulation and to increase the absorption of dsRNA and nucleic acids from the present invention. The penetration enhancers used in the microemulsions of the present invention can be classified as belonging to one of five surfactants of broad categories, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p.92). Each of these classes has been discussed previously.

Liposomes There are many organized surfactant structures in addition to microemulsions that have been studied and used for drug formulation. These include monolayers, micelles, bilayers and vesicles. Vesicles, such as liposomes, have attracted great interest because of their specificity and the duration of action they offer from the point of view of drug release. As used in the present invention, the term "liposome" means a vesicle composed of amphiphilic lipids organized in a spherical bilayer or bilayer. Liposomes are unilamellar or multilamellar vesicles having a membrane formed of a lipophilic material and an aqueous interior. The aqueous portion contains the composition to be released. Cationic liposomes have the advantage of being able to fuse to the cell wall. Non-cationic liposomes, despite not being able to efficiently fuse with the cell wall, are taken by macrophages in vivo. In order to traverse the skin of mammals intact, lipid vesicles must pass through a series of fine pores, each with a diameter less than 50 nm, under the influence of a suitable transdermal gradient. Therefore, it is desirable to use a liposome which is highly deformable and capable of transferring through such fine pores. Additional advantages of liposomes include; Liposomes obtained from natural phospholipids are biocompatible and biodegradable; Liposomes can incorporate a wide range of water and soluble lipid drugs; liposomes can protect drugs encapsulated in their internal compartments of metabolism and degradation (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, NY, volume 1, p. 245). Important considerations in the preparation of liposome formulations are the lipid surface loading, gall bladder size and the aqueous volume of the liposomes. Liposomes are useful for the transfer and release of active ingredients to the site of action. Since the liposomal membrane is structurally similar to biological membranes, when liposomes are applied to a tissue, the liposomes begin to fuse with the cell membranes and as the liposome fusion and cell progress, the liposomal contents are emptied into the cell where the active agent can act. Liposomal formulations have been the focus of extensive research as the mode of release for many drugs. Increasingly there is evidence that for topical administration, liposomes have several advantages over other formulations. Such advantages include reducing side effects related to high systemic absorption of the drug administered, increasing the accumulation of the drug administered in the desired objective, and the ability to administer a wide variety of drugs, both hydroflucos and hydrophobic, in the skin. Several reports have detailed the ability of liposomes to release agents including high molecular weight DNA in the skin. Compounds including analgesics, antibodies, hormones and high molecular weight DNAs have been administered to the skin. The majority of requests resulted from the orientation of the upper epidermis. Liposomes are divided into two broad categories. Cationic liposomes are positively charged liposomes that interact with negatively charged DNA molecules to form a stable complex. The positively charged DNA / liposome complex binds to the negatively charged cell surface and internalizes into an endosome. Due to the acid pH within the endosome, the liposomes are broken, releasing their contents into the cell cytoplasm (Wang et al., Biochem Biophys., Res. Commun., 1987, 147, 980-985). Liposomes that are sensitive to pH or negatively charged trap the DNA instead of complexes with it. Since both DNA and lipid are similarly charged, repulsion instead of complex formation occurs. No 11 ' However, some DNA is trapped within the aqueous interior of these liposomes. PH sensitive liposomes have been used to release the DNA encoding the thymidine kinase gene to cell monolayers in culture. Exogenous gene expression was detected in the target cells (Zhou et al., Journal of Controlled Relay, 1992, 19, 269-274). A major type of liposomal composition includes phospholipids other than naturally occurring phosphatidylcholine. Neutral liposome compositions, for example, can be formed from dimyristoyl phosphatidylcholine (DMPC) or dipalmitoyl phosphatidylcholine (DPPC). Compositions of anionic liposomes are generally formed of dimyristoyl phosphatidylglycerol, while anionic fusogenic liposomes are formed primarily of dioleoyl phosphatidylethanolamine (DOPE). Another type of liposomal composition is formed of phosphatidylcholine (PC) such as, for example, soybeans PC, and egg PC. Another type is formed of mixtures of phospholipid and / or phosphatidylcholine and / or cholesterol. Several studies have evaluated the topical release of liposomal drug formulations to the skin. The application of liposomes containing inferred guinea pig skin results in a reduction of herpes sores on the skin while the release of inferred by other means (eg, as a solution or as an emulsion) were ineffective (Weiner et al., Journal of Drug Targeting, 1992, 2, 405-410). In addition, an additional study proves the efficacy of interferon administered as part of a liposomal formulation to the administration of interferon using an aqueous system, and concludes that the liposomal formulation was superior to aqueous administration (du Plessis et al., Antiviral Research, 1992, 18, 259-265). Nonionic liposomal systems have also been examined to determine their utility in the delivery of drugs to the skin, in particular systems comprising nonionic surfactant and cholesterol. Non-ionic liposomal formulations comprising Novasoma. TM. I (glyceryl dilaurate / cholesterol / polyoxyethylene-10-stearyl ether) and Novasome. TM. II (glyceryl distearate / cholesterol / polyoxyethylene-10-stearyl ether) were used to release cyclosporin-A in the dermis of mouse skin. The results indicate that such non-ionic liposomal systems were effective in facilitating the deposition of cyclosporin-A in different layers of the skin (Hu et al., S.T.P. Pharma, Sci., 1994, 4, 6, 466). Liposomes also include "spherically stabilized" liposomes, a term which, as used herein, refers to liposomes comprising one or more specialized lipids which, when incorporated into liposomes, result in increased circulation lifetime with relationship to liposomes lacking such specialized lipids. Examples of spherically stabilized liposomes are those in which part of the lipid portion formed by the liposome vesicle (A) comprising one or more glycolipids, such as monosialoganglioside Gml, or (B) is derived with one or more hydrophilic polymers, such as a polyethylene glycol (PEG) moiety. Although it is not desired to be bound by any particular theory, it is thought in the art that, at least for spherically stabilized liposomes containing gangliosides, sphingomyelin, or lipids derived from PEG, the increased circulation half life of these spherically stabilized liposomes is derived from a reduced absorption in cells of the reticuloendothelial system (RES) (Alien et al., FEBS Letters, 1987, 223, 42, Wu et al., Cancer Research, 1993, 53, 3765). Various liposomes comprising one or more glycolipids are known in the art. Papahadjopoulos et al. (Ann N. Y. Acad. Sci., 1987, 507, 64) reports the ability of monosialoganglioside Gml, galactocerebroside sulfate and phosphatidylinositol to improve the half-life in blood of liposomes. These findings were reported by Gabizon et al. (Proc. Nati, Acad. Sci. U.S.A., 1988, 85, 6949). Pat. E.U.A. No. 4,837,028 and WO 88/04924, both to Alien et al., Describe liposomes comprising (1) sphingomyelin and (2) ganglioside Gml or a galactocerebroside sulfate ester. Pat.

From U.S. Patent No. 5,543,152 (Webb et al.) Describes liposomes comprising sphingomyelin. Liposomes comprising 1,2-sn-dimyristoylphosphatidylcholine are described in WO 97/13499 (Lim et al). Many liposomes comprise lipids derived with one or more hydroflucos polymers, and preparation methods thereof, are known in the art. Sunamoto et al. (Bull. Chem. Soc. Jpn., 1980, 53, 2778) describes liposomes comprising a nonionic detergent, 2C? 2? SG, containing a PEG portion. Ilium et al. (FEBS Lett., 1984, 167, 79) notes that hydrophilic coating of polystyrene particles with polymeric glycols results in significantly increased half-life in the blood. Synthetic phospholipids modified by the carboxyl group linkage of polyalkylene glycols (eg, PEG) are described by Sears (U.S. Pat. Nos. 4,426,330 and 4,534,899). Klibanov et al. (FEBS Lett., 1990, 268, 235) describes experiments demonstrating that liposomes comprising phosphatidyl ethanolamine (PE) derived with PEG or PEG stearate have significant increase in circulating half-life in the blood. Blume et al. (Biochimica et Biophysica Acta, 1990, 1029, 91) extends these observations to other phospholipids derived from PEG, for example, DSPE-PEG, formed from the combination of distearoylphosphatidylethanolamine (DSPE) and PEG. Liposomes having covalent bonding of PEG portions on their outer surface are described in European Patent No. EP 0 445 131 Bl and WO 90/04384 to Fisher. Liposome compositions containing 1-20 mole percent PE derived with PEG, and methods for use thereof, are described by Woodle et al. (U.S. Pat. Nos. 5,013,556 and 5,356,633) and Martin et al. (U.S. Pat. No. 5,213,804 and European Patent No. EP 0 496 813 Bl). Liposomes comprising a number of other polymeric lipid conjugates are described in WO 91/05545 and Pat. of E.U.A. No. 5,225,212 (both to Martin et al.) And WO 94/20073 (Zalipsky et al.) Liposomes comprising ceramide lipids modified by PEG are described in WO 96/10391 (Choi et al). Pat. of E.U.A. No. 5,540,935 (Miyazaki et al.) And Pat. of E.U.A. No. 5,556,948 (Tagawa et al.) Describes liposomes containing PEG that can also be derived with functional portions on their surfaces. A limited number of liposomes comprising nucleic acids are known in the art. WO 96/40062 to Thierry et al. describes methods for encapsulating high molecular weight nucleic acids in liposomes. Pat. E.U.A. No. 5,264,221 to Tagawa et al. describes liposomes linked to the protein and states that the contents of such liposomes can include dsRNA. Pat. E.U.A. No. 5,665,710 to Rahman et al. describes certain methods of encapsulating oligodeoxynucleotides in liposomes. WO 97/04787 to Love et al. describes liposomes comprising ARNdsA directed to the raf gene.

Transfersomes are still another type of liposomes, and are highly deformable lipid aggregates that are attractive candidates for drug delivery vehicles. Transfersomes can be described as lipid droplets that are so highly deformable that they can easily penetrate through pores that are smaller than droplet. Transfersomes are adaptable to the environment in which they are used, for example, they self-optimize (adaptable to the pores in the skin), self-repair, frequently reach their targets without fragmentation, and often self-charge. To make transfersomes it is possible to add activators to the edge of the surface, usually surfactants, to a standard liposomal composition. Transfusions have been used to release serum albumin to the skin. The transfersome-mediated release of serum albumin has been shown to be effective as a subcutaneous injection of a solution containing serum albumin. Surfactants find wide application in formulations such as emulsions (including microemulsions) and liposomes. The most common way to classify and rank the properties of the many different types of surfactants, both natural and synthetic, is by the use of hydrophilic / lipophilic balance (HLB). The nature of the hydrophilic group (also known as the "head") provides the most useful means for classifying the different surfactants used in the formulations (Rieger, in Pharmaceutical Dosage Forms, Marcel Dekker, Inc., New York, NY, 1988, p. 285). If the surfactant molecule is not ionized, it is classified as a non-ionic surfactant. Nonionic surfactants find wide application in medicinal products and cosmetics and are usable over a wide range of pH values. In general its HLB values in the range from 2 to around 18 depending on its structure. Nonionic surfactants include nonionic ethers such as ethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl esters, sorbitan esters, sucrose esters, and ethoxylated esters. Nonionic alkanolamides and ethers such as fatty alcohol ethoxylates, propoxylated alcohols, and ethoxylated / propoxylated blocking polymers are also included in this class. Polyoxyethylene surfactants are the most popular members of the non-ionic surfactant class. If the surfactant molecule carries a negative charge when it dissolves or disperses in water, the surfactant is classified as anionic. Anionic surfactants include carboxylates such as soaps, acyl lactylates, acyl amides of amino acids, sulfuric acid esters such as alkyl sulfates and ethoxylated alkyl sulfates, sulfonates such as alkyl benzene sulfonates, acyl isethionates, acyl taurates and sulfosuccinates, and phosphates. The most important members of the anionic surfactant classes are alkyl sulphates and soaps. If the surfactant molecule carries a positive charge when it dissolves or disperses in water, the surfactant is classified as cationic. Cationic surfactants include quaternary ammonium salts and ethoxylated amines. Quaternary ammonium salts are the most used members of this class.

If the surfactant molecule has the ability to carry either a positive or a negative charge, the surfactant is classified as amphoteric. Amphoteric surfactants include derivatives of acrylic acid, substituted alkylamides, N-alkylbetaines and phosphatides. The use of surfactants in drug products, formulations and in emulsions has been reviewed (Rieger, in Pharmaceutical Dosage Forms, Marcel Dekker, Inc., New York, N. Y., 1988, p.285).

Penetration Augmentators In one embodiment, the present invention employs various penetration enhancers to effect efficient delivery of nucleic acids, particularly dsRNA, to the skin of animals. Most drugs are presented in solution in both ionized and non-ionized forms. However, usually only lipophilic or lipid soluble drugs easily cross cell membranes. It has been found that even non-lipophilic drugs can cross cell membranes if the membrane to be crossed is treated with a penetration enhancer. In addition to the aid the diffusion of non-lipophilic drugs through cell membranes, penetration enhancers also increase the permeability of lipophilic drugs. Penetration enhancers can be classified as belonging to one of five broad categories, that is, surfactants, fatty acids, bile salts, chelating agents, and non-chelating surfactants (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p.92). Each of the aforementioned classes of penetration enhancers are described below in greater detail. Surfactants: In connection with the present invention, surfactants (or "surface active agents") are chemical entities which, when dissolved in an aqueous solution, reduce the surface tension of the solution or the interfacial tension between the aqueous solution and another liquid, with the result that the absorption of dsRNA through the mucosa is increased. In addition to bile salts and fatty acids, these penetration enhancers include, for example, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether and polyoxyethylene-20-cetyl ether) (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p.92); and perfluorochemical emulsions, such as FC-43 (Takahashi et al., J. Pharm. Pharmacol., 1988, 40, 252). Fatty acids: Various fatty acids and their derivatives that act as penetration enhancers include, for example, oleic acid, lauric acid, capric acid (n-decanoic acid), myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid , dicaprate, tricaprate, monoolein (1-monooleoyl-rac-glycerol), dilaurin, caprylic acid, arachidonic acid, glycerol 1-monocaprate, 1-dodecylazacycloheptan-2-one, acylcarnitines, acylcholines, Ci-Cio alkyl esters thereof ( for example, methyl, isopropyl and t-butyl), and mono- and di-glycerides thereof (ie, oleate, laurate, caprate, myristate, palmitate, stearate, linoleate, etc.) (Lee et al., Critical Reviews in Therapeutic Drug Carryier Systems, 1991, p.92; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; El Hariri et al., J. Pharm. Pharmacol., 1992, 44, 651-654 ). Bile salts: The physiological role of bile includes the facilitation of dispersion and absorption of lipids and fat-soluble vitamins (Brunton, Chapter 38 in: Goodman &Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al. Eds., McGraw-Hill, New York, 1996, pp. 934-935). Various natural bile salts, and their synthetic derivatives, act as penetration enhancers. Thus, the term "bile salts" includes any of the naturally occurring components of bile as well as any of its synthetic derivatives. The bile salts of the invention include, for example, cholic acid (or its pharmaceutically acceptable sodium salt, sodium cholate), dehydrocholic acid (sodium dehydrocolate), deoxycholic acid (sodium deoxycholate), glycolic acid (sodium glucoate), glycolic acid (sodium glycocholate), glycodeoxycholic acid (sodium glycodeoxycholate), taurocholic acid (sodium taurocholate), acid taurodeoxycholic (sodium taurodeoxycholate), chenodeoxycholic acid (sodium chenodeoxycholate), ursodeoxycholic acid (UDCA), tauro-24, sodium 25-dihydro-fusidate (STDHF), sodium glycidohydrofusidate and polyoxyethylene-9-lauryl ether (POE) (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Swinyard, Chapter 39 in: Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, Pa. , 1990, pages 782-783; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; Yamamoto et al., J. Pharm. Exp. Ther., 1992, 263, 25; Yamashita et al., J. Pharm. Sci., 1990, 79, 579-583). Chelating agents: Chelating agents, as used in connection with the present invention, can be defined as compounds that remove metal ions from the solution by forming complexes thereof, with the result that the absorption of dsRNA through the mucosa is increased. Regarding their use as penetration enhancers in the present invention, chelating agents have the additional advantage of also serving as DNase inhibitors, as the majority of characterized DNA nucleases that require a divalent metal ion for catalysis and therefore both inhibit by chelating agents (Jarrett, J. Chromatogr., 1993, 618, 315-339). Chelating agents of the invention include but are not limited to disodium ethylenediaminetetraacetate (EDTA), citric acid, salicylates (eg, sodium salicylate, 5-methoxysalicylate and homovanilate), N-acyl derivatives of collagen, laureth-9 and N-amino acyl derivatives of beta-diketones (enamines) (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; Buur et al., J. Control Reí., 1990, 14, 43-51). Non-chelating surfactants: As used herein, non-chelating non-surfactant penetration enhancing compounds can be defined as compounds that demonstrate negligible activity as chelating agents or as surfactants but which nonetheless increase the uptake of dsRNA by the mucosa. Food (Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33). This class of penetration enhancers include, for example, unsaturated cyclic ureas, 1-alkyl- and 1-alkenylazacycloheptenone derivatives (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92); and non-spheroidal anti-inflammatory agents such as sodium diclofenac, indomethacin and phenylbutazone (Yamashita et al., J. Pharm. Pharmacol., 1987, 39, 621-626). Agents that increase the uptake of dsRNA at the cellular level can also be added to the medicaments and other compositions of the present invention. For example, cationic lipids, such as lipofectin (Junichi et al, US Pat. No. 5, 705, 188), cationic glycerol derivatives, and polycationic molecules, such as polylysine (Lollo et al., PCT Application WO 97 / 30731), are also known to increase the cellular uptake of dsRNA. Other agents can be used to increase the penetration of the administered nucleic acids, including glycols such as ethylene glycol and propylene glycol, pyrroles such as 2-pyrrole, azones, and terpenes such as limonene and menthone.

Carriers Certain compositions of the present invention also incorporate carrier compounds in the formulation. As used herein, "carrier compound" or "carrier" can refer to a nucleic acid, or analog thereof, which is inert (ie, has no biological activity per se) but is recognized as a nucleic acid by in vivo processes that reduce the bioavailability of a nucleic acid having biological activity by, for example, degradation of the biologically active nucleic acid or promoting its elimination from the circulation. The co-administration of a nucleic acid and a carrier compound, typically with an excess of the latter substance, can result in a substantial reduction in the amount of nucleic acid recovered in the liver, kidney or other extracirculatory reservoirs, presumably due to competition. between the carrier compound and the nucleic acid for a common receptor. For example, the recovery of a partially phosphorothioate dsRNA in liver tissue can be reduced when this is co-administered with polyinosinic acid, dextran sulfate, polycyclic acid or 4-acetamido-4 'isothiocyano-stilbene-2, 2'-disulfonic acid. (Miyao et al., Antisense Res. Dev., 1995, 5, 115-121; Takakura et al., Antisense &Nuci, Acid Drug Dev., 1996, 6, 177-183.

Excipients In contrast to a carrier compound, a "pharmaceutical carrier" or "excipient" is a pharmaceutically acceptable solvent, suspending agent or any other pharmacologically inert vehicle for delivering one or more nucleic acids to an animal. The excipient may be liquid or solid and is selected, with the projected form of administration in mind, in order to provide for the desired volume, consistency, etc., when combined with a nucleic acid and the other components of a given pharmaceutical composition . Typical drug carriers include, but are not limited to, binding agents (eg, pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.); fillers (for example, lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium acid phosphate, etc.); lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metal stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.); and wetting agents (e.g., lauryl sodium sulfate, etc.). The pharmaceutically acceptable organic or inorganic excipient suitable for non-parenteral administration that does not detrimentally react with nucleic acids can also be used to formulate the compositions of the present invention. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone, and the like.

Formulations for topical administration of nucleic acids may include sterile or non-sterile aqueous solutions, non-aqueous solutions in common solvents such as alcohols, or solutions of the nucleic acids in liquid or solid oil bases. The solutions may also contain buffer solutions, diluents and other suitable additives. Inorganic or pharmaceutically acceptable inorganic excipients suitable for non-parenteral administration that do not detrimentally react with nucleic acids can be used. Suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethyl cellulose, polyvinyl pyrrolidone, and the like.

Pharmaceutical Compositions for Release to the Respiratory Tract Another aspect of the invention provides for the release of RNAi agents to the respiratory tract, particularly for the treatment of cystic fibrosis. The respiratory tract includes the upper respiratory tract, including the oropharynx and larynx, followed by the lower respiratory tract, which includes the trachea followed by bifurcations in the bronchi and bronchioles. The upper and lower respiratory tracts are called the conductive respiratory tract. The terminal bronchioles are then divided into respiratory bronchioles which in turn give rise to the last respiratory zone, the alveoli, or deep lung. The deep lung, or alveoli, are the primary target of inhaled therapeutic aerosols for systemic release of RNAi agents. The pulmonary release compositions can be released by inhalation by the patient of a dispersion so that the composition, preferably the RNAi agent, within the dispersion can react the lung when it can, for example, be easily absorbed through the alveolar region. directly in the bloodstream. The pulmonary release may be effective both for systemic release and for localized release to treat diseases of the lungs. Pulmonary release can be achieved by different approaches, including the use of nebulized, aerosolized, mycelular and dry powder-based formulations; administration by inhalation may be oral and / or nasal. The release can be achieved with liquid nebulizers, aerosol-based inhalers, and dry powder dispersion devices. Measured dose devices are preferred. One of the benefits of using an atomizer or inhaler is that the potential for contamination is minimized since the devices are self-contained. Dry powder dispersion devices, for example, release drugs that can be easily formulated as dry powders. An RNAi composition can be stored stably as lyophilized or spray-dried powders by themselves or in combination with suitable powder carriers. The release of a composition by inhalation can be mediated by a scheduled dosing element which may include a timer, a dose counter, time measurement device, or a time indicator which when incorporated into the device allows tracking of dose, monitoring compliance, and / or dose activation to a patient during administration of the aerosol medication. Examples of medicament delivery devices for aerosol release include metered dose inhalers (MDIs), dry powder inhalers (DPIs), and airflow nebulizers. Exemplary release systems by inhalation that can be readily adapted for release from the subject RNAi agents are described in, for example, Pat. E.U.A. Nos. 5,756,353; 5,858,784; and PCT applications W098 / 31346; WO98 / 10796; WO00 / 27359; WO01 / 54664; WO02 / 060412. Other aerosol formulations that can be used for the release of the RNAi agents are described in Pat. of E.U.A. Nos. 6,294,153; 6,344,194; 6,071,497, and PCT applications WO02 / 066078; WO02 / 053190; WO01 / 60420; WO00 / 66206. In addition, the methods for releasing the RNAi agents can be adapted from those used in the release of other oligonucleotides (eg, an antisense oligonucleotide) by inhalation, as described in Templin et al, Antisense Nucleic Acid Drug Dev, 2000, 10: 359-68; Sandrasagra et al., Expert Opin Biol Ther, 2001, 1: 979-83; Sandrasagra et al., Antisense Nucleic Acid Drug Dev, 2002, 12: 177-81. The release of the inventive agents may also involve the administration of the so-called "prodrugs", that is, chemical formulations or modifications of a therapeutic substance that requires some form of processing or transport by innate systems to the target organism to release the therapeutic substance, preferably in the place where this action is desired; this latter embodiment can be used in conjunction with the release of the respiratory tract, but also together with other embodiments of the present invention. For example, human lungs can rapidly remove or degrade aerosols deposited in hydrolytically cleavage for periods ranging from minutes to hours. In the upper respiratory tract, epithelial ciliates contribute to the "mucociliary climber" whose particles are swept from the respiratory tract to the mouth. Pavia, D., "Lung Mucociliary Clearance," in Aerosols and the Lung: Clinical and Experimental Aspects, Clarke, SW and Pavia, D., Eds., Butterworths, London, 1984. In deep lungs, alveolar macrophages are capable of making phagocytosis of particles fast after its deposition. Warheit et al. Microscopy Res. Tech., 26: 412-422 (1993); and Brain, J. D., "Physiology and Pathophysiology of Pulmonary Macrophages," in The Reticuloendothelial System, S. M. Reichard and J. Filkins, Eds., Plenum, New York, pp. 315-327, 1985. In preferred embodiments, particularly where systemic dosing with the RNAi agent is desired, the aerosolized RNAi agents are formulated as microparticles. Microparticles that have a diameter between 0.5 and ten microns can penetrate the lungs, passing through most natural barriers. A diameter of less than ten microns is required for throat bypass; A diameter of 0.5 microns or greater is required to avoid being exhaled.

Other Components The compositions of the present invention may additionally contain other complement components conventionally found in pharmaceutical compositions, at their established levels of use in the art. Thus, for example, the compositions may contain additional, compatible, pharmaceutically active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in different physically formulated dosage forms of the compositions. of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention. The formulations can be sterilized and, if desired, mixed with auxiliary agents, for example, lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for osmotic pressure of influence, buffer solutions, colorants, flavors and / or aromatic substances and the like which do not detrimentally interact with the nucleic acids of the formulation. Aqueous suspensions may contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and / or dextran. The suspension may also contain stabilizers. Certain embodiments of the invention provide pharmaceutical compositions containing (a) one or more dsRNA agents and (b) one or more other chemotherapeutic agents that function by a non-RNA interference mechanism. Examples of such chemotherapeutic agents include but are not limited to daunorubicin, daunomycin, dactinomycin, doxorubicin, epirubicin, idarabicin, esorubicin, bleomycin, mafosfamide, ifosfamide, cytosine arabinoside, bis-chloroethylnitrosurea, busulfan, mitomycin C, actinomycin D, mitramycin, prednisone. , hydroxyprogesterone, testosterone, tamoxifen, dacarbazine, procarbazine, hexamethylmelamine, pentamethylmelamine, mitoxantrone, amsacrine, chlorambucil, methylcyclohexylnitrosurea, nitrogen mustards, melphalan, cyclophosphamide, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-azacytidine, hydroxyurea, deoxicoformycin, 4 -hydroxiperoxychicophosphoramide, 5-fluorouracil (5-FU), 5-fluorodeoxyuridine (5-FUdR), methotrexate (MTX), colcicin, taxol, vincristine, vinblastine, etoposide (VP-16), trimetrexate, irinotecan, topotecan, gemcitabine, teniposide , cisplatin and diethylstilbestrol (DES). See, generally, The Merck Manual of Diagnosis and Therapy, 15th Ed. 1987, p. 1206-1228, Berkow et al, eds., Rahway, NJ. When used with the compounds of the invention, such chemotherapeutic agents can be used individually (e.g., 5-FU and oligonucleotide), sequentially (e.g., 5-FU and oligonucleotide for a period of time followed by MTX and oligonucleotide), or in combination with one or more other chemotherapeutic agents (e.g., 5-FU, MTX and oligonucleotide, or 5-FU, radiotherapy and oligonucleotide). Anti-inflammatory drugs, including but not limited to non-spheroidal anti-inflammatory drugs and corticosteroids, and antiviral drugs, including but not limited to ribivirine, vidarabine, acyclovir and ganciclovir, may also be combined in compositions of the invention . See, generally, The Merck Manual of Diagnosis and Therapy, 15th Ed., Berkow et al., Eds., 1987, Rahway, NJ. , pages 2499-2506 and 46-49, respectively). Other non-ARNds chemotherapeutic agents are within the scope of this invention. Two or more combined compounds can be used together or sequentially.

The toxicity and therapeutic efficacy of such compounds can be determined by standard drug procedures in cell cultures or experimental animals, for example, to determine the LD50 (the lethal dose for 50% of the population) and the ED50 (the therapeutically effective dose in 50% of the population). The dose ratio between toxic or therapeutic effects is the Therapeutic Index and this can be expressed as the LD50 / ED50 ratio. Compounds that exhibit high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in the formulation of a dose range for human use. The dose of compositions of the invention generally resides within a range of circulating concentrations that include the ED50 with little or no toxicity. The dose may vary within this range depending on the dosage form employed and the route of administration used. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a concentration range in the circulating plasma of the compound or, where appropriate, the polypeptide product of a target sequence (e.g., achieving a decrease in the concentration of the polypeptide) that includes IC50 (that is, the concentration of the test compound that achieves maximum mean inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful human dose. The plasma levels can be measured, for example, by high-performance liquid chromatography. In addition to its administration individually or as a plurality, as already said, the dsRNA of the invention can be administered in combination with other agents known to be effective in the treatment of influenza infection. In any case, the physician administering can adjust the amount and timing of administration of dsRNA on the basis of the results observed using standard measures of efficacy known in the art or described herein.

Methods of Treatment and Ways of Release A composition that includes an RNAi agent, for example, an RNAi agent that directs influenza virus, can be delivered to a subject by a variety of routes to achieve either local release to the site of release action systemic to the subject. Exemplary routes include direct local administration to the treatment site, such as the lungs and nasal passage as well as intravenous, nasal, buccal, and ocular delivery. The preferred means of administration of the RNAi agents of the present invention is through direct administration to the lungs and nasal passage as a liquid, aerosol or nebulized solution. In general, the release of the RNAi agents of the present invention is achieved upon reaching the release in the subject at the site of infection. The preferred means to achieve this is through either a local administration to the lungs or nasal passage, for example, in the respiratory tissues by means of. inhalation or intranasal administration, or by means of systemic administration, for example, parental administration. Formulations for inhalation or parenteral administration are well known in the art. Such a formulation may include sterile aqueous solutions which may also contain buffer solutions, diluents and other suitable additives. For intravenous use, the total concentration of solutes must be controlled to make the preparation isotonic. The active compounds described herein are preferably administered to the lungs or nasal passage of a subject by any suitable means. The active compounds can be administered by administration of an aerosol suspension of respirable particles comprising the active compound or active compounds, which the subject inhales. The active compound can be 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 can be liquid or solid. The particles may optionally contain other therapeutic ingredients such as amiloride, benzamyl or phenamyl, with the selected compound included in an amount effective to inhibit the reabsorption of water from mucous secretions in the airways, as described in Pat. E.U.A. No. 4,501,729.

The pharmaceutical particle composition can optionally be combined with a carrier to aid in dispersion or transport. A suitable carrier such as a sugar (i.e., lactose, sucrose, trehalose, mannitol) can be mixed with the active compound or compounds in any suitable ratio (e.g., a ratio 1 to 1 by weight). The particles comprising the active compound for practicing the present invention should include particles of respirable size, that is, particles of a size small enough to pass through the mouth or nose and larynx upon inhalation and into the bronchi and alveoli of lungs. In general, particles in the range of about 1 to 10 microns in size (more particularly, less than about 5 microns in size) are respirable. Particles of non-respirable size that are included in the aerosol tend to be deposited in the throat and are ingested, and the amount of non-respirable particles in the aerosol are preferably minimized. For nasal administration, a small individual in the range of 10-500 uM is preferred to ensure retention in the nasal cavity. Liquid pharmaceutical compositions of active compound for producing an aerosol can be prepared by combining the active compound with a suitable vehicle, such as sterile pyrogen free of water. The hypertonic saline solutions used to carry 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 weight percent of the physiologically acceptable salt. The liquid particle aerosols comprising the active compound can be produced by any suitable means, such as with a pressure driven jet nebulizer or an ultrasonic nebulizer. See, for example, Pat. E.U.A. No. 4,501,729. Nebulizers are commercially available devices that transform the solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of accelerating compressed gas, typically air or oxygen, through a narrow venturi or by means of ultrasonic agitation. Formulations suitable for use in nebulizers consist of the active ingredient in a liquid carrier, the active ingredient comprises up to 40% w / w of the formulation, but preferably less than 20% w / w. The carrier is typically water (and more preferably sterile, pyrogen-free water) or a dilute aqueous alcohol solution, preferably rendered isotonic, but can 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 hydrobenzoate, antioxidants, flavoring agents, volatile oils, buffering agents and surfactants.

The aerosols of the solid particles comprising the active compound can also be produced with any solid particle therapeutic aerosol generator. Aerosol generators for administering therapeutic solid particles to a subject produce particles which are respirable and generate an aerosol volume containing a predetermined metered dose of a therapeutic in a ratio suitable for human administration. An illustrative type of aerosol generator of solid particles is an insufflator. Formulations suitable for administration by insufflation include finely ground powders which can be released by means of an insufflator or taken into the nasal cavity in the manner of an inhaler. In the insufflator, the powder (eg, a measured dose thereof effective to carry out the treatments described herein) is contained in capsules or cartridges, typically made of gelatin or plastic, which are either open or perforated in and the dust is released by the air that enters through the device during inhalation or by means of a manually operated pump. The powder employed in the insufflator consists of either only the active ingredient or a powder mixture 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 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 the use of these devices the formulation is discharged through a valve adapted to release a measured volume, typically from 10 to 200 ul, to produce a fine particle mist containing the active ingredient. Suitable propellants include certain chlorofluorocarbon compounds, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof. The formulation may additionally contain one or more co-solvents, for example, ethanol, surfactants, such as oleic acid or sorbitan trioleate, antioxidants and suitable flavoring agents. An RNAi agent can be incorporated into pharmaceutical compositions suitable for administration. For example, the compositions may include one or more species of an RNAi agent and a pharmaceutically acceptable carrier. As used herein, the phrase "pharmaceutically acceptable carrier" is understood to include any and all solvents, dispersion media, coating agents, antibacterials and antifungals, isotonic and delaying absorption agents and the like, compatible with the administration pharmaceutical The use of such a medium and agents for pharmaceutically active substances is well known in the art. Except that any conventional means or agent is incompatible with the active compound, the use thereof in the compositions is contemplated. The active complementary compounds can also be incorporated into the compositions. The administration can be provided by the subject or by another person, for example, a caregiver. A caregiver can be anyone who is involved in providing care to the human: for example, a person who works in a hospital, hospice, doctor's office, ambulant; a health care worker such as a doctor, nurse, or other practitioner, or a spouse or guardian, such as the parents. The medication can be provided in measured doses or in a dispenser which releases a measured dose. The term "therapeutically effective amount" is the amount present in the composition that is necessary to provide the desired level of drug in the subject to be treated to give the anticipated physiological response. The term "physiologically effective amount" is the amount administered to a subject to give the desired palliative or curative effect. The term "pharmaceutically acceptable carrier" means that the carrier can be taken into the lungs without 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 RNAi agents. The agents can be contained in a simple pharmaceutical composition and can be administered at the same time, or the agents can be contained in the separate formulation and administered in series to a subject. While the two agents can be detected in the subject at the same time, the two agents are co-administered. The types of excipient medications that are useful as Carriers include stabilizers such as human serum albumin (HSA), bulking agents such as carbohydrates, amino acids and polypeptides; pH adjusters or buffer solutions, salts such as sodium chloride; and similar. These carriers may be in a crystalline or amorphous form or may be a mixture of the two. Volume agents that are particularly valuable include compatible carbohydrates, polypeptides, amino acids or combinations thereof. Suitable carbohydrates include 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 raffinose, maltodextrins, dextrans and the like; alditols, such as mannitol, xylitol and the like. A preferred group of carbohydrates includes lactose, trehalose, raffinose maltodextrins and mannitol. Suitable polypeptides include aspartame. The amino acids include alanine and glycine, with glycine being preferred. Suitable pH adjusters or buffer solutions include organic salts prepared from organic acids and bases, such as sodium citrate, sodium ascorbate and the like; Sodium citrate is preferred.

Dosage An RNAi agent can be administered in a unit dose of less than about 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 body weight, and less than 200 nmol of the RNAi agent (eg, about 4.4 x 1016 copies) per kg of body weight, 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 the RNAi agent per kg of body weight. The unit dose, for example, can be administered by injection (eg, intravenous or intramuscular, intrathecally or directly into an organ), an inhaled dose or a topical application. The release of an RNAi agent directly to an organ (eg, to the lung) can be at a dose in the order of about 0.00001 mg to about 3 mg per organ, or preferably about 0.0001-0.001 mg per organ, around 0.03-3.0 mg per organ, around 0.1-3.0 mg per eye or around 0.3-3.0 mg per organ. The dosage can be an effective amount to treat or prevent a disease or disorder. This can be given prophylactically or as the primary or a part of a treatment protocol. In one embodiment, the unit dose is administered less frequently than once a day, for example, less than every 2, 4, 8 or 30 days. In another embodiment, the unit dose is not administered with a frequency (eg, not a regular frequency). For example, the unit dose can be administered in a simple time. Because the RNAi agent that mediates silencing can persist for several days after administering the composition of the RNAi agent, in many cases, this is possible to administer the composition less than once a day, or, sometimes , only once for the full therapeutic regimen. In one embodiment, a subject is administered an initial dose, and one or more maintenance doses of an RNAi agent, for example, a double-stranded RNAi agent, or sARNi agent (e.g., a precursor, e.g. larger RNAi agent which can be processed into a sRNA agent, or a DNA encoding an RNAi agent, eg, a double-stranded RNAi agent, or sRNAi agent, or precursor thereof). The dose or maintenance dose is generally less than the initial dose, for example, less than half the initial dose. A maintenance regimen may include treating the subject with a dose or several doses in the range of 0.01 to 75 mg / kg of body weight per day, for example, 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 body weight per day. The maintenance dose is preferably administered no more than once every 5, 10, or 30 days. In addition, the treatment regimen may last for a period of time which varies depending on the nature of the particular disease, its severity and the general condition of the patient. In preferred embodiments the dosage can be administered no more than once per day, for example, no more than once per 24, 36, 48, or more hours, for example, no more than once every 5 or 8 days. Following the treatment, the patient can be monitored for changes in their condition and for relief of the symptoms of the disease state. The dose of the compound can either be increased in the event that the patient does not respond significantly to the current dosage levels, or the dose can be decreased if a relief of the symptoms of the disease state is observed, if the condition of the disease it is eliminated, or if unwanted side effects are observed. The effective dose may be administered in a single dose or in two or more doses, as desired or considered appropriate under the specific circumstances. If it is desired to facilitate repeated or frequent infusions, the implantation of a delivery device, for example, a pump, semi-permanent stent (eg, intravenous, intraperitoneal, int ration st ernal or rac-rat int), or recervoir may be convenient . Following successful treatment, it may be desirable to have the patient under maintenance therapy to prevent recurrence of disease status, wherein the compound of the invention is administered in sustained doses, the range from 0.001 g to 100 g per kg of weight body (see, US 6,107,094). The concentration of the RNAi agent composition is an amount sufficient to be effective in the treatment or prevention of a disorder or to regulate a physiological condition in humans. The concentration or amount of the RNAi agent administered will depend on the parameters determined by the agent and the method of administration, for example, nasal, buccal or pulmonary. For example, nasal formulations tend to require much lower concentrations of some ingredients in order to avoid irritation or burning of the nasal passages. Sometimes it is desirable to dilute an oral formulation up to 10-100 times in order to provide a suitable nasal formulation. Certain factors may influence the dose required to effectively treat a subject, including but not limited to the severity of the disorder or disease, previous treatments, the general health and / or age of the subject, and other diseases present. It will also be appreciated that the effective dose of an RNAi agent such as a sRNA used for treatment to be increased or decreased during the course of a particular treatment. Changes in dosage can result and become apparent from the results of diagnostic tests. For example, the subject can be monitored after administering an RNAi agent composition. Based on the monitoring information, an additional amount of the RNAi agent composition can be administered.

The dosage is dependent on the severity and response of the conditions of the disease to be treated, with the course of treatment lasting several days up to several months, or until a cure is made or a decrease in the state of the disease is effected. Optimal dosing schedules can be calculated from measurements of drug accumulation in the patient's body. People of ordinary skill can easily determine the optimal dosage, dosing methodologies and repetition relationships. The optimal dosages may vary depending on the relative potency of the individual compounds and can generally be estimated based on the EC50 found to be effective in animal models in the vi and ro vi as described above. The invention is further illustrated by the following examples, which should not be construed as additional limitations.

EXAMPLES The nucleic acid sequences are represented below using the standard nomenclature and specifically the abbreviations of Table 3.

Table 3: Abbreviations of the nucleotide monomers used in the representation of the nucleic acid sequence. It is understood that these monomers, when present in an oligonucleotide, are linked to each other by the 5'-3'-phosphodiester bonds. aThe capital letters represent 2 '-deoxyribonucleotides (DNA), the lowercase represent ribonucleotides (RNA) Reagent Source Where the source of a reagent is not specifically given herein, such reagent can be obtained from any supplier of molecular biology reagents in a standard quality / purity for application in molecular biology.

Example 1: Selection of sequences The design of the sRNA was carried out to identify the sRNAs directed to the mRNA of Influence A of the protein MP, NP, PA, PBl and PB2. In a first round, siRNA in silica selection results in 44 sequences directed to MP, 3 sequences directed to NP and 1 sequence directed to PBl. There are no specific sRNAs for Influenza A PA or PB2 genes that pass the first screening process that requires 80% of the target coverage and 80% of the target efficacy (see below). To configure an environment for sequence analysis, the fastA package (Pearson, WR, &Lipman, DJ., PNAS 1988, 85: 2444) is downloaded from ftp://ftp.virginia.edu/pub/ and is installed in a workstation under the Suse Linux® 9.3 operating system with the standard installation configuration. For the purpose of running the perl scripts, this is ensured by the perl interpreter, version 5.8.6 (copyright 1987-2004, Larry Wall), next with the installation, standard Suse Linux 9.3 was functional. The sequence alignment editor BioEdit (Hall, TA, Nucí Acids, Symp.Ser. 1999, 41:95) was downloaded from the Web Brown Lab server on the North Carolina State University website and installed in a computer under the Microsoft Windows2000® operating system. The workflow for in sili co selection was as follows: the influenza A sequences of interest were downloaded, aligned and a statistic was generated to obtain the distribution of the bases in each position in relation to a calculated consensus. A perl script was used to identify the candidate target regions to meet the defined cut criteria. The sARNi sequences for the candidate target regions were analyzed for specificity by the fastA algorithm for the human RefSeq database. Another perl script was used to register sRNAs according to the predicted specificity. Finally, those sRNAs were manually selected that meet the specificity criterion. The influenza A sequences of interest available on June 24, 2005, were downloaded from the NCBI influenza virus database available on the website of the National Center for Biotechnology Information. The number of sequences per gene is shown by MP, NP3 PBl, PB2, and PA in Table 4, the corresponding access numbers are given in Table 4. Table 4: Number of gene sequences for influenza genes MP, NP PBl, PB2, and PA of various viral subtypes that were used in the selection of the sARNi sequences in silica The ClustalW multiple alignment feature (Thompson, JD, et al., Nucleic Acids Res. 1994; 22: 4673) of the sequence alignment editor BioEdit was used to generate a global alignment of all the sequences using the predetermined parameters for each objective. , respectively. A numerical summary result of the positional nucleotide was generated by providing the information based on the distribution in each position in relation to the consensus sequence calculated for each objective. The cutoff criteria for the identification of candidate target regions of 19 nucleotides in length are defined as: Criterion 1, target coverage: at least 80% of all sequences available for the respective influenza A gene are needed to be represented in a candidate region. Criterion 2, objective efficiency: at least 80% of all sequences in which the candidate region was represented are needed to be identical within the candidate region. Criterion 1 was defined in order to avoid the regions for which little sequence information was available, criterion 2 ensures the direction of a high number of subtypes. A perl script was used to detach the numerical summary file from the position nucleotide by exclusion to identify the candidate target regions with a length of 19 aligned bases, the cutoff criterion and to generate a file to be used as a fastA input in the next Analysis stage. For a script entry the total number of sequences was entered for each of the objectives and a value of 80% conservation. All the candidate sense sARNi sequences corresponding to the most frequent sequences in the candidate target regions were extracted and saved in a fastA format file. In order to consider the potential dTdT potential interactions of the sRNAs with the target sequence, all sequences extend at the 5 'end with the PAA' resulting in 21mer input sequences. An additional file was generated for each candidate target region with the information in the properties of the region: targeted targeting efficiency (present sequences), total number of non-aligned, number of conserved sequences, and number of sequences present. For further selection, candidate sARNi were classified according to their predicted potential to interact with the host genes (presently, without limitation, humans) (potential targets). SRNAs with low target potential were assumed to be more specific in vivo. To predict the specific target potential of sRNA, the following hypotheses were made: 1) positions 2 through 9 (counting 5 'to 3') of one strand (seed region) contribute more to the target cut potential than the remaining sequence (without seed region) (Haley, B., and Zamore, PD, Nat Struct Mol Biol. 2004, 11: 599). 2) A record of the cut target can be calculated for each hit, based on the identity for the sARNi sequence and the non-aligned position. 3) by introducing modifications of appropriate nucleotides in the sense strand (for example, all nucleotides comprising a primidine base are nucleotides modified by 2'-O-methyl), the sense strand can be inactivated towards RNA interference; therefore, only the target cut potential of the antisense strand needs to be considered. To identify the potential of the target cut genes, the 21mer sequences corresponding to the candidate target regions plus a 3 'terminal AA end (for the count for the TT coatings) were subjected to a homology search against the mRNA sequences humanly available. For this purpose, fastA searches (version 3.4) were carried out with all the 21mer input sequences against a human RefSeq database (available version downloaded from ftp://ftp.ncbi.nih.gov/refseq/ on 25 -07-2005). The fastA search was executed with parameters of even values b30-g30 in order to take into account the homology on the full length of the 21mer. The search results in a list of potential cutting targets for sARNi candidates. To classify the resulting list of potential cut objectives, the fatsA output files were analyzed to identify the host gene with the highest cut target record. The following cut-off target properties for each 21mer input sequence were extracted for each potential cut-off target to calculate the target cutoff record: 1. The number of identical nucleotides for the 21mer sequence (Identity). 2. Number of non-aligned in the seed region. The objective cutoff record was calculated by considering assumptions 1 and 2 as follows: Identity - 0.2 * number of seed non-alignments. All sARNi were ordered according to their highest cut (ascending) target record. A target cut register of 16.8 was used as a cut-off for the sRNA selection. The 42 sRNAs specific for the influenza A (MP) matrix protein, 3 sRNAs specific for the nucleocapsid protein of influenza A (NP), and 1 sARNi specific for the protein 1 polymerase of influenza A (PBl) have records cutting targets ao below this threshold. Given the comparatively low number of candidate sARNi resulting from the selection procedure above, the positional nucleotide numerical summary was re-examined with cut for criterion 1 (target coverage) set at 70% and criterion 2 (objective specificity) maintained at 80%, followed by an interval placement of the repeated cut objective record as described above. 2 additional specific siDNs for influenza A MP mRNA with an objective efficiency of 79.9% were additionally selected, for a total of 48 sARNi candidates. The sequences of these 48 candidate sRNAs are shown in Table IA. Because the selection processes described above result only in a limited number of candidate agents, the selection criteria were sometimes relaxed to provide additional candidate agents. Specifically, criterion 1 above, relaxed to 50% of the target coverage, criterion 2, objective effectiveness, remains at 80% and the selection process above was repeated. This procedure provides the additional agents AL-DP-8001 to AL-DP-8040, listed in Table 1C. In this process, the objective cut-off registration stage was carried out that leads to the greatest wear ratio in the potential agents. In order to obtain even more candidate agents, the selection process was repeated once again, using criterion 1 up to 80% of the target coverage, criteria 2 to 80% of the objective efficacy and the target cut record was omitted. This procedure provides the additional agents listed in the ID table. Still additional candidate agents, listed in Table 1E, were obtained by repeating the selection one more time using criterion 1 up to 50% of the target coverage, criteria 2 to 80% objective efficacy, and omitting the target registration of cut . Additional candidate RNAi agents were identified by allowing the incorporation of the universal bases. A perl script was used to first identify the candidate sequences that have the target coverage and the 100% objective efficacy when incorporating up to 3 universal bases in the seedless region (corresponding to positions 2-9 of the antisense strand) of the RNAi agent per strand. Table 1F shows the agents identified in this way. In a second round, additional RNAi agents are identified that have the objective coverage and 80% objective efficacy when the incorporation of a universal base is allowed. These RNAi agents are shown in Table 1G.

Example 2: sRNA synthesis Synthesis of nucleotides comprising natural bases Single-stranded RNAs were produced by solid phase synthesis on a 1 μmol scale using an Expedite 8909 synthesizer (Applied Biosystems, Applera Deutschland GmbH, Darmstadt, Germany) and controlled pore glass (CPG, 50TA, Glen Research, Sterling VA) as a solid support. The RNA and RNA containing the 2'-O-methyl nucleotides were generated by the solid phase synthesis using the corresponding phosphoramidates and 2'-0-methyl phosphoramidates, respectively (Proligo Biochemie GmbH, Hamburg, Germany). These building blocks were incorporated at selected sites within the sequence of the oligoribonucleotide chain using standard nucleoside phosphoramidate chemistry as described in Current protocols in nucleic acid chemistry, Beaucage, S.L. et al. (Edrs.), John Wiley & Sons, Inc., New York, NY, USA. Phosphorothioate ligatures are introduced by replacing the iodine oxidation solution with a Beaucage reagent solution (Chruachem Ltd, Glasgow, UK) in acetonitrile (1%). Additional auxiliary reagents were obtained from Mallinckrodt Baker (Griesheim, Germany). The deprotection and purification by HPLC of anion exchange of the crude oligonucleotides were carried out according to established procedures. The yields and concentrations were determined by the UV absorption of a solution of the respective RNA at a wavelength of 260 nm using a spectral photometer (DU 640B, Beckman Coulter GmbH, UnterschleiBheim, Germany). The double-stranded RNA was generated by mixing an equimolar solution of the complementary strands in the buffered buffer solution (20 mM sodium phosphate, pH 6.8, 100 mM sodium chloride), heated in a water bath at 85-90 ° C. for 3 minutes and cooled to room temperature for a period of 3-4 hours. The purified RNA solution was stored at -20 ° C until used. As a result of the synthesis strategy described above, all oligonucleotides synthesized as described above do not comprise a phosphate group at its nucleotide plus 5 '.

The synthesis of nucleotides comprises universal bases. Synthesis of phosphoramidate and controlled pore crystal support of 5 '-0- (4,' -dimethoxytrityl) -2 '-0- (tert-butyldimethylsilyl) -1' - (5-nitroindole) -D-riboside Step A: 1-O-Methyl-D-riboside (102). To a solution of D-ribose (25g) in dry methanol (300mL) was added concentrated sulfuric acid (1.88mL) and stirred at room temperature for 3 days. The reaction mixture was then neutralized with IN sodium hydroxide solution and concentrated to a crude residue. The crude residue was dissolved in methanol (200 mL) and the solids filtered completely. The filtrate was concentrated to a crude residue, which was applied to a column of silica gel eluting with dichloromethane-methanol (5: 1) to give a pure compound (23. Og, 82%) as a syrup.

Step B: l-O-Methyl-2, 3, 5-tri-0- (2,4-dichlorobenzyl) -D-riboside (103). To a solution of 1-O-methyl-D-riboside (13.43g, 81.83mmol), 18-crown-6 (1.34g) in dry THF (100mL) was added powdered potassium hydroxide (69g, 1.23mol) and it was stirred at room temperature for 40 to 60 min. 2, 4-Dichlorobenzyl chloride (51mL, 368.2mmol) was added dropwise and the reaction mixture was stirred at the same temperature overnight. The solids were completely filtered and the filtrate was concentrated to a crude residue which was applied to a column of silica gel eluted with hexanes-ethyl acetate (4: 1) to give a pure compound (48g, 92%) as a solid white. XH-NMR (CDC13, 400 MHz): d 7.46-7.34 (m, 5 H, Ar H), 7.24-7.16 (m, 4 H, Ar H), 4.99 (s, 1 H 3 HI), 4.71 (dd, 2 H , Jgem = 12.8 Hz, OCH2Ar), 4.63-4.61 (m, 4 H, 2 OCH2Ar), 4.38-4.36 (m, 1 H), 4.19-4.16 (dd, 1 H), 3.98 (d, 1 H, J - 4.4 Hz), 3.75 (dd, 1 H, J = 3.6, 7 = 10.2 Hz, H-5a), 3.66 (dd, 1 H, J = 3.6, J = 10.4 Hz, H-5b), 3.37 (s , 3 H, OCH 3).

Step B: l-Bromo-2, 3, 5-tri- (9- (2,4-dichlorobenzyl) -D-ribose (104)) To a cold solution of 10-methyl-2, 3, 5-tri- O- (2,4-dichlorobenzyl) -D-riboside (3.22g, 5.02mmol) in dry dichloromethane (50mL) cooled with an ice bath was added HOAc-HBr (5.3mL, 30%) and stirred at 0 ° C. -25 ° C for 3 h The reaction mixture was concentrated in a crude residue which coevaporated with toluene (3x 30mL) in a crude residue which was dried under a good vacuum and used for the next reaction without purification and identification. like a syrup.

Step D: 1- (5-Nitroindol) -2, 3, 5-tri-O- (2,4-dichlorobenzyl) -D-riboside (105). To a solution of 5-nitroindole (2.44 g, 15.06 mmol) in dry CH3CN (30 mL) was added sodium hydride (602 mg, 15.06 mmol, 60%) and stirred at room temperature for 3-4 h under an argon atmosphere . The sugar donor obtained above (104) in dry CH3CN (10 mL) was added and stirred at the same temperature under an argon atmosphere overnight. The solids were completely filtered and the filtrate was concentrated in a crude residue which was applied to a column of silica gel eluted with hexanes-ethyl acetate (3: 1) to give a pure compound 105 (2.16g, 60%) as a mixture and ß (1: 1) • Steps E, F: 5 '-O- (4,4'-dimethoxytrityl) -1' - (5-nitroindole) -D-riboside (106) and (107) To a cold solution of 1- (5-nitroindole) -2, 3, 5-tri-O- (2,4-dichlorobenzyl) -D-riboside 105 (1.16g, 1.51 mmol) in dry dichloromethane (100 mL) at -78 ° C was added BC13 in dichloromethane (23mL, 1.0M) and stirred at the same temperature for 2 h under an argon atmosphere and at -40 ° C for 2 h. The reaction mixture was quenched with methanol-dichloromethane (1: 1, 50mL) and neutralized with ammonium-methanol solution. The solids were completely filtered and the filtrate was concentrated in a crude residue which was applied to a column of silica gel eluted with dichloromethane-methanol (10: 1) to give a pure compound (300mg, 68%) as a mixture to ß (1: 1). To a solution of the compound obtained above (840mg, 2.86mmol) in dry pyridine (3-4ml) and DMAP (90mg) was added DMTrCl (1.06g) and stirred at room temperature under an argon atmosphere overnight. The reaction mixture was concentrated to a crude residue which was applied to a column of silica gel eluting with hexanes-ethyl acetate (1: 1) to give a pure compound 106 (550mg) and compound 107 (190mg), a mixture of compound 106 and 107 (360mg).

Compound 106: XH-NMR (CDC13, 2D g-COZY and 2D NOESY, 400 MHz): d 8.49 (d, 1 H, J = 1.6 Hz), 8.35 (d, 1 H), 8.03 (dd, 1 H, J = 2.0, J = 9.0 Hz), 7.70-7.69 (m, 2 H), 7.47-7.14 (m, 8 H, Ar H), 6.86-6.81 (m, 5 H, Ar H), 6.71 (d, 1 H , J = 3.6 Hz), 6.41 (d, J = 5.2 Hz, H '-1), 4.73 (t, 1 H, J = 4.8 Hz, H'-2), 4.46-4.42 (m, 3H, H' -3, H'-4, H'-5), 3.79 (s, 6 H, 20CH3), 3.51 (dd, 1 H, J = 3.2, J = 10.4 Hz, H '-5a), 3.26 (dd, 1 H, J = 3.2, J = 10.6 Hz, H '-5b). Compound 107: XH-NMR (CDC13, 2D g-COZY and 2D NOESY, 400 MHz): d 8.55 (d, 1 H, J = 2.0 Hz), 7.98 (dd, 1 H, J = 2.4, J = 9.2 Hz ), 7.60 (d, 1 H, J = 9.2 Hz), 7.53 (d, 1 H, J = 3.2 Hz), 7.44-7.42 (m, 2 H), 7.34-7.24 (m, 7 H, ArH), 6.84-6.81 (m, 4 H, ArH), 6.68 (d, 1 H, J = 3.2 Hz), 6.00 (d, 1 H, J = 5.2 Hz, H'-l), 4.53 (t, 1 H, J = 7.6 Hz), 4.46-4.44 (m, 1 H), 4.23-4.20 (m, 1 H), 3.80-3.76 (m, 7 H, 20CH3, H'-5), 3.55 (dd, 1 H, H'-5a), 3.43 (dd, 1 H, H '-5b).

Step G: 5 '-O- (4,4' -dimethoxytrityl) -2 '-O- (tert-butyldimethylsilyl) -l' - (5-nitroindol) -D-riboside (108) and 5 '-O- ( 4,4'-dimethoxytrityl) -3 '-O- (tert-butyldimethylsilyl) -1' - (5-nitroindole) -D-riboside (109) To a solution of 5'-O- (4, '-dimethoxytrityl) -1 '- (5-nitroindol) -D-riboside (106) (550mg, 0.92mmol), AgN03 (188mg, 1104mmol), and pyridine (0.74mL, 9.2mmol) in dry THF (9.2 mL) was added. TBDMSC1 (188mg, 1196mmol) and stirred at room temperature under an argon atmosphere overnight. The solids were completely filtered and the filtrate was concentrated to a crude residue which was applied to a column of silica gel eluting with hexanes-ethyl acetate (4: 1) to give a pure compound 108 (230 mg, 35%), compound 109 (150mg, 23%), and a mixture of compound 108 and 109 (11Omg, 17%) in total yield of 75%. Compound 108: XH-NMR (CDC13, 2D g-COZY, 2D NOESY, 400 MHz): d 8.56 (d, 1 H, J = 2.4 Hz), 7.88 (dd, 1 H, J = 2.4, J = 8.8 Hz ), 7.62 (d, 1 H, J = 9.2 Hz), 7.54 (d, 1 H, J = 3.6 Hz), 7.46-7.44 (m, 2 H), 7.36-7.25 (m, 6 H, ArH), 6.85-6.83 (d, 5 H, ArH), 6.69 (d, 1 H, J = 3.6 Hz), 5.94 (d, 1 H, J = 7.2 Hz, H '-l), 4.69 (dd, 1 H, H '-2), 4.31-4.29 (m, 2 H, H' -3, H '-4), 3.80 (s, 6 H, 20CH3), 3.58 (dd, 1 H, J = 2.0, J = 10.6 Hz, H '-5a), 3.40 (dd, 1 H, J = 2.0, J = 10.4 Hz, H' -5b), 2.85 (d, 1 H, J = 0.8 Hz, 3 '-0H), 0.78 ( s, 9 H, t-Bu), -.016 (s, 3 H, SÍCH3), - 0.43 (s, 3 H, SÍCH3). Compound 109: XH-NMR (CDC13, 2D g-COZY, 2D NOESY, 400 MHz): d 8.61 (d, 1 H, J = 2.4 Hz), 8.05 (dd, 1 H, J = 2.0, J = 8.8 Hz), 7.69-7.65 (m, 2 H), 7.47-7.45 (m , 2 H, Ar H), 7.36-7.27 (m, 5 H, Ar H), 6.86-6.83 (m, 3 H, Ar H), 6.71 (d, 1 H, J = 3.2 Hz), 5.99 (d, 1 H , J = 4.8 Hz, H '-l), 4.51 (t, 1 H, J = 4.8 Hz, J = 5.6 Hz, H' -3), 4.40-4.36 (m, 1 H, H '-2), 4.17-4.15 (m, 2 H, H '-4, H' -5), 3.82 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 3.63 (dd, 1 H, J = 2.4 , J = 11.0 Hz, H'-5a), 3.31 (dd, 1 H, J = 2.8, J = 11.0 Hz, H'-5b), 2.95 (d, 1 H, J = 6.0 Hz, 2'-OH ), 0.91 (s, 9H, t-Bu), 0.05 (s, 3 H, SiCH3), 0.00 (s, 3 H, SiCH3).

Step H: 5 '-O- (4,4' -dimethoxytrityl) -2 '-O- (tert-butyldimethylsilyl) -1' - (5-nitroindol) -D-riboside-3 '-0-cainoethyl-N, N-diisopropylphosphoramidate (UO) 2-Cyanoethyl-N, N-diisopropylchlorophosphoramidite (153 mg, 0.646 mmol) was added to a solution of 5'-0- (4,4'-dimethoxytrityl) -3'-0- (tert- butyldimethylsilyl) -1- (5-nitroindol) -D-β-riboside 108 (230 mg, 0.323 mmol), diisopropylethylamine (306uL, 1.78 mmol) and DMAP (10 mg) in dry dichloromethane (3 mL) and stirred at room temperature for 4-6 h under an argon atmosphere. The reaction mixture was concentrated to a crude residue which was applied to a column of silica gel which was saturated with 2% triethylamine in hexanes and eluted with hexanes-ethyl acetate (2: 1) to give a pure title 110 (250mg, 85%) as an amorphous solid. 31P-NMR (CDC13, 400MHz): 149.54 (s), 146.57 (s). Analysis calculated for C5oH65N4OgPSi: 924.43. Found: 947.43 [M + Na] +.

Step I: Solid supports of 2 '-hydroxyl or 3' -hydroxyl of 5 '-O- (4,4'-dimethoxytrityl) -1- (5-nitroindole) -D-riboside (111).

Succinic anhydride was added to a solution of a mixture of 2 '-OTBDMS (108) or 3'-0-TBDMS of 5' -0- (4, '-Dimethoxytrityl) -1- (5-nitroindole) -D-β -riboside (109), and DMAP in dry dichloromethane. The reaction mixture was stirred at room temperature under an argon atmosphere for 6 h. Another portion of anhydrous succinic and DMAP were added and stirred for a total of 16 h. The mixture was concentrated to a crude residue which was dissolved in ethyl acetate (50 ml), washed with citric acid (400 mg / 20 ml), brine, and dried (Na 2 SO). The organic layer was concentrated to a crude nucleoside succinate which was used directly for the next reaction without further purification. The nucleoside succinate, DMAP, DTNP, and Ph3P were stirred at room temperature for 20 min [Nucleoside and nucleotides, 1996, 15 (4), 879-888.]. Then lcaa-CPG is added and stirred at the same temperature for 45 min. The solids are completely filtered and washed with CH 3 CN, dichloromethane, and ether. The solid supports were dried, covered under standard procedure, and washed to give a solid support. The controlled glass support comprising nitroindol and phosphoramidate thus obtained is used in the synthesis of standard oligonucleotide as described above by the oligonucleotides comprising natural bases.

Example 3: sRNA test in vitro The ability of RNAi agents to inhibit replication of influenza virus was tested on human cell lines in vitro, or tested in mice in vivo. The RNAi agent is transfected into the cells, for example, by transfection or electrophoresis, allowing it to act on the cells for a certain time, for example, 24 hours, and the levels of infectivity were determined by plaque formation or ELISA assay. By complementing these targeted assays, the inhibition of target gene expression was tested by the RNAi agents for several influenza genes recombinantly expressed in host cells of mammals.

Virus and cell lines Influenza virus A / PR / 8/34 (PR8), subtype H1N1, was obtained from Charles River Laboratories (ATCC # VR-1469). The A / WSN / 33 (WSN), subtype H1N1, can be obtained from Thomas Chambers, University of Kentucky, Lexington, KY. USA (see Castrucci, M.R., et al., J. Virol. 1992, 66: 4647), or Dr. Peter Palese, Mount Sinai School of Medicine, New York City, NY, USA (see WO 04/028471). Virus stocks were propagated in the allantoic cavity of the embryonated chicken eggs at 34 ° C for 48-72 h (PR8) or 37 ° C for 24 h (WSN) (Tompkins, SM, et al., Proc. Nati. Acad. Sci. 2004, 101: 8682). MDCK cells were obtained from American Type Culture Collection (ATCC, Rockville MD, USA; ATCC # CCL-34) and were grown in MEM containing 8% heat inactivated fetal bovine serum (FBS), 2 mM L-glutamine, 1 M sodium pyruvate, 1.5 g / L sodium bicarbonate and amino acids non-essential at 37 ° C under an atmosphere of 5% C02 / 95% air. Vero E6 African green monkey kidney epithelial cells were obtained from ATCC (Rockville MD, USA, ATCC # CRL-1586) and grown in a DMEM supplemented with 4.5 g / 1 D-Glucose, 2 mM L-Glutamine, 110 mg / 1 sodium pyruvate, 10% fetal bovine serum (Hyclone, Cat # 30070.03) and 0.1% Penicillin / Streptomycin at 37 ° C under an atmosphere 5% C02 / 95% air. Cos-7 African green monkey kidney cells were obtained from the German collection of microorganisms and cell cultures (DSMZ, Braunschweig, Germany, DSMZ # ACC 60) and grown in Dulbecco MEM, 10% fetal calf serum, 2 mM L-glutamine, 1.2 μg / ml sodium bicarbonate, 100 μg penicillin / 100 μg / ml streptomycin (Biochrom AG, Berlin, Germany).

Example 3.1: Plaque forming assay Cell culture, transfection of sRNA, and virus infection MDCK cells were plated from 24 wells at 7.5 x 10 4 cells per well in 0.5 ml of growth medium one day before transfection. The MDCK cells were 80% confluent on the day of the sARNi transfection. Before transfection the cells are fed with 0.25 ml of growth medium.

Prior to the addition to the cells, 1.5 ml (50 μl per well) of Optimem I (Invitrogen) and 90 μl (3 μl per well) of Lipofectamine 2000 (Invitrogen), the amount sufficient for the transfection of a 24-well plate , were combined is a 2 ml Sarstedt tube and incubated for 10-15 minutes at room temperature. The appropriate amount of sRNA dissolved in the quenched buffer is then added to the Optimem / lipofectamine 2000 mixture to give the desired final concentration, mixed, and incubated an additional 15-25 minutes at room temperature. Next, 50 μl of the sARNi / reagent complex is added dropwise to each well as dictated by the experimental design. The plates were then shaken gently to ensure complete mixing and incubated at 37 ° C at 5% C02 / 95% air for 14 hours. Subsequently, the transfection medium was aspirated gently, the cells were washed once with 0.25-0.5 ml of PBS, and 100 μl of varying concentrations of PR8 in MEM medium was added to each well. After incubation at 37 ° C for 1-2 hours, 0.5 ml of the overlapping medium (MEM, 20 mM HEPES, 0.075% NaHCO3, 2mM glutamine, 0.6% agarose, 0.5 μg / ml TPCK-trypsin) were added, and plates were incubated for 48 hrs at 37 ° C in a 5% C02 / 95% air incubator. The plates were then fixed and immunostained by viral plates as described below.

Immunostaining and viral quantitation 48 hours after infection, the cells were fixed in neutral buffered 10% formalin for 45 minutes, and the wells were rinsed with PBS. The wells were then blocked with permeabilization buffer (1 x PBS, 2% FBS, 0.5% saponin, 0.1% sodium azide) for 15 minutes at room temperature, and 125 μl of a solution containing 0.5 μg / ml of antibody MAB8258B Biotinylated mouse anti-influenza A (Chemicon) was added. After incubation for 1 hr at room temperature, the wells were rinsed twice with PBS to remove unbound antibody and 125 μl of a solution of 1 μg / ml horseradish peroxidase (HRP) conjugated with streptavidin (Vector Laboratories) in PBS per well was added, plates were incubated for 45 min, and washed three times with PBS. 200 μl of the TMB substrate (Vector Laboratories # SK-4400) per well were added. Following the incubation for 5-10 minutes at room temperature in the dark, the colorimetric reaction was stopped with distilled water, the water was discarded and the plates were air-dried. The stained influenza plates were counted by an inverted light microscope at 4X magnification. The plaque forming activity was compared to cells transfected with Lipofectamine only (imitation model), and is expressed in terms of [(plaque forming activity in treated cells) / (plaque forming activity in imitation model cells)] x 100 =% remaining infectivity.

Example 3.2: ELISA assay: MDCK or Vero cells were plated in 96-well plates at 10 4 cells per well in 0.1 ml of growth medium one day before transfection. The cells were 80% confluent on the day of the sARNi transfection. Before transfection, the cells were fed with 44 μl of growth medium. 1.08 ml (9 μl per well) of Optimem I (Invitrogen) and 42 μl (0.35 μl per well) of Lipofectamine 2000 (Invitrogen), the amount sufficient for transfection of a 96-well plate, were combined in a Sarstedt tube. 2 ml and incubated for 10-15 minutes at room temperature. The appropriate amount of sRNA was dissolved in warm buffer solution then added to the Optimem / lipofectamine 2000 mixture to give the desired final concentration, 15-25 additional minutes were mixed and incubated at room temperature. Next, 10 μl of the sRNAi / reagent complex was added to each well as dictated by the experimental design. Plates were shaken gently to ensure complete mixing and then incubated at 37 ° C in a 5% C02 / 95% air incubator for 14 hours. Subsequently, the cells were washed once with PBS, infected with PR8 influenza virus in 50 μl of MEM per well, and incubated for 1-2 hours. Subsequently, the plates were raised once with PBS, and 200 μl of MEM with 0.25 / 0.5 μg / ml (MDCK / VERO, respectively) of trypsin were added. Two days after infection, the plates were fixed in 10% formalin buffer for 15 min. The cells were rinsed with PBS, blocked with blocking buffer for 15 minutes at room temperature, and 50 μl of a solution containing 0.5 μg / ml monoclonal antibody MAB8258B biotinylated anti-influenza A (Chemicon) per well were added. . The plates were incubated at room temperature for 1 hour, washed twice with PBS, and 50 μl per well of a solution containing 1 μg / ml streptavidin conjugated to AP (Vector Laboratories) in blocking buffer was added. After incubation for 45 min and 3X washing with PBS, 100 μl per well of the substrate solution pNPP was added. The plates were grown at room temperature in the dark and read at 405 nm.

Example 3.3: Inhibition of influenza target genes recombinantly expressed by sARNi: MP consensus sequences (SEQ ID NO: 1453), NP (SEQ ID NO: 1454), PA (SEQ ID NO: 1455), PBl (SEQ ID NO: 1456). and PB2 (SEQ ID NO: 1457) (see Table 5) were synthesized by GENEART (Regensburg, Germany) and cloned into the standard GENEART vectors. The MP and PA were subcloned into psiCheck-2 (Promega, Mannheim, Germany) via the AsiSI and Notl sites (both NEBn, Frankfurt, Germany), NP, (PBl) and PB2 via Xhol and Notl, resulting in a construct with the gene flu between the stop codon and the polyA signal of renilla luciferase. The correct cloning was confirmed by the final sequence processing carried out by GATC Biotech (Konstanz, Germany).

Transfections: Cos-7 cells were seeded at 1.5 x 10 4 cells / well in the 96 well white plates with clear bottom (Greiner Bio-One GmbH, Frickenhausen, Germany) in 75 μl of growth medium. Directly after seeding the cells, 50 ng of plasmid / well was transfected with Lipofectamine 2000 (Invitrogen) as described below for the sRNAs, with the plasmid diluted in Opti-MEM to a final volume of 12.5 μl / well, prepared as a master mix for the complete plate. The sRNA transfections were performed in quadruplicates 4 hours after transfection of the plasmid. For each well 0.5 μl Lipofectamine 2000 (Invitrogen GmbH, Karlsruhe, Germany) were mixed with 12 μl Opti-MEM (Invitrogen) and incubated for 15 minutes at room temperature. For a sRNA concentration of 50 nM in the transfection volume of 100 μl, 1 μl of a 5 μM sRNA was mixed with 11.5 μl Opti-MEM per well, combined with the Lipofectamine 2000-Opti-MEM mixture and again they were incubated for 15 minutes at room temperature. During the incubation, the growth medium was removed from the cells and replaced by 75 μl / well of fresh medium. The sARNi-Lipof ectamine 2000 complexes were completely applied (25 μl each per well) to the cells and the cells were incubated for 24 h at 37 ° C and 5% C02 in a humidified incubator (Heraeus GmbH, Hanau, Germany) . Cells were harvested by removal of the growth medium and application of 150 μl of a 1: 1 mixture consisting of the Dual-Glo luciferase medium and substrate, from the Dual-Glo luciferase assay system (Promega, Mannheim, Germany). ). The luciferase assay was performed according to the manufacturer's protocol for the Dual-Glo luciferase assay and the luminescence was measured on a Victor-Light 1420 luminescence counter (Perkin Elmer, Rodgau-Jugesheim, Germany). The values obtained with Renilla luciferase were normalized to the respective values obtained with firefly luciferase. The values acquired with sARNi directed against an influenza gene were normalized to the value obtained with a nonspecific sRNA (directed against the neomycin resistance gene) established at 100%. The sRNAs effective for the selection were further characterized by the dose response curves. Transfections of the dose response curves were performed at the following concentrations of sRNAs according to the protocol above: 100 nM, 25 nM, 6.3 nM, 1.6 nM, 400 pM, 100 pM, 24 pM, 6 pM, 1.5 pM 380 fM. The IC50 values were determined by placing the curve alignment in parameters using the XLfit program.

Table 5: Virtual consensus sequences for the influenza genes MP (SEQ ID NO: 1453), NP (SEQ ID NO: 1454), PA (SEQ ID NO: 1455), PBl (SEQ ID NO: 1456) and PB2 ( SEQ ID NO: 1457) for cloning in Cos-7 cells. P: virtual consensus derived from gi | 13383290 | gb | AB049165 | influenza A virus (A / parakeet / chiba / 1/97 (H9N2)) M1 genes, M2 for the membrane ion channel, matrix protein, complete cds. ATGAGTCTTC TAACCGAGGT CGAAACGTAC GTTCTCTCTA TCATCCCGTC AGGCCCCCTC 60 AAAGCCGAGA TCGCGCAGAG ACTTGAAGAT GTCTTTGCAG AGAAGAACAC AGATCTCGAG 120 GCTCTCATGG AATGGCTAAA GACAAGACCA ATCCTGTCAC CTCTGACTAA GGGGATTTTA 180 GGGTTTGTGT TCACGCTCAC CGTGCCCAGT GAGCGAGGAC TGCAGCGTAG ACGCTTTGTC 240 CAGAATGCCC TAAATGGGAA TGGAGACCCA AACAACATGG ACAGGGCAGT TAAACTATAC 300 AAGAAGCTGA AGAGGGAAAT AACATTCCAT GGGGCTAAGG AAGTTGCACT CAGTTACTCT 360 GCTGGTGCAC TTGCCAGTTG CATGGGTCTC ATATACAACC GGATGGGAAC AGTGACCACA 420 GAAGTGGCTC TTGGCCTAGT GTGTGCCACT TGTGAGCAGA TTGCAGATTC ACAACATCGO 480 TCCCACAGGC AGATGGCGAC TACCACCAAC CCACTAATCA GACATGAGAA CAGAATGGTG 540 CTGGCCAGCA CTACAGCTAA GGCTATGGAG CAGATGGCTG GATCAAGTGA GCAGGCAGCG 600 GAAGCCATGG AAGTCGCAAG TCAGGC AGG CAGATGGTGC AGGCAATGAG GACAATTGGG 660 ACTCATCCTA GCTCCAGTGC AGGTCTAAAA GATAATCTTC TTGAAAATTT GCAGGCCTAC 720 CAGAAACGAA TGGGGGTGCA GATGCAGCGA TTCAAGTGAT CCTCTCGTTG TTGCAGCAAO 780 TATCATTGGG ATCTTGCACT TGATATTGTG GATTCTTGAT CGTCTTTTCT TCAAATGCAT 840 TTATCGTCGC CTTAAATACG GTTTGAAAAG AGGGCCTTCT ACGGAAGGAG TACCTGAGTC 900 TATGAGGGAA GAGTATCGAC AGGAACAGCA GAGTGCTGT G GATGTTGACG ATGGTCATTT 960 TGTCAACATA GAGCTGGAGT AA 982 SEQ ID NO: 1453 NP: virtual consensus derived from H5N1 gi 114326108 | AP370122 | influenza A virus (A / goose / Guangdong / 3/97 (H5N1)) nucleoprotein gene, complete cds. CTCACTGAGT GACATCAAAA TCATGGCGTC TCAAGGCACC AAACGATCTT ATGAACAGAT 60 GGAAACTGGT GGAGAACGCC AGAATGCTAC TGAGATCAGA GCATCTGTTG GAAGAATGGT 120 TGGTGGAGTT GGGAGGTTTT ATATACAGAT GTGCACTGA ^ CTCAAACTCA GCGACTATGA 180 AGGAAGGCTG ATTCAGAACA GCATAACAAT AGAGAGAATG GTTGTCTCTG CATTTGATGA 2 0 AAGGAGGAAC AAATACCTGG AAGAACATCC CAGTGCGGGG AAGGACCCAA AGAAAACTGG 300 AGGTCCAATC TACCGAAGAA GAGACGGGAA ATGGGTGAGA GAGCTGATTC TGTATGACAA 360 AGAGGAGATC AGGAGAATTT GGCGTCAAGC GAACAATGGA GAAGATGCAA CTGCTGGTCT 420 CACTCACCTG ATGATCTGGC ATTCCAATCT AAATGATGCC ACATACCAGA GAACAAGAGC 480 TCTCGTGCGT ACTGGGATGG ACCCTAGAAT GTGCTCTCTG ATGCAAGGAT CAACTCTCCC 540 GAGGAGATCT GGAGCTGCTG GTGCGGCAGT AAAGGGAGTC GGAACTATGG TGATGGAACT 600 AATTCGGATG ATAAAGCGAG GGATTAACGA TCGGAATTTC TGGAGAGGTG AAAATGGGCG 660 AAGAACAAGG ATTGCATATG AGAGAATGTG CAACATTCTC AAAGGGAAAT TCCAAACAGC 720 AGCACAAAGA GCAATGATGG ATCAGGTACG GGAAAGCAGA AATCCTGGGA ATGCTGAGAT 780 CGAAGATCTC ATATT CTGG CACGGTCTGC ACTCATCCTG AGAGGATCAG TGGCCCACAA 840 GTCCTGCTTG CCTGCTTGTG TGTACGGGCT TGCCGTGGCC AGTGGATATG ACTTTGAGAG 900 AGAAGGGTAC TCTCTGGTCG GGATTGATCC TTTCCGTCTG CTGCAAA? VCA GCCAGGTCTT 950 TAGTCTAATT AGACCAAATG AGAATCCAGC ACATAAAAGT CAATTGGTGT GGATGGCATG 1020 CCATTCTGCA GCATTTGAAG ATCTGAGAGT CTCAAGCTTC ATCAGAGGGA CAAGAGTGGC 1080 CCCAAGGGGA CAACTATCTA CTAGAGGAGT ACAAATTGCT TCAAATGAGA ACATGGAAAC 1140 AATGGACTCC AGCACTCTTG AACTGAGAAG CAGATATTGG GCTATAAGGA CCAGGAGTGG 1200 AGGAAACACC AAC CAGCAGA GAGCATCTGC AGGACAAATC AGTGTGCAGC CTACTTTCTC 1260 GGTACAGAGA AATCTTCCCT TCGAAAGAGC GACCATTATG GCGGCATTCA CAGGGAATAC 1320 AGAGGGCAGA ACATCTGACA TGAGGACTGA AATCATAAGG ATGATGGAAA GCTCCAGACC 1380 AGAAGATGTG TCTTTCCAGG GGCGGGGAGT CTTCGAGCTC TCGGACGAAA AGGCAACGAA 1440 CCCGATCGTG CCTTCCTTTG ACATGAGTAA TGAAGGATCT TATTTCTTCG GAGACAATGC 1500 AGAGGAGTAT GACAATTGAA G 1521 SEQ ID NO: 1454 PA: virtual consensus denvado of H5Nlgi 1471565001 AY585473 | influenza A virus (A / duck / Guangxi / 35/2001 (H5N1)) polymerase mRNA (PA), complete cds.

ATGGAAGACT TTGTGCGACA ATGCTTCAAT CCAATGATTG TCGAGCTTGC GGAAAAGGCA 60 ATGAAAGAAT ATGGGGAAGA TCCGAAAATC GAAACGAACA AATTTGCAGC AATATGCACA 120 CACTTAGAAG TCTGTTTCAT GTATTCAGAT TTTCACTTTA TTGATGAACG GGGCGAATCA 180 ATAATTGTAG AATCTGGCGA TCCGAATGCA TTATTGAAAC ACCGATTTGA AATAATTGAA 240 GGAAGAGACC GAACAATGGC CTGGACAGTG GTGAATAGTA TCTGCAACAC CACAGGAGTT 300 GAGAAACCTA AATTTCTCCC AGATTTGTAT GACTACAAAG AGAACCGATT CATTGAAATT 360 GGAGTGACAC GGAGGGAAGT TCATATATAC TATCTAGAGA AAGCCAACAA GATAAAATCC 420 GAGAAGACAC ACATTCACAT ATTCTCATTC ACTGGGGAGG AAATGGCCAC CAAAGCGGAC 480 TACACCCTTG ATGAAGAGAG CAGGGCAAGA ATCAAAACCA GGCTGTTCAC CATAAGGCAG 5 0 GAAATGGCCA GTAGGGGTCT ATGGGATTCC TTTCGTCAGT CCGAGAGAGG CGAAGAGACA 600 ATTGAAGAAA GATTTGAAAT CACAGGAACC ATGCGCAGGC TTGCCGACCA AAGTCTCCCA 660 CCGAACTTCT CCAGCCTTGA AAACTTTAGA GCCTATGTGG ATGGATTCGA ACCGAACGGC 720 TGCATTGAGG GCAAGCTTTC TCAAATGTCA AAAGAAGTGA ACGCCAGAAT TGAGCCATTT 780 CTGAAGACAA CACCACGCCC TCTCAGATTA CCTGATGGGC CTCCCTGCTC TCAGCGGTCG 840 AAGTTCTTGC TGATGGATGC CCTTAAATTA AGCATCGAAG ACCCGAGTCA TGAGGGGGAG 900 GGGATACCGC TATATGATGC AATCAAATGC ATGAAAACAT TTTTCGGCTG GAAAGAGCCC 960 AACATCGTAA AACCACATGA AAAAGGCATA AACCCCAATT ACCTCCTGGC TTGGAAGCAA 1020 GTGCTGGCAG AACTCCAAGA TATTGAAAAT GAGGAGAAAA TCCCAAAAAC AAAGAACATG 1080 AAGAAAACAA GCCAATTGAA GTGGGCACTC GGTGAGAACA TGGCACCAGA GAAAGTAGAC 1140 TTTGAGGATT GCAAAGATGT TAGCGATCTA AGACAGTATG ACAGTGATGA ACCAGAGCCT 1200 AGATCACTAG CAAGCTGGAT CCAGAGTGAA TTCAACAAGG CATGTGAATT GACAGATTCG 1260 AGTTGGATTG AACTTGATGA AATAGGGGAA GACGTTGCTC CAATTGAGCA CATTGCAAGT 1320 ATGAGAAGGA ACTATTTCAC AGCGGAAGTA TCCCATTGCA GGGCCACTGA ATACAT TG 1380 AAGGGGGTGT ACATAAACAC AGCTCTGTTG AATGCATCCT GTGCAGCCAT GGATGACTTT 1440 CMCTGATTC CAATGAT G CAAATGCAGA ACCAAAGAAG GAAGACGGAA AACTAACCTG 1500 TATGGATTCA TTATAAAAGG AAGATCCCAT TTGAGGAATG ATACCGATGT GGTAAACTTT 1560 GTGAGTATGG AATTCTCTCT TACTGACCCG AGGCTGGAGC CACACAAGTG GGAAAAGTAC 1620 TGTGTTCTCG AGATAGGAGA CATGCTCCTA CGGACTGCAA TAGGCCAAGT TTCAAGGCCC 1680 ATGTTCCTGT ATGTGAGAAC CAATGGAACC TCCAAGATCA AAATGAAATG GGGAATGGAG 1740 ATGAGGCGAT GCCTTCTTCA ATCCCTTCAA CAGATTGAGA GCATGATTGA GGCCGAGTCT 1800AGAAAGACAT GACCAAAGAA TTCTTTGAAA ACAAATCAGA AACATGGCCA 1860 ATTGGAGAGT CACCCAAAGG AGTGGAGGAA GGCTCCATCG GGAAGGTGTG CAGAACCTTA 1920 CTGGCGAAAT CTGTGTTCAA CAGTCTATAT GCATCTCCAC AACTCGAGGG GTTTTCAGCT 1980 GAATCAAGAA AATTGCTTCT CATTGTTCAG GCACTTAGGG ACAACCTGGA ACCTGGGACC 2040 TTCGATCTTG GAGGGCTATA TGAAGCAATT GAGGAGTGCC TGATTAATGA TCCCTGGGTT 2100 TTGCTTAATG CGTCTTGGTT CAACTCCTTC CTCACACATG CACTGAAATA GTT 2153 SEQ ID NO: 1455 PB1 virtual consensus derived from H5Nlgi | 58531084 | AB166860 | influenza A virus (A / chicken / Yamaguchi / 7/2004 (H5N1)) PB1 protein gene basic polymerase 1, complete cds ATGGATGTCA ATCCGACTTT ACTTTTCTTG AAAGTACCAG TGCAAAATGC TATAAGTACC 60 ACATTCCCTT ATACTGGAGA CCCTCCATAC AGCCATGGAA CAGGGACAGG ATACACCATG 120 GACACAGTCA ACAGAACACA CCAATATTCA GAAAAGGGGA AGTGGACAAC AAACACAGAG 180 ACTGGAGCAC CCCAACTCAA CCCGATTGAT GGACCACTAC CTGAGGATAA TGAGCCCTGT 240 GGGTATGCAC AAACAGATTG TGTATTGGAA GCAATGGCTT TCCTTGAAGA ATCCCACCCA 300 GGGATCTTTG AAAACTCGTG TCTTGAAACG ATGGAAATTG TTCAACAAAC AAGAGTGGAT 360 AAACTGACCC AAGGTCGCCA GACCTATGAC TGGACATTGA ATAGAAACCA ACCGGCTGCA 420 ACTGCTTTGG CCAACACTAT AGAAATCTTC AGATCGAACG GTCTAACAGC CAATGAATCG 480 GGACGGCTAA TAGATTTCCT CAAGGATGTG ATGGAATCAA TGGATAAGGA AGAAATGGAG 540 ATAACAACAC ATTTCCAGAG AAAGAGAAGA GTGAGGGACA ACATGACCAA GAAAATGGTC 600 ACACAAAGAA CAATAGGGAA GAAAAAACAA AGGCTGAACA AAAAGAGCTA CCTGATAAGA 660 GCACTGACAC TGAACACAAT GACAAAAGAT GCAGAAAGAG GCAAATTGAA GAGGCGAGCA 720 ATTGCAACAC CCGGAATGCA AATCAGAGGA T TCGTGTACT TTGTTGAAAC ACTAGCGAGG 780 AGTATCTGTG AGAAACTTGA GCAATCTGGA CTCCCAGTCG GAGGGAATGA GAAGAAGGCT 840 AAATTGGCAA ACGTCGTGAG GAAGATGATG ACTAACTCAC AAGATACTGA ACTCTCCTTT 900 ACAATTACTG GAGACAATAC CAAATGGAAT GAGAATCAGA ATCCTAGGAT GTTTCTGGCA 960 ATGATAACGT ACATCACAAG GAACCAGCCA GAATGGTTTC GGAATGTCTT AAGCATTGCC 1020 CCTATAATGT TCTCAAACAA AATGGCGAGA TTAGGAAAAG GATACATGTT CGAAAGTAAG 1080 AGCATGAAGT TACGAACACA AATACCAGCA GAAATGCTTG CAAACATTGA TCTCAAATAC 1140 TTCAATGAAT TAACGAAAAA GAAAATTGAG AAAATAAGAC CTCTATTAAT AGATGGTACA 1200 GCCTCATTGA GCCCTGGAAT GATGATGGGC ATGTTCAACA TGCTGAGTAC AGTCCTAGGA 1260 GTCTCAATCC TGAATCTTGG ACAGAAAAGG TACACCAAAA CCACATATTG GTGGGACGGA 1320 CTCCAATCCT CTGATGATTT CGCTCTCATC GTAAATGCAC CGAATCATGA GGGAATACAA 1380 GCAGGAGTGG ATAGGTTTTA TAGGACTTGT AAACTAGTTG GAATCAATAT GAGCAAGAAG 1440 AAGTCTTACA TAAATCGGAC AGGGACATTT GAATTCACGA GCTTTGTCT? CCGCTATGGA 1500 TTTGTAGCCA ATTTCAGTAT GGAGCTGCCC AGTTTTGGAG TGTCTGGAAT TAATGAATCG 1560 GCCGACATGA GCATTGGTGT TACAGTGATA AAGAACAATA TGATAAACAA CGACCTTGGG 1620 CCAGCAACAG CTCAGATGGC TCTTCAGCTA TTCATCAAGG ACTACAGATA CACATACCGA 1680 TGCCACAGAG GGGATACGCA AATCCAAACG AGGAGATCAT TCGAGCTGAA GAAGCTGTGG 1740 GAGCAAACCC GTTCAAAGGC AGGACTGTTG GTTTCAGATG GAGGACCAAA TCTATACAAT 1800 ATCCGAAATC TCCATATTCC TGAGGTCTGC TTAAAATGGG AATTGATGGA TGAAGATTAC 1860 CAGGGCAGAC TGTGTAATCC TCTGAATCCG TTCGTCAGCC ATAAGGAAAT TGAATCTGTC 1920 AACAATGCTG TAGTAATGCC AGCTCATGGC CCGGCCAAAA GCGTGGAATA TGATGCCGTT 1980 GCAACTACAC ATTCATGGAT TCCTAAAAGG AATCGTTCCA TTCTCAATAC GAGTCAAAGG 2040 GGAATTCTTG AGGATGAACA GATGTACCAG AAGTGCTGCA ATCTATTCGA GAAATTCTTC 2100 CCCAGCAGTT CATATCGGAG GCCAGTTGGA ATTTCCAGCA TGGTGGAGGC CATGGTGTCT 2160 AGGGCCCGAA TTGACGCACG AATTGATTTC GAGTCTGGAA GGATTAAGAA AGAAGAGTTT 2220 GCTGAGATCA TGAAGATCTG TTCCACCATT GAAGAGCTCA GACGGCAAAA ATAG_2274_SEQ ID NO: 1456 PB2 consensus virtual derivative of H5Nlgi 1 1969785 9 | AY059525 1 influenza A virus (A / duck / Hong Kong / 2986. 1/2000 (H5N1)) gene (PB2) polymerase segment 1 partial cds. ATGGAGAGAA TAAAAGAATT AAGAGATCTA ATGTCGCAGT CTCGCACTCG CGAGATACTA 60 ACAAAAACCA CTGTGGACCA TATGGCCATA ATCAAGAAAT ACACATCAGG AAGACAAGAG 120 AAGAACCCTG CTCTCAGAAT GAAATGGATG ATGGCAATGA AATATCCAAT CACAGCAGAC 180 AAGAGAATAA TAGAGATGAT TCCTGAAAGG AATGAACAAG GGCAGACGCT TTGGAGCAAG 240 ACAAATGATG CTGGATCGGA CAGGGTGATG GTGTCTCCCC TAGCTGTAAC TTGGTGGAAT 300 AGGAATGGGC CGACGACAAG TGCAGTCTAT TATCCAAAGG TTTACAAAAC ATACTTTGAG 360 AAGGTTGAAA GGTTAAAACA TGGAACCTTC GGTCCCGTTC ATTTCCGAAA CCAAATTAAA 420GAGTTGATAT AAATCCTGGC CATGCAGATC TCAATGCTAA AGAAGCACAA 480 GATGTCATCA TGGAGGTCGT TTTCCCAAAT GAAGTGGGAG CTAGAATATT GACATCAGAG 540 TCGCAATTGA CAATAACGAA AGAAAAGAAA GAAGAGCTCC AGGATTGTAA GATTGCTCCT 600 TTAATGGTTG CATACATGTT GGAAAGGGAA CTGGTCCGCA AAACCAGATT CCTACCGGTA 660 GCAGGCGGAA CAAGCAGTGT GTACATTGAG GTATTGCATT TGACTCAAGG GACCTGCTGG 720 GAACAGATGT ACACTCCAGG CGGAGAAGTG AGAAATGACG ATGTTATCCA GAGTATGATC 780 ATCGCTGCCA GAAACATTGT TAGGAGAGCA ACGGTATCAG CGGATCCACT GGCATCACTG 840 CTGGAGATGT GTCACAGCAC ACAAATTGGT GGGATA? GGA TGGTGGACAT CCTTAGGCAA 900 AATCCAACTG AGGAACAAGC TGTGGATATA TGCAAAGCAG CAATGGGTTT GAGGATCAGT 960 TCATCCTTTA GCTTTGGAGG CTTCACTTTC AAAAGAACAA GTGGAACATC CGTCAAGAAG 1020 GAAGAGGAAG TGCTTACAGG CAACCTCCAA ACATTGAAAA TAAGAGTACA TGAGGGGTAT 1080 GAGGAATTCA CAATGGTTGG GCGGAGGGCA ACAGCTATCC TGAGGAAAGC AACTAGAAGG 1140 CTGATTCAGT TGATAGTAAG TGGAAGAGAC GAACAATCAA TCGCTGAGGC AATCATTGTA 1200 GCAATGGTGT TCTCACAGGA GGATTGCATG ATAAAGGCAG TCCGAGGCGA TCTGAATTTC 1260 GTAAACAGAG CAAA CCAAAG ATTAAACCCC ATGCATCAAC TCCTGAGACA TTTTCAAAAG 1320 GATGCAAAAG TGCTATTTCA GAATTGGGGA ATTGAACCCA TTGATAATGT CATGGGGATG 1380 ATCGGAATAT TACCTGACAT GACTCCCAGC ACAGAAATGT CACTGAGAGG AGTAAGAGTT 1440 AGTAAAATGG GAGTGGATGA ATATTCCAGC ACTGAGAGAG TAGTTGTAAG TATTGACCGT 1500 TTCTTAAGGG TTCGAGATCA GCGGGGGAAC GTACTCTTAT CTCCCGAAGA GGTCAGCGAA 1560 ACACAGGGAA CAGAGAAATT GGCAATAACA TATTCATCAT CAATGATGTG GGAAATCAAC 1620 GGTCCTGAGT CAGTGCTTGT TAACACCTAT CAATGGATCA TCAGAAACTG GGAGACTGTG 1680 AAGATTCAAT GGTCTCAAGA CCCCACGATG CTGTACAATA AGATGGAGTT TGAACCGTTC 17 0 CAATCCTTGG TACCTAAAGC TGCCAGAGGT CAATACAGTG GATTTGTGAG AACACTATTC 1800 CAACAAATGC GTGACGTACT GGGGACATTT GATACTGTCC AGATAATAAA GCTGCTACCA 1860 TTTGCAGCAG CCCCACCGGA GCAGAGCAGA ATGCAGTTTT CTTCTCTA * IC TGTGAATGTG 1920 AGAGGCTCAG GAATGAGAAT ACTTGTAAGG GGCAATTCCC CTGTGTTCAA CTACAATAAG 1980 GCAACCAAAA GGCTTACCGT TCTTGGAAAG GACGCAGGTG CATTAACAGA GGATCCAGAT 2040 GAGGGAACAG CCGGAGTGGA ATCTGCAGTA CTGAGGGGAT TCCTAATTCT AGGCAAGGAG 2100 GACAAAAGAT ATGGACC AGC ATTGAGCATC AATGAACTGA GCAATCTTGC GAAAGGGGAG 2160 AAAGCTAATG TGCTGATAGG GCAAGGAGAC GTGGTGTTGG TAATGAAACG GAAACGGGAC 2220 TCTAGCATAC TTACTGACAG CCAGACAGCG ACCAAAAGAA TTCGGATGGC CATCAATTAG_2280_SEQ ID NO: 1457 Table IA, C, D and E lists the blunt identifier, the sequences of the sense and antisense strand, the objective genes of the agents, and the results of the above tests, where they were carried out, to select exemplary agents of the invention. Table IB and 1H lists the double identifier, the double identifier of the corresponding unmodified sequence, the sense and antisense strand sequences, and the target genes of the agents, to select exemplary agents carrying modified nucleic acid groups, with a view to of stabilizing these agents against degradation, in which all the pyrimidine bases comprise nucleotides comprising a 2'-O-methyl group in the sense strand, and all nucleotides comprising pyrimidine bases in a sequence-5 context. '-ca-3' or 5 '-ua-3' which comprises a T-0-methyl group in the antisense strand, except for those agents where the antisense strand does not comprise the nucleotides in a context of the sequence of 5'- ca-3 'or 5' -ua-3 ', in which all the uridines in a context of the sequence of 5'-ug-3' are nucleotides modified by 2'-O-methyl in the antisense strand (e.g. , AL-DP-2295, AL-DP-2301, and AL-DP-2302). Table 2 lists the concentrations at 50% of the calculated maximum inhibition of dose response determinations in Cos-7 cells engineered to express the influenza genes for some particularly preferred RNAi agents of the invention.

Table 6: Sequences used in the analysis of influenza A protein matrix (MP) AY180470 Influenza virus strain AA / Quail / Nanchang / 12-340 / 2000 (H1N1) matrix protein gene (M), cds partial AY633213 Influenza A virus (A / wild turkey / Alberta / 211/98 (H1N1)) matrix protein gene (M), complete cds. AY664487 Influenza A virus (A / wild turkey / Alberta / 119/98 (H1N1)) non-functional matrix protein mRNA, partial sequence. M55476 Gene protein matrix (Ml) type A influenza virus, complete cds and gene (M2) of M2 protein, complete cds. M55479 Gene of matrix protein (Ml) type A influenza virus, complete cds and Gen (M2) of M2 protein, complete cds. M55480 gene of matrix protein (Ml) type A of influenza virus, complete cds and gene (M2) of M2 protein, complete cds. M63528 Influenza A virus (A / turkey / Minnesota / 166/81 (H1N1)) protein Ml membrane and M2 protein membrane, complete cds. U49119 Gene (M) of the Ml and M2 proteins of influenza A virus matrix, complete cds.

K26859 M and M2 genes of type A influenza virus for matrix protein. Z26860 M and M2 genes of type A influenza virus for matrix protein. AY422021 Influenza A virus (A / duck / Hokkaido / 95/01 (H2N2)) matrix protein gene 1 (M), partial cds. M12699 Avian Influenza / Wild Turkey / NY / 6750/78 Ml and M2 protein encoding segment 7 of RNA, complete cds. AF213915 Influenza A virus (A / Chicken / Italy / 5945/95 (H3N2)) matrix protein gene (M) of segment 7, partial cds. AY180498 Strain of influenza A virus A / Chicken / Nanchang / 3-120 / 2001 (H3N2) protein matrix gene (M), partial cds. AY664458 Influenza A virus (A / sandbird / Delaware / 142/99 (H3N2)) non-functional matrix protein mRNA, partial sequence. AY769614 Influenza A virus (A / turkey / Ohio / 313053/04 (H3N2)) matrix protein gene, partial cds. AY779257 Influenza A virus (A / turkey / North Carolina / 12344/03 (H3N2)) matrix protein gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY779258 Influenza A virus (A / turkey / Minnesota / 764-2 / 03 (H3N2)) matrix protein gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds.

AY862623 Influenza A virus (A / chicken / Korea / S6 / 03 (H3N2)) matrix protein gene (M), complete cds. AY862624 Influenza A virus (A / duck / Korea / S7 / 03 (H3N2)) matrix protein gene (M), complete cds. AY862625 Influenza A virus (A / duck / Korea / S8 / 03 (H3N2)) matrix protein gene (M), complete cds. AY862626 Influenza A virus (A / duck / Korea / S9 / 03 (H3N2)) matrix protein gene (M), complete cds. AY862627 Influenza A virus (A / duck / Korea / S10 / 03 (H3N2)) matrix protein gene (M), complete cds. AY862628 Influenza A virus (A / pigeon / Korea / Sll / 03 (H3N2)) matrix protein gene (M), complete cds. Z26858 M and M2 genes of type A influenza virus for matrix protein. AB166865 Influenza A virus (A / chicken / Yamaguchi / 7/2004 (H5N1)) Ml and M2 genes for matrix protein and membrane ion channel, complete cds. AB188819 Influenza A virus (A / chicken / Oita / 8/2004 (H5N1)) M2 genes, Ml for the membrane ion channel 2, protein matrix 1, complete cds. AF509043 Influenza A virus (A / Chicken / Hong Kong / FY150 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509044 Influenza A virus (A / Pheasant / Hong Kong / FY155 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509045 Influenza A virus (A / Chicken silky / Hong Kong / SF189 / 01 (H5N1)) protein Ml gene (Ml), complete cds.

AF509046 Influenza A virus (A / Quail / Hong Kong / SF203 / 01 (H5N1)) Ml protein gene (Ml), complete cds.

AF509047 Influenza A virus (A / Pigeon / Hong Kong / SF215 / 01 (H5N1)) protein Ml gene (Ml), complete cds.

AF509048 Influenza A virus (A / Chicken / Hong Kong / SF219 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509049 Influenza A virus (A / Chicken / Hong Kong / 715.5 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509050 Influenza A virus (A / Chicken / Hong Kong / 751.1 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509051 Influenza A virus (A / Chicken / Hong Kong / 822.1 / 01 (H5N1)) Ml protein gene (Ml), complete cds. AF509052 Influenza A virus (A / Chicken / Hong Kong / 829.2 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509053 Influenza A virus (A / Chicken / Hong Kong / 830.2 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509054 Influenza A virus (A / Chicken / Hong Kong / 858.3 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509055 Influenza A virus (A / Chicken / Hong Kong / 866.3 / 01 (H5N1)) protein gene Ml (Ml), complete cds. AF509056 Influenza A virus (A / Chicken / Hong Kong / 867.1 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509057 Influenza A virus (A / Chicken / Hong Kong / 879.1 / 01 (H5N1)) protein Ml gene (Ml), complete cds.

AF509058 Influenza A virus (A / Chicken / Hong Kong / 873.3 / 01 (H5N1)) protein gene Ml (Ml), complete cds. AF509059 Influenza A virus (A / Chicken / Hong Kong / 876.1 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509060 Influenza A virus (A / Chicken / Hong Kong / 891.1 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509061 Influenza A virus (A / Chicken / Hong Kong / 893.2 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509062 Influenza A virus (A / Goose / Hong Kong / 76.1 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509063 Influenza A virus (A / Goose / Hong Kong / wwl00 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509064 Influenza A virus (A / Pato / Hong Kong / 573.4 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509065 Influenza A virus (A / Duck / Hong Kong / 646.3 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AY059506 Influenza A virus (A / Goose / Hong Kong / ww26 / 2000 (H5N1)) matrix protein gene (M) of segment 7, partial cds. AY059507 Influenza A virus (A / Goose / Hong Kong / ww28 / 2000 (H5N1)) matrix protein gene (M) of segment 7, partial cds. AY059508 Influenza A virus (A / Pato / Hong Kong / ww381 / 2000 (H5N1)) matrix protein gene (M) of segment 7, partial cds.

AY059509 Influenza A virus (A / Pato / Hong Kong / ww461 / 2000 (H5N1)) matrix protein gene (M) of segment 7, partial cds. AY059510 Influenza A virus (A / Goose / Hong Kong / ww491 / 2000 (H5N1)) matrix protein gene (M) of segment 7, partial cds. AY059511 Influenza A virus (A / Pato / Hong Kong / 2986.1 / 2000 (H5N1)) matrix protein gene (M) of segment 7, partial cds. AY059512 Influenza A virus (A / Goose / Hong Kong / 3014.8 / 2000 (H5N1)) matrix protein gene (M) of segment 7, partial cds. AY075029 Influenza A virus (A / Chicken / Hong Kong / 317.5 / 2001 (H5N1)) protein matrix 1 and protein gene matrix 2 (M), complete cds. AY075035 Influenza A virus (A / Pato / Hong Kong / 380.5 / 2001 (H5N1)) protein matrix 1 and protein gene matrix 2 (M), complete cds. AY221530 Influenza A virus (A / Chicken / Hong Kong / NT873.3 / 01-MB (H5Nl)) matrix protein gene (M), complete cds. AY221531 Influenza A virus (A / Chicken / Hong Kong / NT873.3 / 01 (H5N1)) matrix protein gene (M), complete cds. AY221532 Influenza A virus (A / Chicken / Hong Kong / PY150 / 01-MB (H5N1)) matrix protein gene (M), complete cds. AY221533 Influenza A virus (A / Chicken / Hong Kong / FY150 / 01 (H5N1)) matrix protein gene (M), complete cds. AY221534 Influenza A virus (A / Pheasant / Hong Kong / FY155 / 01-MB (H5N1)) matrix protein gene (M), complete cds. AY221535 Influenza A virus (A / Pheasant / Hong Kong / FY155 / 01 (H5N1)) matrix protein gene (M), complete cds. AY221536 Influenza A virus (A / Chicken / Hong Kong / YU822.2 / 01-MB (H5Nl)) matrix protein gene (M), complete cds. AY221537 Influenza A virus (A / Chicken / Hong Kong / YU822.2 / 01 (H5N1)) matrix protein gene (M), complete cds. AY221538 Influenza A virus (A / Chicken / Hong Kong / YU562 / 01 (H5N1)) matrix protein gene (M), complete cds. AY518361 Influenza A virus (A / duck / China / E319-2 / 03 (H5N1)) M2 membrane ion channel and Ml (M) matrix protein gene, complete cds. AY575895 Influenza A virus (A / Gs / HK / 739.2 / 02 (H5N1)) matrix protein gene (M), complete cds. AY575896 Influenza A virus (A / Eg / HK / 757.3 / 02 (H5N1)) matrix protein gene (M), partial cds.

AY575897 Influenza A virus (A / G. H / HK / 793.1 / 02 (H5N1)) matrix protein gene (M), partial cds. AY575898 Influenza A virus (A / Dk / HK / 821/02 (H5N1)) matrix protein gene (M), partial cds. AY575899 Influenza A virus (A / Ck / HK / 31.4 / 02 (H5N1)) matrix protein gene (M), complete cds. AY575900 Influenza A virus (A / Ck / HK / 61.9 / 02 (H5N1)) matrix protein gene (M), complete cds. AY575901 Influenza A virus (A / Ck / HK / YU777 / 02 (H5N1)) matrix protein gene (M), complete cds. AY575902 Influenza A virus (A / Ck / HK / 96.1 / 02 (H5N1)) matrix protein gene (M), complete cds. AY575903 Influenza A virus (A / Ck / HK / 409.1 / 02 (H5N1)) matrix protein gene (M), complete cds. AY575904 Influenza A virus (A / Ph / HK / sv674.15 / 02 (H5N1)) matrix protein gene (M), complete cds. AY585378 Influenza A virus (A / duck / Fuj ian / 01/2002 (H5N1)) matrix protein mRNA, complete cds. AY585379 Influenza A virus (A / duck / Fuj ian / 13/2002 (H5N1)) matrix protein mRNA, complete cds. AY585380 Influenza A virus (A / duck / Fuj ian / 17/2001 (H5N1)) matrix protein mRNA, complete cds. AY585381 Influenza A virus (A / duck / Fuj ian / 19/2000 (H5N1)) matrix protein mRNA, complete cds. AY585382 Influenza A virus (A / duck / Guangdong / 01/2001 (H5N1)) matrix protein mRNA, complete cds. AY585383 Influenza A virus (A / duck / Guangdong / 07/2000 (H5N1)) matrix protein mRNA, complete cds. AY585384 Influenza A virus (A / duck / Guangdong / 12/2000 (H5N1)) matrix protein mRNA, complete cds. AY585385 Influenza A virus (A / duck / Guangdong / 22/2002 (H5N1)) matrix protein mRNA, complete cds. AY585386 Influenza A virus (A / duck / Guangdong / 40/2000 (H5N1)) matrix protein mRNA, complete cds. AY585387 Influenza A virus (A / duck / Guangxi / 07/1999 (H5N1)) matrix protein mRNA, complete cds. AY585388 Influenza A virus (A / duck / Guangxi / 22/2001 (H5N1)) matrix protein mRNA, partial cds. AY585389 Influenza A virus (A / duck / Guangxi / 35/2001 (H5N1)) matrix protein mRNA, complete cds. AY585390 Influenza A virus (A / duck / Guangxi / 53/2002 (H5N1)) matrix protein mRNA, complete cds. AY585391 Influenza A virus (A / duck / Shangai / 08/2001 (H5N1)) matrix protein mRNA, complete cds. AY585392 Influenza A virus (A / duck / Shangai / 13/2001 (H5N1)) matrix protein mRNA, complete cds. AY585393 Influenza A virus (A / duck / Shangai / 35/2002 (H5N1)) matrix protein mRNA, complete cds. AY585394 Influenza A virus (A / duck / Shangai / 37/2002 (H5N1)) matrix protein mRNA, complete cds.

AY585395 Influenza A virus (A / duck / Shangai / 38/2001 (H5N1)) matrix protein mRNA, complete cds. AY585396 Influenza A virus (A / duck / Zhej iang / 11/2000 (H5N1)) matrix protein mRNA, complete cds. AY585397 Influenza A virus (A / duck / Zhej iang / 52/2000 (H5N1)) matrix protein mRNA, complete cds. AY585398 Influenza A virus (A / duck / Guangxi / 50/2001 (H5N1)) matrix protein mRNA, complete cds. AY590578 Influenza A virus (A / chicken / Nakorn-Patom / Thailand / CU-K2 / 2004 (H5N1)) M2 matrix protein and Ml (M) matrix protein gene, complete and partial cds. AY609315 Influenza A virus (A / chicken / Guangdong / 174/04 (H5N1)) segment 7, complete sequence. AY651374 Influenza A virus (A / Ck / Indonesia / BL / 2003 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651375 Influenza A virus (A / Dk / Indonesia / MS / 2004 (H5N1)) ion channel of membrane 2 and protein gene of matrix 1 (M), complete cds. AY651376 Influenza A virus (A / Ck / Indonesia / PA / 2003 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651377 Influenza A virus (A / Ck / Indonesia / 2A / 2003 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds.

AY651378 Influenza A virus (A / Ck / Indonesia / 4/2004 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651379 Influenza A virus (A / Ck / Indonesia / 5/2004 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651380 Influenza A virus (A / Ck / Thailand / 1/2004 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651381 Influenza A virus (A / Ck / Thailand / 73/2004 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651382 Influenza A virus (A / Ck / Thailand / 9.1 / 2004 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651383 Influenza A virus (A / Qa / Thailand / 57/2004 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651384 Influenza A virus (A / bird / Thailand / 3.1 / 2004 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651385 Influenza A virus (A / Dk / Thailand / 71.1 / 2004 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds.

AY651386 Influenza A virus (A / Gs / Thailand / 79/2004 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651391 Influenza A virus (A / Ck / Vietnam / 33/2004 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651392 Influenza A virus (A / Ck / Vietnam / 35/2004 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651393 Influenza A virus (A / Ck / Vietnam / 36/2004 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651394 Influenza A virus (A / Ck / Vietnam / 37/2004 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651395 Influenza A virus (A / Ck / Vietnam / 38/2004 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651396 Influenza A virus (A / Ck / Vietnam / 39/2004 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651397 Influenza A virus (A / Ck / Vietnam / C57 / 2004 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651398 Influenza A virus (A / Dk / Vietnam / 11/2004 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651399 Influenza A virus (A / Gf / HK / 38/2002 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), partial cds. AY651400 Influenza A virus (A / Ck / HK / 31.2 / 2002 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651401 Influenza A virus (A / Ck / HK / 37.4 / 2002 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651402 Influenza A virus (A / SCk / HK / YU100 / 2002 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651403 Influenza A virus (A / Ck / HK / YU22 / 2002 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651404 Influenza A virus (A / Ck / HK / 3176.3 / 2002 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), partial cds. AY651405 Influenza A virus (A / Ck / HK / 3169.1 / 2002 (H5N1)) matrix protein 1 and membrane ion channel gene 2 (M), partial cds. AY651406 Influenza A virus (A / Ck / HK / FY157 / 2003 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651407 Influenza A virus (A / Ck / HK / YU324 / 2003 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651408 Influenza A virus (A / Ck / HK / 2133.1 / 2003 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), partial cds. AY651409 Influenza A virus (A / Ck / HK / NT93 / 2003 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651410 Influenza A virus (A / Ck / HK / SSP141 / 2003 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651411 Influenza A virus (A / Ck / HK / WF157 / 2003 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651412 Influenza A virus (A / peregrine falcon / HK / D0028 / 2004 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651413 Influenza A virus (A / greyhound gull / HK / 12.1 / 2003 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651414 Influenza A virus (A / gray heron / HK / 861.1 / 2002 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651415 Influenza A virus (A / wild pigeon / HK / 862.7 / 2002 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), complete cds. AY651416 Influenza A virus (A / sparrow miller / HK / 864/2002 (H5N1)) protein matrix 1 and channel ion gene of membrane 2 (M), partial cds. AY651417 Influenza A virus (A / teal / China / 2978.1 / 2002 (H5N1)) membrane ion channel 2 and matrix protein gene 1 (M), partial cds. AY651418 Influenza A virus (A / Dk / HN / 5806/2003 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651419 Influenza A virus (A / Dk / ST / 4003/2003 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix 1 matrix gene (M), complete cds. AY651420 Influenza A virus (A / Ck / ST / 4231/2003 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651421 Influenza A virus (A / Dk / YN / 6255/2003 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651422 Influenza A virus (A / Dk / YN / 6445/2003 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds.

AY651423 Influenza A virus (A / Ck / YN / 374/2004 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651424 Influenza A virus (A / Dk / HN / 101/2004 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651425 Influenza A virus (A / Dk / HN / 303/2004 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651426 Influenza A virus (A / Ph / ST / 44/2004 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY651427 Influenza A virus (A / Ck / YN / 115/2004 (H5N1)) membrane ion channel gene 2 (M), partial cds; and matrix protein gene 1 (M), complete cds. AY653194 Influenza A virus (A / chicken / Jilin / 9/2004 (H5N1)) segment 7, complete sequence. AY676045 Virus strain of influence A (A / duck / Hong Kong / 821/02 (H5N1)) membrane protein gene (M), complete cds. AY676046 Strain of virus A (A / Heron / Hong Kong / 757.2 / 03 (H5N1)) membrane protein gene (M-), complete cds. AY676047 Virus strain of influence A (A / chicken / Korea / ES / 03 (H5N1)) membrane protein gene (M), complete cds. AY676048 Virus strain of influence A (A / duck / Korea / ESDl / 03 (H5N1)) membrane protein gene (M), complete cds. AY684709 Influenza A virus (A / chicken / Hubei / 327/2004 (H5N1)) protein matrix 2 (M2) and protein matrix 1 (Ml) genes, complete cds. AY737292 Influenza A virus (A / chicken / Guangdong / 191/04 (H5N1)) segment 7, complete sequence. AY737298 Influenza A virus (A / chicken / Guangdong / 178/04 (H5N1)) segment 7, complete sequence. AY737306 Influenza A virus (A / duck / Guangdong / 173/04 (H5N1)) segment 7, complete sequence. AY770077 Influenza A virus (A / chicken / Hubei / 489/2004 (H5N1)) protein matrix 2 (M2) and protein matrix 1 (Ml) genes, complete cds. AY770998 Influenza A virus (A / chicken / Ayutthaya / Thailand / CU-23/04 (H5N1)) matrix protein gene, complete cds. AY818145 Influenza A virus (A / chicken / Vietnam / C58 / 04 (H5N1)) protein Ml matrix gene, complete cds. AY818146 Influenza A virus (A / quail / Vietnam / 36/04 (H5N1)) protein Ml matrix gene, complete cds. AY856865 Influenza A virus (A / duck / Shandong / 093/2004 (H5N1)) segment 7, complete sequence.

DQ055851 Influenza A virus (A / chicken / Yunnan / K001 / 2004 (H5N1)) matrix protein Ml gene, complete cds. AB189048 Influenza A virus (A / chicken / Kyoto / 3/2004 (H5N1)) M2 genes, Ml for the membrane ion channel; M2, protein matrix 1, complete cds. AB189056 Influenza A virus (A / raven / Kyoto / 53/2004 (H5N1)) M2 genes, Ml for the membrane ion channel; M2, protein matrix 1, complete cds. AB189064 Influenza A 'virus (A / raven / Osaka / 102/2004 (H5N1)) M2 genes, Ml for the membrane ion channel; M2, protein matrix 1, complete cds. AF046082 Influenza A virus (A / Chicken / Hong Kong / 220/97 (H5N1)) protein matrix 2 (M2) and matrix protein 1 (Ml), complete cds. AF098560 Influenza A virus (A / Chicken / Hong Kong / 258/97 (H5N1)) matrix protein genes Ml (M) and protein matrix M2 (M), partial cds. AF098561 Influenza A virus (A / Chicken / Hong Kong / y388 / 97 (H5N1)) matrix protein genes Ml (M) and matrix protein M2 (M), partial cds. AF098562 Influenza A virus (A / Chicken / Hong Kong / 728/97 (H5N1)) matrix protein genes Ml (M) and matrix protein M2 (M), partial cds. AF098563 Influenza A virus (A / Chicken / Hong Kong / 786/97 (H5N1)) matrix protein Ml (M) and matrix protein M2 (M), partial cds. AF098564 Influenza A virus (A / Chicken / Hong Kong / 915/97 (H5N1)) Ml (M) matrix protein and matrix protein genes M2 (M), partial cds. AF098566 Influenza A virus (A / Duck / Hong Kong / p46 / 97 (H5N1)) Ml (M) matrix protein and matrix protein genes M2 (M), partial cds. AF098567 Influenza A virus (A / Pato / Hong Kong / y283 / 97 (H5N1)) matrix protein Ml (M) and matrix protein M2 (M), partial cds. AF098568 Influenza A virus (A / Goose / Hong Kong / w355 / 97 (H5N1)) matrix protein genes Ml (M) and protein matrix M2 (M), partial cds. AF144306 Influenza A virus (A / Goose / Guangdong / 1/96 (H5N1)) protein gene Ml and M2 (M), alternatively spliced products, complete cds. AF216711 Influenza A virus (A / Environment / Hong Kong / 437-4 / 99 (H5N1)) matrix 1 protein and matrix 2 protein genes, complete cds. AF216719 Influenza A virus (A / Environment / Hong Kong / 437-6 / 99 (H5N1)) matrix 1 protein and matrix protein genes, complete cds. AF216727 Influenza A virus (A / Environment / Hong Kong / 437-8 / 99 (H5N1)) matrix 1 protein and matrix 2 protein genes, complete cds.

AF216735 Influenza A virus (A / Environment / Hong Kong / 437-10 / 99 (H5N1)) matrix 1 protein and matrix 2 protein genes, complete cds. AF359560 Influenza A virus (A / Goose / Guangdong / 3/97 (H5N1)) matrix protein 1 and matrix protein gene 2 (M), complete cds. AF398429 Influenza A virus (A / Goose / Hong Kong / 385.3 / 2000 (H5N1)) matrix protein gene 1 (M), partial cds. AF398430 Influenza A virus (A / Goose / Hong Kong / 385.5 / 2000 (H5N1)) matrix protein gene 1 (M), partial cds. AF468843 Influenza A virus (A / Pato / Anyang / AVL-1/2001 (H5N1)) protein matrix 1 and protein matrix 2 genes, complete cds. AF509040 Influenza A virus (A / Chicken / Hong Kong / FY77 / 01 (H5N1)) gene (Ml) protein Ml (Ml), complete cds. AF509041 Influenza A virus (A / Chicken / Hong Kong / YU562 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF509042 Influenza A virus (A / Chicken / Hong Kong / YU563 / 01 (H5N1)) protein Ml gene (Ml), complete cds. AF073180 Influenza A virus (A / Chicken / New Jersey / 15086-3 / 94 (H7N3NSA)) protein matrix 1 (Ml) and protein matrix 2 (M2), complete cds. AF073197 Influenza A virus (A / Turkey / Oregon / 71 (H7N3NSB)) protein matrix 1 (MI) and protein matrix 2 (M2), complete cds. AY664433 Influenza A virus (A / sandbird / New Jersey / 65/85 (H7N3)) non-functional matrix protein mRNA, partial sequence. AY677732 Influenza A virus (A / chicken / British Columbia / CN7-3 / 04 (H7N3)) protein matrix gene 1 (Ml), complete cds. AF073198 Influenza A virus (A / Pavo / Colorado / 13356/91 (H7N3NSA)) protein matrix 1 (MI) and protein matrix 2 (M2) genes, complete cds. AF073200 Influenza A virus (A / Quail / Arkansas / 16309- 7/94 (H7N3NSA)) genes of matrix protein 1 (Ml) and matrix protein 2 (M2), complete cds. AF073201 Influenza A Virus (A / Turkey / Utah / 24721-10 / 95 (H7N3NSA)) genes of matrix protein 1 (Ml) and matrix protein 2 (M2), complete cds. AJ627492 Influenza A virus (A / turkey / Italy / 214845/2002 (H7N3)) gene for membrane protein 1 and gene for membrane protein 2, genomic RNA. AJ627497 Influenza A virus (A / turkey / Italy / 220158/2002 (H7N3)) gene for membrane protein 1 and gene for membrane protein 2, genomic RNA. AY241600 Influenza A virus (A / Chicken / New York / 12273-11 / 99 (H7N3)) matrix 1 protein and matrix 2 protein genes, complete cds. AY241602 Influenza A virus (A / chicken / NY / 14714-9 / 99 (H7N3)) protein matrix 1 and protein matrix 2 genes, complete cds. AY241615 Influenza A virus (A / Pato / NJ / 117228-7 / 01 (H7N3)) matrix 1 protein and matrix 2 protein genes, complete cds. AY241616 Influenza A virus (A / Pato / PA / 143585/01 (H7N3)) matrix 1 protein and matrix 2 protein genes, complete cds. AY300975 Influenza A virus (A / Blue-winged teal / TX / 2/01 (H7N3) membrane protein gene (M), complete cds AY303652 Influenza A virus (A / chicken / Chile / 176822/02 ( H7N3)) matrix 1 protein and matrix 2 protein genes, complete cds AY303653 Influenza A virus (A / chicken / Chile / 4322/02 (H7N3)) matrix 1 protein and matrix 2 protein genes, complete cds. AY303654 Influenza A virus (A / chicken / Chile / 4957/02 (H7N3)) protein matrix gene 1, complete cds, and protein gene matrix 2, partial cds AY303655 Influenza A virus (A / chicken / Chile / 4968/02 (H7N3)) matrix 1 protein and matrix 2 protein genes, complete cds.

AY303656 Influenza A virus (A / chicken / Chile / 4977/02 (H7N3)) matrix 1 protein and matrix 2 protein genes, complete cds. AY303657 Influenza A virus (A / turkey / Chile / 4418/02 (H7N3)) protein matrix gene 1, complete cds; and protein gene 2 matrix, partial cds. AY586427 Influenza A virus (A / turkey / Italy / 214845/02 (H7N3)) matrix protein gene, partial cds. AY586428 Influenza A virus (A / turkey / Italy / 220158/2002 (H7N3)) matrix protein gene, partial cds. AY586429 Influenza A virus (A / wild turkey / Italy / 43/01 (H7N3)) matrix protein gene, partial cds. AY586430 Influenza A virus (A / wild turkey / Italy / 33/01 (H7N3)) matrix protein gene, partial cds. AY611525 Influenza A virus (A / chicken / British Columbia / 04 (H7N3)) protein matrix 2 (M) and protein matrix 1 (M), complete cds. AY646079 Influenza A virus (A / chicken / British Columbia / GSC_human_B / 04 (H7N3)) matrix protein 2 and matrix protein gene 1 (M), complete cds. AY648288 Influenza A virus (A / GSC_pollo_B / British Columbia / 04 (H7N3)) protein matrix 2 (M) and protein matrix 1 (M), complete cds.

AY650271 Influenza A virus (A / GSC_pollo / British Columbia / 04 (H7N3)) protein matrix 2 (M) and protein matrix 1 (M), complete cds. AJ619676 Influenza A virus (A / chicken / Germany / R28 / 03 (H7N7)) Ml gene for membrane protein 1, genomic RNA. AY340086 Influenza A virus (A / Netherlands / 124/03 (H7N7)) matrix protein gene, partial cds. AY340087 Influenza A virus (A / Netherlands / 126/03 (H7N7)) matrix protein gene, partial cds. AY340088 Influenza A virus (A / Netherlands / 127/03 (H7N7)) matrix protein gene, partial cds. AY340089 Influenza A virus (A / Netherlands / 219/03 (H7N7)) matrix protein gene, complete cds. AY340090 Influenza A virus (A / Netherlands / 33/03 (H7N7)) matrix protein gene, complete cds. AY340091 Influenza A virus (A / chicken / Netherlands / 1/03 (H7N7)) matrix protein gene, complete cds. AY664468 Influenza A virus (A / sandbird / Delaware / 134/99 (H7N7)) non-functional matrix protein mRNA, partial sequence. L37795 Influenza virus A / chicken / Brescia / 1902 (H7N7) protein matrix gene (Ml) and transmembrane protein gene (M2), complete cds. L37796 A / FPV / Dobson influenza virus (H7N7) matrix protein gene (Ml) and transmembrane protein gene (M2), complete cds. L37797 Influenza A virus / FPV / Weybridge (H7N7) protein matrix gene (Ml) and transmembrane protein gene (M2), complete cds. M23917 Influenza A / chicken / FPV / Weybridge (H7N7) gene Ml protein matrix, complete cds. M23921 Influenza A / chicken / FPV / Weybridge (H7N7) gene M2 protein matrix, complete cds. M38299 Influenza A / FPV / Weybridge (H7N7) protein matrix (M) gene (sec 7), complete cds. M63523 Influenza A virus (A / chicken / Victoria / 1/85 (H7N7)) Ml membrane protein genes and membrane M2 protein, complete cds. M63526 Influenza virus type A (strain A / FPV / Dobson / 27 (H7N7)) Ml membrane protein genes and M2 membrane protein, complete cds. AB049165 Influenza A virus (A / parakeet / Chiba / 1/97 (H9N2)) Ml genes, M2 for membrane ion channel, matrix protein, complete cds. AB049166 Influenza A virus (A / parakeet / Narita / 92A / 98 (H9N2)) Ml genes, M2 for membrane ion channel, matrix protein, complete cds. AF222671 Influenza A virus (A / Silky chicken / Hong Kong / SF44 / 99 (H9N2)) gene Ml (Ml) of segment 7, partial cds.

AF508684 Influenza A virus (A / Ostrich / South Africa / 9508103/95 (H9N2)) Ml matrix protein gene segment 7 (M), complete cds. AF508685 Influenza A virus (A / Chicken / Pakistan / 4/99 (H9N2)) protein Ml matrix gene of segment 7 (M), partial cds. AF508686 Influenza A virus (A / Chicken / Pakistan / 5/99 (H9N2)) protein gene of Ml matrix of segment 7 (M), partial cds. AF508687 Influenza A virus (A / Chicken / Germany / R45 / 98 (H9N2)) protein gene of Ml matrix of segment 7 (M), complete cds. AF508688 Influenza A virus (A / Pato / Germany / 113/95 (H9N2)) Ml matrix protein gene of segment 7 (M), complete cds. AF508689 Influenza A virus (A / Chicken / Iran / llT / 99 (H9N2)) protein Ml matrix gene of segment 7 (M), partial cds. AF508690 Influenza A virus (A / Chicken / Saudi Arabia / 532/99 (H9N2)) protein Ml matrix gene of segment 7 (M), partial cds. AF508691 Influenza A virus (A / Pheasant / Ireland / PV18 / 97 (H9N2)) gene protein matrix Ml segment 7 (M), complete cds. AF508692 Influenza A virus (A / Chicken / Korea / 99029/99 (H9N2)) gene protein matrix Ml segment 7 (M), complete cds. AF508693 Influenza A virus (A / Chicken / Beij ing / 8/98 (H9N2)) matrix protein Ml of segment 7 (M), complete cds. AF508694 Influenza A virus (A / Chicken / Guangdong / 10/00 (H9N2)) matrix protein Ml of segment 7 (M), complete cds. AF508695 Influenza A virus (A / Chicken / Guangdong / 11/97 (H9N2)) gene protein matrix Ml segment 7 (M), complete cds. AF508696 Influenza A virus (A / Chicken / Heilongj iang / 10/97 (H9N2)) matrix protein Ml of segment 7 (M), complete cds. AF508697 Influenza A virus (A / Chicken / Henan / 62/00 (H9N2)) protein Ml matrix gene of segment 7 (M), complete cds. AF508698 Influenza A virus (A / Chicken / Ningxia / 5/99 (H9N2)) matrix protein Ml of segment 7 (M), complete cds. AF508699 Influenza A virus (A / Chicken / Sichuan / 5/97 (H9N2)) Ml matrix protein gene of segment 7 (M), partial cds. AF508700 Influenza A virus (A / Chicken / Shandong / 6/96 (H9N2)) matrix protein Ml of segment 7 (M), complete cds. AF508701 Influenza A virus (A / Chicken / Shij iazhuang / 2/99 (H9N2)) protein gene of Ml matrix of segment 7 (M), partial cds. AF508702 Influenza A virus (A / Chicken / Shenzhen / 9/97 (H9N2)) protein gene of Ml matrix of segment 7 (M), complete cds. AF508703 Influenza A virus (A / Pato / Nanjing / 1/97 (H9N2)) matrix protein Ml of segment 7 (M), complete cds. AF508704 Influenza A virus (A / Quail / Shangai / 8/96 (H9N2)) gene protein matrix Ml segment 7 (M), complete cds. AF523482 Influenza A virus (A / Pato / Shantou / 1043/00 (H9N2)) matrix protein gene (M), complete cds. AF523483 Influenza A virus (A / Pato / Shantou / 2134/00 (H9N2)) matrix protein gene (M), complete cds. AF523484 Influenza A virus (A / Wild Duck / Shantou / 4808/01 (H9N2)) matrix protein gene (M), complete cds. AF523485 Influenza A virus (A / Pato / Shantou / 1042/00 (H9N2)) matrix protein gene (M), complete cds. AF523486 Influenza A virus (A / Pato / Shantou / 2143/00 (H9N2)) matrix protein gene (M), complete cds. AF523487 Influenza A virus (A / Pato / Shantou / 2144/00 (H9N2)) matrix protein gene (M), complete cds. AF523488 Influenza A virus (A / Pato / Shantou / 1881/00 (H9N2)) matrix protein gene (M), complete cds. AF523489 Influenza A virus (A / Pato / Shantou / 1796/00 (H9N2)) matrix protein gene (M), complete cds. AF523490 Influenza A virus (A / Pato / Shantou / 2102/00 (H9N2)) matrix protein gene (M), complete cds. AF523491 Influenza A virus (A / Pato / Shantou / 830/00 (H9N2)) matrix protein gene (M), complete cds. AF523492 Influenza A virus (A / Pato / Shantou / 2088/01 (H9N2)) matrix protein gene (M), complete cds. AF523493 Influenza A virus (A / Pato / Shantou / 1605/01 (H9N2)) matrix protein gene (M), complete cds. AF523494 Influenza A virus (A / Pato / Hong Kong / 610/79 (H9N2)) matrix protein gene (M), complete cds. AF523495 Influenza A virus (A / Pato / Hong Kong / 552/79 (H9N2)) matrix protein gene (M), complete cds. AF523496 Influenza A virus (A / Pato / Hong Kong / 289/78 (H9N2)) matrix protein gene (M), complete cds. AF523497 Influenza A virus (A / Pato / Hong Kong / 86/76 (H9N2)) matrix protein gene (M), complete cds. AF523498 Influenza A virus (A / Pato / Hong Kong / 366/78 (H9N2)) matrix protein gene (M), partial cds. AF536719 Influenza A virus (A / Chicken / Beij ing / 1/95 (H9N2)) nonfunctional matrix protein gene, partial sequence. AF536720 Influenza A virus (A / Chicken / Beij ing / 2/97 (H9N2)) non-functional matrix protein gene, partial sequence. AF536721 Influenza A virus (A / Chicken / Beij ing / 3/99 (H9N2)) non-functional matrix protein gene, partial sequence. AF536722 Influenza A virus (A / Chicken / Guangdong / 97 (H9N2)) non-functional matrix protein gene, partial sequence. AF536723 Influenza A virus (A / Chicken / Hebei / 1/96 (H9N2)) non-functional matrix protein gene, partial sequence. AF536724 Influenza A virus (A / Chicken / Hebei / 2/98 (H9N2)) non-functional matrix protein gene, partial sequence. AF536725 Influenza A virus (A / chicken / Hebei / 3/98 (H9N2)) non-functional matrix protein gene, partial sequence. AF536726 Influenza A virus (A / Chicken / Henan / 98 (H9N2)) non-functional matrix protein gene, partial sequence. AF536727 Influenza A virus (A / chicken / Liaoning / 99 (H9N2)) non-functional matrix protein gene, partial sequence. AF536728 Influenza A virus (A / Chicken / Shandong / 98 (H9N2)) non-functional matrix protein gene, partial sequence. AJ291398 Influenza A virus (A / Chicken / Pakistan / 2/99 (H9N2)) Gene Ml for Protein matrix 1 (exon 1) and M2 gene for protein matrix 2 (exons 1 and 2), genomic RNA AJ427865 Influenza A virus (A / quail / Hong Kong / FY298 / 00 (H9N2)) partial m gene for matrix protein, genomic RNA AY180461 Influenza virus strain AA / Pichon / Nanchang / 2-0461 / 2000 (H9N2) matrix protein gene ( M), partial cds. AY180462 Strain of influenza virus A A / Pato / Nanchang / 11-290 / 2000 (H9N2) gene of matrix protein (M), partial cds.

AY180463 Virus strain of influenza A A / Pato / Nanchang / 11-197 / 2000 (H9N2) gene of matrix protein (M), partial cds.

AY180464 Influenza virus strain A A / Pato / Nanchang / 11-392 / 2000 (H9N2) matrix protein gene (M), partial cds. AY180477 Influenza virus strain A A / Chicken / Nanchang / 4-361 / 2001 (H9N2) matrix protein gene (M), partial cds.

AY180485 Virus strain of influenza A A / Pigeon / Nanchang / 11-145 / 2000 (H9N2) gene of matrix protein (M), partial cds. AY180486 Influenza virus strain A A / Duck / Nanchang / 1-0070 / 2000 (H9N2) matrix protein gene (M), partial cds.

AY180489 Influenza virus strain A A / Pato / Nanchang / 10-389 / 2000 (H9N2) matrix protein gene (M), partial cds.

AY180490 Influenza virus strain A A / Chicken / Nanchang / 1-0016 / 2000 (H9N2) matrix protein gene (M), partial cds.

AY180492 Influenza virus strain A A / Pigeon / Nanchang / 7-058 / 2000 (H9N2) matrix protein gene (M), partial cds. AY180495 Influenza virus strain A A / Quail / Nanchang / 2-0460 / 2000 (H9N2) matrix protein gene (M), partial cds. AY180502 Strain of influenza virus A A / Chicken / Nanchang / 4-010 / 2000 (H9N2) gene of matrix protein (M), partial cds.

AY180504 Influenza virus strain A A / Quail / Nanchang / 4-040 / 2000 (H9N2) matrix protein gene (M), partial cds. AY180506 Influenza virus strain A A / Chicken / Nanchang / 4-301 / 2001 (H9N2) matrix protein gene (M), partial cds. AY180516 Influenza virus strain A A / Pato / Nanchang / 7-092 / 2000 (H9N2) matrix protein gene (M), partial cds. AY180519 Virus strain of influenza A A / Wild duck / Nanchang / 2-0480 / 2000 (H9N2) gene of matrix protein (M), partial cds. AY253755 Influenza A virus (A / Chicken / Shangai / F / 98 (H9N2)) protein Ml matrix and M2 membrane ion channel, complete cds. AY496852 Influenza A virus (A / chicken / Mudanjiang / 0823/2000 (H9N2)) protein mRNA matrix (Ml), complete cds. AY633165 Influenza A virus (A / wild turkey / Alberta / 17/91 (H9N2)) matrix protein gene (M), complete cds. AY633277 Influenza A virus (A / wild turkey / Alberta / 321/88 (H9N2)) matrix protein gene (M), complete cds. AY633293 Influenza A virus (A / wild turkey / Alberta / 11/91 (H9N2)) matrix protein gene (M), complete cds. AY664464 Influenza A virus (A / beach bird / Delaware / 276/99 (H9N2)) non-functional matrix protein mRNA, partial sequence. AY664679 Influenza A virus (A / chicken / Hong Kong / CSW153 / 03 (H9N2)) M2 membrane protein gene (M), partial cds; and membrane protein gene Ml (M), complete cds. AY664680 Influenza A virus (A / chicken / Hong Kong / AP45 / 03 (H9N2)) protein M2 membrane gene (M), partial cds; and membrane protein gene Ml (M), complete cds. AY664681 Influenza A virus (A / chicken / Hong Kong / BD90 / 03 (H9N2)) membrane protein gene M2 (M), partial cds; and membrane protein gene Ml (M), complete cds. AY664682 • Influenza A virus (A / chicken / Hong Kong / CSW291 / 03 (H9N2)) M2 membrane protein gene (M), partial cds; and membrane protein gene Ml (M), complete cds.

Y664683 Influenza A virus (A / chicken / Hong Kong / CSW304 / 03 (H9N2)) membrane protein M2 (M) and protein M1 membrane (M), partial cds. AY664684 Influenza A virus (A / chicken / Hong Kong / FY23 / 03 (H9N2)) M2 membrane protein gene (M), partial cds; and membrane protein gene Ml (M), complete cds. AY664685 Influenza A virus (A / guinea fowl / Hong Kong / NT101 / 03 (H9N2)) M2 membrane protein gene (M), partial cds; and membrane protein gene Ml (M), complete cds. AY664686 Influenza A virus (A / chicken / Hong Kong / NT142 / 03 (H9N2)) protein M2 membrane gene (M), partial cds; and membrane protein gene Ml (M), complete cds. AY664687 Influenza A virus (A / chicken / Hong Kong / SFl / 03 (H9N2)) membrane protein gene M2 (M), partial cds; and membrane protein gene Ml (M), complete cds. AY664688 Influenza A virus (A / chicken / Hong Kong / SSP101 / 03 (H9N2)) protein M2 membrane gene (M), partial cds; and membrane protein gene Ml (M), complete cds. AY664689 Influenza A virus (A / chicken / Hong Kong / TP38 / 03 (H9N2)) protein M2 membrane gene (M), partial cds; and membrane protein gene Ml (M), complete cds. AY664690 Influenza A virus (A / chicken / Hong Kong / WF126 / 03 (H9N2)) M2 membrane protein gene (M), partial cds; and membrane protein gene Ml (M), complete cds. AY664691 Influenza A virus (A / pigeon / Hong Kong / WF53 / 03 (H9N2)) M2 membrane protein gene (M), partial cds; and membrane protein gene Ml (M), complete cds. AY664692 Influenza A virus (A / pheasant / Hong Kong / WF54 / 03 (H9N2)) M2 membrane protein gene (M), partial cds; and membrane protein gene Ml (M), complete cds. AY664693 Influenza A virus (A / guinea fowl / Hong Kong / NT184 / 03 (H9N2)) membrane protein gene M2 (M), partial cds; and membrane protein gene Ml (M), complete cds. AY664694 Influenza A virus (A / chicken / Hong Kong / WF120 / 03 (H9N2)) membrane protein genes M2 (M) and membrane protein Ml (M), partial cds. AY664695 Influenza A virus (A / chicken / Hong Kong / NT366 / 03 (H9N2)) protein M2 membrane gene (M), partial cds; and membrane protein gene Ml (M), complete cds. AY664696 Influenza A virus (A / chicken / Hong Kong / SSP418 / 03 (H9N2)) membrane protein gene M2 (M), partial cds; and membrane protein gene Ml (M), complete cds. AY664697 Influenza A virus (A / chicken / Hong Kong / YU427 / 03 (H9N2)) M2 membrane protein gene (M), partial cds; and membrane protein gene Ml (M), complete cds. AY800234 Influenza A virus (A / chicken / Korea / Sl / 2003 (H9N2)) matrix protein gene (M), complete cds. AY862614 Influenza A virus (A / silky chicken / Korea / S3 / 03 (H9N2)) matrix protein gene (M), complete cds. AY862615 Influenza A virus (A / chicken / Korea / S4 / 03 (H9N2)) matrix protein gene (M), complete cds. AY862616 Influenza A virus (A / chicken / Korea / S5 / 03 (H9N2)) matrix protein gene (M), complete cds. AY862617 Influenza A virus (A / chicken / Korea / S12 / 03 (H9N2)) matrix protein gene (M), complete cds. AY862618 Influenza A virus (A / duck / Korea / S13 / 03 (H9N2)) matrix protein gene (M), complete cds. AY862619 Influenza A virus (A / pigeon / Korea / S14 / 03 (H9N2)) matrix protein gene (M), partial cds. AY862620 Influenza A virus (A / chicken / Korea / S15 / 03 (H9N2)) matrix protein gene (M), complete cds. AY862621 Influenza A virus (A / chicken / Korea / S16 / 03 (H9N2)) matrix protein gene (M), complete cds. AY862622 Influenza A virus (A / chicken / Korea / S18 / 03 (H9N2)) matrix protein gene (M), complete cds. AF156458 Influenza A virus (A / Chicken / Hong Kong / G9 / 97 (H9N2)) matrix protein Ml segment 7 (Ml) and matrix protein genes M2 (M2), complete cds. AF156459 Influenza A virus (A / Chicken / Hong Kong / G23 / 97 (H9N2)) matrix protein Ml segment 7 (Ml) and matrix protein genes M2 (M2), complete cds.

AF156460 Influenza A virus (A / Pigeon / Hong Kong / Y233 / 97 (H9N2)) matrix protein Ml segment 7 (Ml) and matrix protein genes M2 (M2), complete cds. AF156461 Influenza A virus (A / Pato / Hong Kong / Y280 / 97 (H9N2)) matrix protein Ml segment 7 (Ml) and matrix protein genes M2 (M2), complete cds. AF156462 Influenza A virus (A / Duck / Hong Kong / Y439 / 97 (H9N2)) matrix protein Ml segment 7 (Ml) and matrix protein genes M2 (M2), complete cds. AF156463 Influenza A virus (A / Quail / Hong Kong / Gl / 97 (H9N2)) matrix protein Ml gene of segment 7 (Ml), complete cds; and matrix protein gene M2 (M2), partial cds. AF156464 Influenza A virus (A / Chicken / Hong Kong / 739/94 (H9N2)) matrix protein Ml of segment 7 (MI), complete cds; and matrix protein gene M2 (M2), partial cds. AF156465 Influenza A virus (A / Quail / Hong Kong / AF157 / 92 (H9N2)) gene protein matrix Ml segment 7 (Ml), complete cds; and matrix protein gene M2 (M2), partial cds. AF156466 Influenza A virus (A / Chicken / Beij ing / 1/94 (H9N2)) gene protein matrix Ml segment 7 (Ml), complete cds; and matrix protein gene M2 (M2), partial cds. AF156467 Influenza A virus (A / Chicken / Korea / 38349-p96323 / 96 (H9N2)) protein gene matrix Ml segment 7 (MI), complete cds; and matrix protein gene M2 (M2), partial cds. AF156468 Influenza A virus (A / Chicken / Korea / 25232-96006 / 96 (H9N2)) gene protein matrix Ml segment 7 (Ml), full cds; and matrix protein gene M2 (M2), partial cds. AF156469 Influenza A virus (A / Beach bird / Delaware / 9/96 (H9N2)) protein gene matrix Ml segment 7 (Ml), complete cds; and matrix protein gene M2 (M2), partial cds. AF156470 Influenza A virus (A / Quail / Arkansas / 29209-1 / 93 (H9N2)) gene protein matrix Ml segment 7 (Ml), complete cds; and matrix protein gene M2 (M2), partial cds. AF156471 Influenza A virus (A / Pavo / California / 189/66 (H9N2)) matrix protein Ml of segment 7 (Ml), complete cds; and matrix protein gene M2 (M2), partial cds. AF203788 Influenza A virus (A / Chicken / Korea / MS96 / 96 (H9N2)) matrix protein mRNA 1, complete cds; and matrix protein mRNA 2, partial cds. AF222662 Influenza A virus (A / Quail / Hong Kong / A17 / 99 (H9N2)) gene Ml (Ml) of segment 7, partial cds.

AF222663 Influenza A virus (A / Pigeon / Hong Kong / FY6 / 99 (H9N2)) gene Ml (Ml) of segment 7, partial cds. AF222664 Influenza A virus (A / Chicken / Hong Kong / NT16 / 99 (H9N2)) gene Ml (Ml) of segment 7, partial cds.

AF222665 Influenza A virus (A / Quail / Hong Kong / SSP10 / 99 (H9N2)) gene Ml (MI) of segment 7, partial cds. AF222666 Influenza A virus (A / Pheasant / Hong Kong / SSPll / 99 (H9N2)) gene Ml (Ml) of segment 7, partial cds. AF222667 Influenza A virus (A / Chicken / Hong Kong / FY20 / 99 (H9N2)) gene Ml (Ml) of segment 7, partial cds, AF222668 Influenza A virus (A / Chicken / Hong Kong / KC12 / 99 (H9N2 )) gene Ml (Ml) of segment 7, partial cds. AF222669 Influenza A virus (A / Quail / Hong Kong / NT28 / 99 (H9N2)) gene Ml (Ml) of segment 7, partial cds. AF222670 Influenza A virus (A / Chicken / Hong Kong / SF2 / 99 (H9N2)) gene Ml (Ml) of segment 7, partial cds.

Sequences used in the analysis of Nucleocapsid Protein of Influenza A (NP) AF156415 Influenza A virus (A / Pavo / California / 189/66 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF523423 Influenza A virus (A / Pato / Hong Kong / 86/76 (H9N2)) nucleocapsid protein (NP) gene, complete cds. AF523424 Influenza A virus (A / Pato / Hong Kong / 366/78 (H9N2)) nucleocapsid protein gene (NP), partial cds.

AF523421 Influenza A virus (A / Pato / Hong Kong / 289/78 (H9N2)) nucleocapsid protein (NP) gene, complete cds. AF523422 Influenza A virus (A / Pato / Hong Kong / 552/79 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AY633279 Influenza A virus (A / wild turkey / Alberta / 321/88 (H9N2)) nucleprotein gene (NP), complete cds. AY633295 Influenza A virus (A / wild turkey / Alberta / 11/91 (H9N2)) nucleotide gene (NP), partial cds. AY633167 Influenza A virus (A / wild turkey / Alberta / 17/91 (H9N2)) nucleotide gene (NP), complete cds. AF156410 Influenza A virus (A / Quail / Hong Kong / AF157 / 92 (H9N2)) nucleoprotein gene of segment 5 (NP), complete cds. AF156414 Influenza virus -A (A / Quail / Arkansas / 29209- 1/93 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF156408 Influenza A virus (A / Chicken / Hong Kong / 739/94 (H9N2)) nucleoprotein gene of segment 5 (NP), complete cds. AF156409 Influenza A virus (A / Chicken / Beij ing / 1/94 (H9N2)) nucleoprotein gene of segment 5 (NP), complete cds.

AF536699 Influenza A virus (A / Chicken / Beij ing / 1/95 (H9N2)) nucleotide gene (NP), partial cds. AF508596 Influenza A virus (A / Ostrich / South Africa / 9508103/95 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF508600 Influenza A virus (A / Pato / Germany / 113/95 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AB020778 Influenza A virus gene for nucleoprotein, complete cds. AF508613 Influenza A virus (A / Chicken / Shandong / 6/96 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF508617 Influenza A virus (A / Quail / Shangai / 8/96 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF536703 Influenza A virus (A / Chicken / Hebei / 1/96 (H9N2)) nucleotide gene (NP), partial cds. AF156411 Influenza A virus (A / Chicken / Korea / 38349-96323 / 96 (H9N2)) segment 5 nucleoprotein gene (NP), complete cds. AF156412 Influenza A virus (A / Chicken / Korea / 25232-96006 / 96 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. M63779 Influenza A / FPV / Dobson / 'Dutch' / 27 (H7N7) Nucleoprotein mRNA, complete cds. M63784 Influenza A / Teal / Iceland / 29/80 (H7N7) Nucleoprotein mRNA, complete cds. AJ620352 Influenza A virus (A / Chicken / Germany / R28 / 03 (H7N7)) NP gene for nucleopreotein, genomic RNA. AY342425 Influenza A virus (A / Netherlands / 219/03 (H7N7)) nucleocapsid protein gene, complete cds. AY342426 Influenza A virus (A / Netherlands / 033/03 (H7N7)) Nucleocapsid protein gene, complete cds. AY342427 Influenza A virus (A / chicken / Netherlands / 1/03 (H7N7)) nucleocapsid protein gene, complete cds. AF156413 Influenza A virus (A / Beach bird / Delaware / 9/96 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF203787 Influenza A virus (A / Chicken / Korea / MS96 / 96 (H9N2)) Nucleoprotein mRNA, complete cds. AF156402 Influenza A virus (A / Chicken / Hong Kong / G9 / 97 (H9N2)) segment 5 nucleoprotein gene (NP), complete cds. AF156403 Influenza A virus (A / Chicken / Hong Kong / G23 / 97 (H9N2)) nucleoprotein gene of segment 5 (NP), complete cds. AF156404 Influenza A virus (A / Pigeon / Hong Kong / Y233 / 97 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds.

AF156405 Influenza A virus (A / Pato / Hong Kong / Y280 / 97 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF156406 Influenza A virus (A / Pato / Hong Kong / Y439 / 97 (H9N2)) nucleoprotein gene of segment 5 (NP), complete cds. AF156407 Influenza A virus (A / Quail / Hong Kong / Gl / 97 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF508612 Influenza A virus (A / Chicken / Sichuan / 5/97 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF536702 Influenza A virus (A / Chicken / Guangdong / 97 (H9N2)) nucleotide gene (NP), partial cds. AF536700 Influenza A virus (A / Chicken / Beij ing / 2/97 (H9N2)) nucleotide gene (NP), partial cds. AF508615 Influenza A virus (A / Chicken / Shenzhen / 9/97 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF508616 Influenza A virus (A / Pato / Nanjing / 1/97 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AB049161 Influenza A virus (A / parakeet / Chiba / 1/97 (H9N2)) NP gene for nucleopreoteine, complete cds. AF508603 Influenza A virus (A / Pheasant / Ireland / PV18 / 97 (H9N2)) Nucleoprotein gene of segment 5 (NP), partial cds. AF508607 Influenza A virus (A / Chicken / Guangdong / 11/97 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF508609 Influenza A virus (A / Chicken / Heilongj iang / 10/97 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF508608 Influenza A virus (A / Chicken / Hebei / 4/98 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF508605 Influenza A virus (A / Chicken / Beij ing / 8/98 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF508599 Influenza A virus (A / Chicken / Germany / R45 / 98 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF536708 Influenza A virus (A / Chicken / Shandong / 98 (H9N2)) nucleotide gene (NP), partial cds. AY253753 Influenza A virus (A / Chicken / Shangai / F / 98 (H9N2)) nucleotide gene (NP), complete cds. AF536704 Influenza A virus (A / Chicken / Hebei / 2/98 (H9N2)) nucleotide gene (NP), partial cds. AF536705 Influenza A virus (A / Chicken / Hebei / 3/98 (H9N2)) nucleotide gene (NP), partial cds. AF536706 Influenza A virus (A / Chicken / Henan / 98 (H9N2)) nucleotide gene (NP), partial cds. AB049162 Influenza A virus (A / parakeet / Narita / 92A / 98 (H9N2)) NP gene for nucleopreoteine, complete cds. AF186270 Influenza A virus (A / Quail / Hong Kong / NT28 / 99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF186271 Influenza A virus (A / Chicken Silkie / Hong Kong / SF43 / 99 (H9N2)) Nucleoprotein gene of segment 5 (NP), partial cds. AF186272 Influenza A virus (A / Chicken / Hong Kong / SF2 / 99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF222614 Influenza A virus (A / Quail / Hong Kong / A17 / 99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF222615 Influenza A virus (A / Pigeon / Hong Kong / FY6 / 99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF222616 Influenza A virus (A / Chicken / Hong Kong / NT16 / 99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF222617 Influenza A virus (A / Quail / Hong Kong / SSP10 / 99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF222618 Influenza A virus (A / Pheasant / Hong Kong / SSPll / 99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF536707 Influenza A virus (A / Chicken / Liaoning / 99 (H9N2)) nucleotide gene (NP), partial cds. AJ291394 Influenza A virus (A / Chicken / Pakistan / 2/99 (H9N2)) NP gene for nucleopreotein, genomic RNA. AF536701 Influenza A virus (A / Chicken / Beij ing / 3/99 (H9N2)) nucleprotein gene (NP.), Partial cds. AF508611 Influenza A virus (A / Chicken / Ningxia / 5/99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF508614 Influenza A virus (A / Chicken / Shij iazhuang / 2/99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF508604 Influenza A virus (A / Chicken / Korea / 99029/99 (H9N2)) segment 5 nucleoprotein gene (NP), partial cds. AF222619 Influenza A virus (A / Chicken / Hong Kong / FY20 / 99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF222620 Influenza A virus (A / Chicken / Hong Kong / KC12 / 99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF222621 Influenza A virus (A / Chicken silky / Hong Kong / SF44 / 99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF508601 Influenza A virus (A / Chicken / Iran / llT / 99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF508602 Influenza A virus (A / Chicken / Arabia Saudi / 532/99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF508597 Influenza A virus (A / Chicken / Pakistan / 4/99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. } AF508598 Influenza A virus (A / Chicken / Pakistan / 5/99 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF508606 Influenza A virus (A / Chicken / Guangdong / 10/00 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF508610 Influenza A virus (A / Chicken / Henan / 62/00 (H9N2)) nucleoprotein gene of segment 5 (NP), partial cds. AF523410 Influenza A virus (A / Pato / Shantou / 1043/00 (H9N2)) Nucleocapsid protein gene (NP), partial cds. AF523411 Influenza A virus (A / Pato / Shantou / 2134/00 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AF523413 Influenza A virus (A / Pato / Shantou / 1042/00 (H9N2)) Nucleocapsid protein gene (NP), partial cds.

AF523415 Influenza A virus (A / Pato / Shantou / 2102/00 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AF523416 Influenza A virus (A / Pato / Shantou / 830/00 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AF523417 Influenza A virus (A / Pato / Shantou / 2144/00 (H9N2)) Nucleocapsid protein gene (NP), partial cds. AF523419 Influenza A virus (A / Pato / Shantou / 2143/00 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AF523420 Influenza A virus (A / Pato / Shantou / 1881/00 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AJ427864 Influenza A virus (A / quail / Hong Kong / FY298 / 00 (H9N2)) partial NP gene for nucleopreotein, genomic RNA AY180525 Influenza A virus (A / Pigeon / Nanchang / 2-0461 / 2000 (H9N2)) gene of nucleotide (NP), partial cds. AY180534 Influenza virus strain A A / Pato / Nanchang / 7-092 / 2000 (H9N2) nucleotide gene (NP), partial cds. AY180537 Influenza virus strain A A / Pato / Nanchang / 11-392 / 2000 (H9N2) nucleprotein gene (NP), partial cds. AY180538 Influenza A virus (A / Pigeon / Nanchang / 11-145 / 2000 (H9N2)) nucleprotein gene (NP), partial cds. AY180542 Virus strain of influenza A A / Pato / Nanchang / 11-197 / 2000 (H9N2) nucleotide gene (NP), partial cds. AY180544 Virus strain of influenza A A / Pato / Nanchang / 11-290 / 2000 (H9N2) gene of nucleotide (NP), partial cds.

AY180560 Influenza A virus (A / Pigeon / Nanchang / 7-058 / 2000 (H9N2)) nucleotide gene (NP), partial cds. AY180562 Strain of influenza virus A A / Chicken / Nanchang / 4-010 / 2000 (H9N2) nucleotide gene (NP), partial cds. AY180563 Influenza virus strain A A / Quail / Nanchang / 4-040 / 2000 (H9N2) nucleotide gene (NP), partial cds. AY180564 Influenza A virus (A / Wild Duck / Nanchang / 2-0480 / 2000 (H9N2)) nucleotide gene (NP), partial cds. AY180575 Influenza A virus (A / Quail / Nanchang / 2-0460 / 2000 (H9N2)) nucleotide gene (NP), partial cds. AY496851 Influenza A virus (A / chicken / Mudanjiang / 0823/2000 (H9N2)) Nucleoprotein mRNA (np), complete cds. AY180581 Influenza A virus (A / Chicken / Nanchang / 1-0016 / 2000 (H9N2)) nucleotide gene (NP), partial cds. AY180583 Influenza virus strain A A / Pato / Nanchang / 10-389 / 2000 (H9N2) nucleprotein gene (NP), partial cds. AY180584 Virus strain of influenza A A / Pato / Nanchang / 1-0070 / 2000 (H9N2) nucleotide gene (NP), partial cds. AY768567 Influenza A virus (A / chicken / Korea / SNU0028 / 00 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AY768568 Influenza A virus (A / chicken / Korea / SNU0037 / 00 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AY768569 Influenza A virus (A / chicken / Korea / SNU0057 / 00 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AY768570 Influenza A virus (A / chicken / Korea / SNU0073 / 00 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AY768571 Influenza A virus (A / chicken / Korea / SNU0091 / 00 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AY768572 Influenza A virus (A / chicken / Korea / SNU0140 / 00 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AY768573 Influenza A virus (A / chicken / Korea / SNU0146 / 00 (H9N2)) Nucleocapsid protein gene (NP), partial cds. AY768574 Influenza A virus (A / chicken / Korea / SNU1035C / 00 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AY268949 Influenza A virus (A / chicken / Wangcheng / 4/2001 (H9N2)) Nucleoprotein mRNA, complete cds. AY180578 Strain of influenza virus A A / Chicken / Nanchang / 4-301 / 2001 (H9N2) nucleotide gene (NP), partial cds. AY180551 Influenza A virus (A / Chicken / Nanchang / 4-361 / 2001 (H9N2)) nucleotide gene (NP), partial cds. AF523418 Influenza A virus (A / Pato / Shantou / 2088/01 (H9N2)) Nucleocapsid protein gene (NP), partial cds. AF523414 Influenza A virus (A / Pato / Shantou / 1605/01 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AF523412 Influenza A virus (A / Wild Duck / Shantou / 4808/01 (H9N2)) Nucleocapsid protein gene (NP), partial cds. AY800236 Influenza A virus (A / chicken / Korea / Sl / 2003 (H9N2)) nucleotide gene (NP), partial cds. AY862646 Influenza A virus (A / silky chicken / Korea / S3 / 03 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AY862647 Influenza A virus (A / chicken / Korea / S4 / 03 (H9N2)) Nucleocapsid protein (NP) gene, partial cds. AY862648 Influenza A virus (A / chicken / Korea / S5 / 03 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AY862649 Influenza A virus (A / chicken / Korea / S12 / 03 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AY862650 Influenza A virus (A / duck / Korea / S13 / 03 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AY862651 Influenza A virus (A / pigeon / Korea / S14 / 03 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AY862652 Influenza A virus (A / chicken / Korea / S15 / 03 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AY862653 Influenza A virus (A / chicken / Korea / S16 / 03 (H9N2)) nucleocapsid protein (NP) gene, partial cds. AY862654 Influenza A virus (A / chicken / Korea / S18 / 03 (H9N2)) Nucleocapsid protein gene (NP), partial cds. AY664717 Influenza A virus (A / chicken / Hong Kong / CSW153 / 03 (H9N2)) nucleotide gene (NP), complete cds. AY664718 Influenza A virus (A / chicken / Hong Kong / AP45 / 03 »(H9N2)) nucleprotein gene (NP), complete cds. AY664719 Influenza A virus (A / chicken / Hong Kong / BD90 / 03 (H9N2)) nucleotide gene (NP), complete cds. AY664720 Influenza A virus (A / chicken / Hong Kong / CSW291 / 03 (H9N2)) nucleprotein gene (NP), complete cds. AY664721 Influenza A virus (A / chicken / Hong Kong / CSW304 / 03 (H9N2)) nucleotide gene (NP), complete cds. AY664722 Influenza A virus (A / chicken / Hong Kong / FY23 / 03 (H9N2)) nucleprotein gene (NP), complete cds. AY664723 Influenza A virus (A / guinea fowl / Hong Kong / NT101 / 03 (H9N2)) nucleotide gene (NP), complete cds. AY664724 Influenza A virus (A / chicken / Hong Kong / NT142 / 03 (H9N2)) nucleotide gene (NP), complete cds. AY664725 Influenza A virus (A / chicken / Hong Kong / SFl / 03 (H9N2)) nucleotide gene (NP), complete cds. AY664726 Influenza A virus (A / chicken / Hong Kong / SSP101 / 03 (H9N2)) nucleprotein gene (NP), complete cds. AY664727 Influenza A virus (A / chicken / Hong Kong / TP38 / 03 (H9N2)) nucleotide gene (NP), complete cds. AY664728 Influenza A virus (A / chicken / Hong Kong / WF126 / 03 (H9N2)) nucleotide gene (NP), complete cds. AY664729 Influenza A virus (A / pigeon / Hong Kong / WF53 / 03 (H9N2)) nucleotide gene (NP), complete cds AY664730 Influenza A virus (A / pheasant / Hong Kong / WF54 / 03 (H9N2) ) Nucleprotein gene (NP), complete cds. AY664731 Influenza A virus (A / guinea fowl / Hong Kong / NT184 / 03 (H9N2)) nucleotide gene (NP), complete cds. AY664732 Influenza A virus (A / chicken / Hong Kong / WF120 / 03 (H9N2)) nucleotide gene (NP), complete cds. AY664733 Influenza A virus (A / chicken / Hong Kong / NT366 / 03 (H9N2)) nucleotide gene (NP), partial cds. AY664734 Influenza A virus (A / chicken / Hong Kong / SSP418 / 03 (H9N2)) nucleotide gene (NP), partial cds. AY664735 Influenza A virus (A / chicken / Hong Kong / YU427 / 03 (H9N2)) nucleprotein gene (NP), partial cds. AY788915 Influenza A virus (A / chicken / China / HSS2004 (H9N2)) nucleotide gene (NP), complete cds. AY586423 Influenza A virus (A / wild turkey / Italy / 33/01 (H7N3)) nucleoprotein gene, partial cds. AY586424 Influenza A virus (A / wild turkey / Italy / 43/01 (H7N3)) nucleoprotein gene, partial cds. AY586425 Influenza A virus (A / turkey / Italy / 220158/2002 (H7N3)) nucleoprotein gene, partial cds. AY586426 Influenza A virus (A / turkey / Italy / 214845/02 (H7N3)) nucleoprotein gene, partial cds. AJ627486 Influenza A virus (A / turkey / Italy / 214845/2002 (H7N3)) NP gene for nucleopreotein, genomic RNA. AJ627495 Influenza A virus (A / turkey / Italy / 220158/2002 (H7N3)) NP gene for nucleopreotein, genomic RNA. AY303658 Influenza A virus (A / chicken / Chile / 176822/02 (H7N3)) nucleoprotein gene, complete cds. AY303659 Influenza A virus (A / chicken / Chile / 4957/02 (H7N3)) nucleoprotein gene, complete cds. AY611527 Influenza A virus (A / chicken / British Columbia / 04 (H7N3)) nucleotide gene (NP), complete cds.

AY646081 Influenza A virus (A / chicken / British Columbia / GSC_human_B / 04 (H7N3)) nucleotide gene (NP), complete cds. AY648290 Influenza A virus (A / GSC_pollo_B / British Columbia / 04 (H7N3)) nucleprotein gene (NP), complete cds.

AY650273 Influenza A virus (A / GSC_pollo / British Columbia / 04 (H7N3)) nucleotide gene (NP), complete cds.

AF144303 Influenza A virus (A / Goose / Guangdong / 1/96 (H5N1)) nucleocapsid protein (NP) gene, complete cds. AF046084 Influenza A virus (A / Chicken / Hong Kong / 220/97 (H5N1)) nucleoprotein gene, complete cds. AF057293 Influenza A virus (A / chicken / Hong Kong / 258/97 (H5N1)) Nucleoprotein mRNA, complete cds. AF098617 Influenza A virus (A / Chicken / Hong Kong / y388 / 97 (H5N1)) nucleotide gene (NP), complete cds. AF098618 Influenza A virus (A / Chicken / Hong Kong / 728/97 (H5N1)) nucleotide gene (NP), complete cds. AF098619 Influenza A virus (A / Chicken / Hong Kong / 786/97 (H5N1)) nucleotide gene (NP), complete cds. AF098620 Influenza A virus (A / Chicken / Hong Kong / 915/97 (H5N1)) nucleotide gene (NP), complete cds. AF098621 Influenza A virus (A / Duck / Hong Kong / p46 / 97 (H5N1)) nucleotide gene (NP), complete cds. AF098622 Influenza A virus (A / Pato / Hong Kong / y283 / 97 (H5N1)) nucleotide gene (NP), complete cds. AF098623 Influenza A virus (A / Goose / Hong Kong / w355 / 97 (H5N1)) nucleotide gene (NP), complete cds. AF370122 Influenza A virus (A / Goose / Guangdong / 3/97 (H5N1)) nucleoprotein gene, complete cds. AF216712 Influenza A virus (A / Environment / Hong Kong / 437- / 99 (H5N1)) nucleoprotein gene, complete cds. AF216720 Influenza A virus (A / Environment / Hong Kong / 437-6 / 99 (H5N1)) nucleoprotein gene, complete cds. AF216728 Influenza A virus (A / Environment / Hong Kong / 437- / 99 (H5N1)) nucleoprotein gene, complete cds. AF216736 Influenza A virus (A / Environment / Hong Kong / 437-10 / 99 (H5N1)) nucleoprotein gene, complete cds. AY585429 Influenza A virus (A / duck / Guangxi / 07/1999 (H5N1)) Nucleoprotein mRNA (np), complete cds.

AY585439 Influenza A virus (A / duck / Zhej iang / 11/2000 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585440 Influenza A virus (A / duck / Zhej iang / 52/2000 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585428 Influenza A virus (A / duck / Guangdong / 40/2000 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585423 Influenza A virus (A / duck / Fuj ian / 19/2000 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585425 Influenza A virus (A / duck / Guangdong / 07/2000 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585426 Influenza A virus (A / duck / Guangdong / 12/2000 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY059492 Influenza A virus (A / Goose / Hong Kong / ww26 / 2000 (H5N1)) protein nucleocapsid segment 5 (NP), partial cds. AY059493 Influenza A virus (A / Goose / Hong Kong / ww28 / 2000 (H5N1)) nucleocapsid protein gene segment 5 (NP), partial cds. AY059494 Influenza A virus (A / Pato / Hong Kong / ww381 / 2000 (H5N1)) nucleocapsid protein gene segment 5 (NP), partial cds. AY059495 Influenza A virus (A / Pato / Hong Kong / ww461 / 2000 (H5N1)) Nucleocapsid protein gene segment 5 (NP), partial cds. AY059496 Influenza A virus (A / Goose / Hong Kong / ww491 / 2000 (H5N1)) nucleocapsid protein gene segment 5 (NP), partial cds. AY059497 Influenza A virus (A / Pato / Hong Kong / 2986.1 / 2000 (H5N1)) nucleocapsid protein gene segment 5 (NP), partial cds. AY059498 Influenza A virus (A / Goose / Hong Kong / 3014.8 / 2000 (H5N1)) Nucleocapsid protein gene segment 5 (NP), partial cds. AF398419 Influenza A virus (A / Goose / Hong Kong / 385.3 / 2000 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF398420 Influenza A virus (A / Goose / Hong Kong / 385.5 / 2000 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF468842 Influenza A virus (A / Pato / Anyang / AVL-1/2001 (H5N1)) nucleotide gene (NP), complete cds. AF509117 Influenza A virus (A / Chicken / Hong Kong / FY77 / 01 (H5N1)) nucleocapsid protein (NP) gene, complete cds. AF509118 Influenza A virus (A / Chicken / Hong Kong / YU562 / 01 (H5N1)) nucleocapsid protein (NP) gene, complete cds. AF509119 Influenza A virus (A / Chicken / Hong Kong / YU563 / 01 (H5N1)) nucleocapsid protein (NP) gene, complete cds. AY585438 Influenza A virus (A / duck / Shangai / 38/2001 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY221548 Influenza A virus (A / Chicken / Hong Kong / NT873.3 / 01-MB (HSNl)) Nucleocapsid protein gene (NP), partial cds. AY221549 Influenza A virus (A / Chicken / Hong Kong / NT873.3 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY221550 Influenza A virus (A / Chicken / Hong Kong / FY150 / 01-MB (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY221551 Influenza A virus (A / Chicken / Hong Kong / FY150 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY221552 Influenza A virus (A / Pheasant / Hong Kong / FY155 / 01-MB (HSNl)) Nucleocapsid protein gene (NP), partial cds. AY221553 Influenza A virus (A / Pheasant / Hong Kong / FY155 / 01 (H5N1)) Nucleocapsid protein gene (NP), partial cds. AY221554 Influenza A virus (A / Chicken / Hong Kong / YU822.2 / 01-MB (HSNl)) Nucleocapsid protein gene (NP), partial cds. AY221555 Influenza A virus (A / Chicken / Hong Kong / YU822.2 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY221556 Influenza A virus (A / Chicken / Hong Kong / YU562 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509120 Influenza A virus (A / Chicken / Hong Kong / FY150 / 01 (H5N1)) nucleocapsid protein (NP) gene, complete cds. AF509121 Influenza A virus (A / Pheasant / Hong Kong / FY155 / 01 (H5N1)) nucleocapsid protein (NP) gene, complete cds. AF509122 Influenza A virus (A / Chicken silky / Hong Kong / SF189 / 01 (H5N1)) Nucleocapsid protein gene (NP), partial cds. AF509123 Influenza A virus (A / Quail / Hong Kong / SF203 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509124 Influenza A virus (A / Pigeon / Hong Kong / SF215 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509125 Influenza A virus (A / Chicken / Hong Kong / SP219 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509126 Influenza A virus (A / Chicken / Hong Kong / 715.5 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509127 Influenza A virus (A / Chicken / Hong Kong / 751.1 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509128 Influenza A virus (A / Chicken / Hong Kong / 822.1 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509129 Influenza A virus (A / Chicken / Hong Kong / 829.2 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509130 Influenza A virus (A / Chicken / Hong Kong / 830.2 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds.

AF509131 Influenza A virus (A / Chicken / Hong Kong / 858.3 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509132 Influenza A virus (A / Chicken / Hong Kong / 866.3 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509133 Influenza A virus (A / Chicken / Hong Kong / 867.1 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509134 Influenza A virus (A / Chicken / Hong Kong / 879.1 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509135 Influenza A virus (A / Chicken / Hong Kong / 873.3 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509136 Influenza A virus (A / Chicken / Hong Kong / 876.1 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509137 Influenza A virus (A / Chicken / Hong Kong / 891.1 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509138 Influenza A virus (A / Chicken / Hong Kong / 893.2 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509139 Influenza A virus (A / Goose / Hong Kong / 76.1 / 01 (H5N1)) nucleocapsid protein (NP) gene, complete cds. AF509140 Influenza A virus (A / Goose / Hong Kong / wwl00 / 01 (H5N1)) Nucleocapsid protein gene (NP), partial cds. AF509141 Influenza A virus (A / Pato / Hong Kong / 573.4 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AF509142 Influenza A virus (A / Pato / Hong Kong / 646.3 / 01 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY585424 Influenza A virus (A / duck / Guangdong / 01/2001 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585422 Influenza A virus (A / duck / Fuj ian / 17/2001 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585430 Influenza A virus (A / duck / Guangxi / 22/2001 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585431 Influenza A virus (A / duck / Guangxi / 35/2001 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585432 Influenza A virus (A / duck / Guangxi / 50/2001 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585434 Influenza A virus (A / duck / Shangai / 08/2001 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585435 Influenza A virus (A / duck / Shangai / 13/2001 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585436 Influenza A virus (A / duck / Shangai / 35/2002 (H5N1)) nucleoprotein mRNA (np), complete cds. AY585437 Influenza A virus (A / duck / Shangai / 37/2002 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585433 Influenza A virus (A / duck / Guangxi / 53/2002 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585427 Influenza A virus (A / duck / Guangdong / 22/2002 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585420 Influenza A virus (A / duck / Fuj ian / 01/2002 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY585421 Influenza A virus (A / duck / Fuj ian / 13/2002 (H5N1)) Nucleoprotein mRNA (np), complete cds.

AY575907 Influenza A virus (A / Gs / HK / 739.2 / 02 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY575908 Influenza A virus (A / Eg / HK / 757.3 / 02 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY575909 Influenza A virus (A / G. H / HK / 793.1 / 02 (H5N1)) Nucleocapsid protein gene (NP), partial cds. AY575910 Influenza A virus (A / Dk / HK / 821/02 (H5N1)) Nucleocapsid protein (NP) gene, partial cds. AY575911 Influenza A virus (A / Ck / HK / 31.4 / 02 (H5N1)) nucleocapsid protein (NP) gene, complete cds. AY575912 Influenza A virus (A / Ck / HK / 61.9 / 02 (H5N1)) nucleocapsid protein (NP) gene, complete cds. AY575913 Influenza A virus (A / Ck / HK / YU777 / 02 (H5N1)) Nucleocapsid protein gene (NP), partial cds. AY575914 Influenza A virus (A / Ck / HK / 96.1 / 02 (H5N1)) Nucleocapsid protein gene (NP), partial cds. AY575915 Influenza A virus (A / Ck / HK / 409.1 / 02 (H5N1)) Nucleocapsid protein (NP) gene, partial cds. AY575916 Influenza A virus (A / Ph / HK / sv674.15 / 02 (H5N1)) Nucleocapsid protein gene (NP), partial cds. DQ023146 Influenza A virus (A / chicken / sd / 1/02 (H5N1)) Nucleoprotein mRNA (np), complete cds. AY676037 Influenza A virus (A / duck / Hong Kong / 821/02 (H5N1)) nucleotide gene (NP), complete cds. AY651510 Influenza A virus (A / Gf / HK / 38/2002 (H5N1)) nucleocapsid protein (NP) gene, complete cds. AY651511 Influenza A virus (A / Ck / HK / 31.2 / 2002 (H5N1)) nucleocapsid protein (NP) gene, complete cds. AY651512 Influenza A virus (A / Ck / HK / 37.4 / 2002 (H5N1)) nucleocapsid protein (NP) gene, complete cds. AY651513 Influenza A virus (A / SCk / HK / YU100 / 2002 (H5N1)) nucleocapsid protein (NP) gene, complete cds. AY651514 Influenza A virus (A / Ck / HK / YU22 / 2002 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651521 Influenza A virus (A / Ck / HK / 3176.3 / 2002 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651522 Influenza A virus (A / Ck / HK / 3169.1 / 2002 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651524 Influenza A virus (A / wild chick / HK / 862.7 / 2002 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651525 Influenza A virus (A / sparrow miller / HK / 864/2002 (H5N1)) Nucleocapsid protein gene (NP), partial cds. AY651526 Influenza A virus (A / Gray Heron / HK / 861.1 / 2002 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651527 Influenza A virus (A / teal / China / 2978.1 / 2002 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651523 Influenza A virus (A / greyish-headed gull / HK / 12.1 / 2003 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651487 Influenza A virus (A / Ck / Indonesia / PA / 2003 (H5N1)) Nucleocapsid protein (NP) gene, partial cds. AY651515 Influenza A virus (A / Ck / HK / 2133.1 / 2003 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651516 Influenza A virus (A / Ck / HK / NT93 / 2003 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651517 Influenza A virus (A / Ck / HK / SSP141 / 2003 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651518 Influenza A virus (A / Ck / HK / WP157 / 2003 (H5N1)) Nucleocapsid protein gene (NP), partial cds. AY651519 Influenza A virus (A / Ck / HK / FY157 / 2003 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651520 Influenza A virus (A / Ck / HK / YU324 / 2003 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651490 Influenza A virus (A / Ck / Indonesia / 2A / 2003 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY676038 Influenza A virus (A / heron / Hong Kong / 757.2 / 03 (H5N1)) nucleotide gene (NP), complete cds. AY676039 Influenza A virus (A / chicken / Korea / ES / 03 (H5N1)) nucleotide gene (NP), complete cds. AY676040 Influenza A virus (A / duck / Korea / ESDl / 03 (H5N1)) nucleotide gene (NP), complete cds. AY651529 Influenza A virus (A / Dk / HN / 5806/2003 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651532 Influenza A virus (A / Ck / ST / 4231/2003 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651534 Influenza A virus (A / Dk / ST / 4003/2003 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651535 Influenza A virus (A / Dk / YN / 6255/2003 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651536 Influenza A virus (A / Dk / YN / e445 / 2003 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651485 Influenza A virus (A / Ck / Indonesia / BL / 2003 (H5N1)) Nucleocapsid protein (NP) gene, partial cds. AY518364 Influenza A virus (A / duck / China / E319-2 / 03 (H5N1)) nucleocapsid protein (NP) gene, complete cds. AY574189 Influenza A virus (A / chicken / Vietnam / HDl / 2004 (H5N1)) nucleoprotein gene, partial cds. AY574192 Influenza A virus (A / chicken / Vietnam / HD2 / 2004 (H5N1)) nucleoprotein gene, partial cds. AJ867076 Influenza A virus (A / Hatay / 2004 / (H5N1)) NP gene for nucleopreotein, genomic RNA AY651486 Influenza A virus (A / Dk / Indonesia / MS / 2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY590579 Influenza A virus (A / chicken / Nakorn-Patom / Thailand / CU-K2 / 2004 (H5N1)) Nucleocapsid protein gene (NP), complete cds. AY609313 Influenza A virus (A / chicken / Guangdong / 174/04 (H5N1)) segment 5, complete sequence. AY576929 Influenza A virus (A / chicken / Vietnam / CM / 2004 (H5N1)) nucleoprotein gene of segment 5, partial cds. AY576931 Influenza A virus (A / Creole duck / Vietnam / MdGL / 2004 (H5N1)) nucleoprotein gene of segment 5, partial cds. AB166863 Influenza A virus (A / chicken / Yamaguchi / 7/2004 (H5N1)) NP gene for nucleopreoteine, complete cds. AB188817 Influenza A virus (A / chicken / Oita / 8/2004 (H5N1)) NP gene for nucleopreoteine, complete cds. AY651537 Influenza A virus (A / Ck / YN / 374/2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651538 Influenza A virus (A / Ck / YN / 115/2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY653196 Influenza A virus (A / chicken / Jilin / 9/2004 (H5N1)) segment 5, complete sequence. AY651533 Influenza A virus (A / Ph / ST / 44/2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651530 Influenza A virus (A / Dk / HN / 303/2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651531 Influenza A virus (A / Dk / HN / 101/2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY684707 Influenza A virus (A / chicken / Hubei / 327/2004 (H5N1)) nucleotide gene (NP), complete cds. AY737290 Influenza A virus (A / chicken / Guangdong / 191/04 (H5N1)) segment 5, complete sequence. AY737297 Influenza A virus (A / chicken / Guangdong / 178/04 (H5N1)) segment 5, complete sequence. AY737305 Influenza A virus (A / duck / Guangdong / 173/04 (H5N1)) segment 5, complete sequence. AY770081 Influenza A virus (A / chicken / Hubei / 489/2004 (H5N1)) nucleotide gene (NP), complete cds. AY770996 Influenza A virus (A / chicken / Ayutthaya / Thailand / CU-23/04 (H5N1)) nucleoprotein gene, partial cds. AY818139 Influenza A virus (A / chicken / Vietnam / C58 / 04 (H5N1)) NP nucleoprotein gene, complete cds. AY818140 Influenza A virus (A / quail / Vietnam / 36/04 (H5N1)) NP nucleoprotein gene, complete cds. AY856864 Influenza A virus (A / duck / Shandong / 093/2004 (H5N1)) segment 5, complete sequence. AB189046 Influenza A virus (A / chicken / Kyoto / 3/2004 (H5N1)) NP gene for nucleopreoteine, complete cds ,. AB189054 Influenza A virus (A / raven / Kyoto / 53/2004 (H5N1)) NP gene for nucleopreoteine, complete cds ,. AB189062 Influenza A virus (A / raven / Osaka / 102/2004 (H5N1)) NP gene for nucleopreoteine, complete cds,. AY651491 Influenza A virus (A / Ck / Thailand / 1/2004 (H5N1)) Nucleocapsid protein gene (NP), partial cds. AY651492 Influenza A virus (A / Ck / Thailand / 73/2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651493 Influenza A virus (A / Ck / Thailand / 9.1 / 2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651494 Influenza A virus (A / Qa / Thailand / 57/2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651495 Influenza A virus (A / bird / Thailand / 3.1 / 2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651496 Influenza A virus (A / Dk / Thailand / 71.1 / 2004 (H5N1)) Nucleocapsid protein gene (NP), partial cds. AY651497 Influenza A virus (A / Gs / Thailand / 79/2004 (H5N1)) Nucleocapsid protein gene (NP), partial cds. AY651502 Influenza A virus (A / Ck / Vietnam / 33/2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651503 Influenza A virus (A / Ck / Vietnam / 35/2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651504 Influenza A virus (A / Ck / Vietnam / 36/2004 (H5N1)) Nucleocapsid protein gene (NP), partial cds. AY651505 Influenza A virus (A / Ck / Vietnam / 37/2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651506 Influenza A virus (A / Ck / Vietnam / 38/2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651507 Influenza A virus (A / Ck / Vietnam / 39/2004 (H5N1)) Nucleocapsid protein (NP) gene, partial cds. AY651508 Influenza A virus (A / Ck / Vietnam / C57 / 2004 (H5N1)) Nucleocapsid protein gene (NP), partial cds. AY651509 Influenza A virus (A / Dk / Vietnam / 11/2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651488 Influenza A virus (A / Ck / Indonesia / 4/2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. AY651489 Influenza A virus (A / Ck / Indonesia / 5/2004 (H5N1)) Nucleocapsid protein (NP) gene, partial cds. AY651528 Influenza A virus (A / peregrine falcon / HK / D0028 / 2004 (H5N1)) nucleocapsid protein (NP) gene, partial cds. M22573 Influenza A / duck / Hong Kong / 7/75 (H3N2), nucleoprotein (sec 5), RNA. AY180555 Influenza A virus (A / Chicken / Nanchang / 3-120 / 2001 (H3N2)) nucleprotein gene (NP), partial cds. AY779261 Influenza A virus (A / turkey / North Carolina / 12344/03 (H3N2)) nucleotide gene (NP), partial cds. AY779262 Influenza A virus (A / turkey / Minnesota / 764-2 / 03 (H3N2)) nucleotide gene (NP), partial cds. AY862655 Influenza A virus (A / chicken / Korea / S6 / 03 (H3N2)) nucleocapsid protein (NP) gene, partial cds. AY862656 Influenza A virus (A / duck / Korea / S7 / 03 (H3N2)) nucleocapsid protein (NP) gene, partial cds. AY862657 Influenza A virus (A / duck / Korea / S8 / 03 (H3N2)) Nucleocapsid protein gene (NP), partial cds.

AY862S58 Influenza A virus (A / duck / Korea / S9 / 03 (H3N2)) nucleocapsid protein (NP) gene, partial cds. AY862659 Influenza A virus (A / duck / Korea / S10 / 03 (H3N2)) Nucleocapsid protein gene (NP),, partial cds. AY862660 Influenza A virus (A / pigeon / Korea / Sll / 03 (H3N2)) Nucleocapsid protein gene (NP), partial cds. D00050 Influenza A virus gene for nucleoprotein, complete cds. M14921 Influenza A / Wild turkey / NY / 6750/78 (H2N2) nucleoprotein (sec 5) RNA, complete cds. AY422026 Influenza A virus (A / duck / Hokkaido / 95/01 (H2N2)) nucleotide gene (NP), partial cds. U49093 Nucleoprotein mRNA of influenza A (NP) virus, partial cds. M22574 Influenza A / duck / Bavaria / 2/77 (H1N1), nucleoprotein (sec 5), RNA. M76603 Influenza A / turkey / England / 647/77 (H1N1) mRNA, complete cds. M63783 Influenza A / Duck / Australia / 749/80 (H1N1) Nucleoprotein mRNA, complete cds. M63778 Influenza A / Turkey / Minnesota / 1661/81 (H1N1) Nucleoprotein mRNA, complete cds. Z26855 NP gene of influenza virus type A for nucleopreotein M76609 Influenza A / turkey / North Carolina / 1790/88 (H1N1) mRNA, complete cds. Z26857 Gen NP of influenza virus type A for nucleopreoteine AF213905 Influenza A virus (A / wild turkey / Italy / 24/95 (H1N1)) nucleoprotein gene of segment 5 (NP), partial cds. AF213906 Influenza A virus (A / Chicken / Italy / 24/95 (H1N1)) nucleoprotein gene of segment 5 (NP), partial cds. AY633215 Influenza A virus (A / wild turkey / Alberta / 211/98 (H1N1)) nucleprotein gene (NP), complete cds. AY180543 Influenza A virus (A / Quail / Nanchang / 12-340 / 2000 (H1N1)) nucleotide gene (NP), partial cds.

Sequences used in the analysis of Influenza A Basic Polymerase 1 (PBl) protein AY633218 Influenza A virus (A / wild turkey / Alberta / 211/98 (H1N1)) Pl RNA polymerase (PBl) subunit gene targeted to RNA, partial cds. U48284 Polymerase mRNA of influenza A virus (PBl), partial cds. AY180855 Virus strain of influenza A A / Quail / Nanchang / 12-340 / 2000 (HlNl) polymerase subunit gene PBl (PBl), partial cds.

AY422038 Influenza A virus (A / duck / Hokkaido / 95/01 (H2N2)) polymerase subunit gene (PBl), partial cds. M25926 Influenza A / Wild turkey / New York / 6750/78 (H2N2) gen PBl, complete cds. AY180871 Virus strain of influenza A A / Chicken / Nanchang / 3 -120/2001 (H3N2) polymerase subunit gene PBl (PBl), partial cds. AY779265 Influenza A virus (A / turkey / North Carolina / 12344/03 (H3N2)) polymerase 1 basic protein gene (PBl), partial cds. AY779266 Influenza A virus (A / turkey / Minnesota / 764-2 / 03 (H3N2)) polymerase 1 basic protein gene (PBl), partial cds. AY862703 Influenza A virus (A / chicken / Korea / S6 / 03 (H3N2)) PBl gene (PBl), partial cds. AY862704 Influenza A virus (A / duck / Korea / S7 / 03 (H3N2)) gene PBl (PBl), partial cds. AY862705 Influenza A virus (A / duck / Korea / S8 / 03 (H3N2)) Gen PBl (PBl), partial cds. AY862706 Influenza A virus (A / duck / Korea / S9 / 03 (H3N2)) Gen PBl (PBl), partial cds. AY862707 Influenza A virus (A / duck / Korea / S10 / 03 (H3N2)) Gen PBl (PBl), partial cds. AY862708 Influenza A virus (A / pigeon / Korea / Sll / 03 (H3N2)) gene PBl (PBl), partial cds.

AF213911 Influenza A virus (A / Chicken / Italy / 5945/95 (H3N2)) polymerase protein gene PBl segment 8, partial cds. AB166860 Influenza A virus (A / chicken / Yamaguchi / 7/2004 (H5N1)) gene PBl for polymerase 1 basic protein, complete cds. AB188814 Influenza A virus (A / chicken / Oita / 8/2004 (H5N1)) gene PBl for polymerase 1 basic protein, complete cds. AF398423 Influenza A virus (A / Goose / Hong Kong / 385.3 / 2000 (H5N1)) polymerase gene (PBl), partial cds. AF398424 Influenza A virus (A / Goose / Hong Kong / 385.5 / 2000 (H5N1)) polymerase gene (PBl), partial cds. AF468839 Influenza A virus (A / Pato / Anyang / AVL-1/2001 (H5N1)) polymerase 1 basic protein gene (PBl), complete cds. AF509169 Influenza A virus (A / Chicken / Hong Kong / FY77 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509170 Influenza A virus (A / Chicken / Hong Kong / YU5S2 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509171 Influenza A virus (A / Chicken / Hong Kong / YU563 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509172 Influenza A virus (A / Chicken / Hong Kong / FY150 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509173 Influenza A virus (A / Pheasant / Hong Kong / FY155 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509174 Influenza A virus (A / Chicken silky / Hong Kong / SF189 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509175 Influenza A virus (A / Quail / Hong Kong / SF203 / 01 (H5N1)) polymerase gene (PBl), partial cds.

AF509176 Influenza A virus (A / Pigeon / Hong Kong / SF215 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509177 Influenza A virus (A / Chicken / Hong Kong / SF219 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509178 Influenza A virus (A / Chicken / Hong Kong / 715.5 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509179 Influenza A virus (A / Chicken / Hong Kong / 751.1 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509180 Influenza A virus (A / Chicken / Hong Kong / 822.1 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509181 Influenza A virus (A / Chicken / Hong Kong / 829.2 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509182 Influenza A virus (A / Chicken / Hong Kong / 830.2 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509183 Influenza A virus (A / Chicken / Hong Kong / 858.3 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509184 Influenza A virus (A / Chicken / Hong Kong / 866.3 / 01 (H5N1)) polymerase gene (PBl), partial cds.

AF509185 Influenza A virus (A / Chicken / Hong Kong / 867.1 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509186 Influenza A virus (A / Chicken / Hong Kong / 879.1 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509187 Influenza A virus (A / Chicken / Hong Kong / 873.3 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509188 Influenza A virus (A / Chicken / Hong Kong / 876.1 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509189 Influenza A virus (A / Chicken / Hong Kong / 891.1 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509190 Influenza A virus (A / Chicken / Hong Kong / 893.2 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509191 Influenza A virus (A / Goose / Hong Kong / 76.1 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509192 Influenza A virus (A / Goose / Hong Kong / wwl00 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509193 Influenza A virus (A / Pato / Hong Kong / 573.4 / 01 (H5N1)) polymerase gene (PBl), partial cds. AF509194 Influenza A virus (A / Pato / Hong Kong / 6 6.3 / 01 (H5N1)) polymerase gene (PBl), partial cds. AY035888 Influenza A virus (A / goose / Guangdong / 3/97 (H5N1)) polymerase 1 basic protein gene (PBl), complete cds. AY059513 Influenza A virus (A / Goose / Hong Kong / ww26 / 2000 (H5N1)) polymerase gene segment 2 (PBl), partial cds. AY059514 Influenza A virus (A / Goose / Hong Kong / ww28 / 2000 (H5N1)) segment 2 polymerase gene (PBl), partial cds. AY059515 Influenza A virus (A / Pato / Hong Kong / ww381 / 2000 (H5N1)) segment 2 polymerase gene (PBl), partial cds. AY059516 Influenza A virus (A / Pato / Hong Kong / ww461 / 2000 (H5N1)) polymerase gene segment 2 (PBl), partial cds. AY059517 Influenza A virus (A / Goose / Hong Kong / ww491 / 2000 (H5N1)) polymerase gene segment 2 (PBl), partial cds. AY059518 Influenza A virus (A / Pato / Hong Kong / 2986.1 / 2000 (H5N1)) polymerase gene segment 2 (PBl), partial cds. AY059519 Influenza A virus (A / Goose / Hong Kong / 3014.8 / 2000 (H5N1)) polymerase gene segment 2 (PBl), partial cds. AY221575 Influenza A virus (A / Chicken / Hong Kong / NT873.3 / 01-MB (H5N1)) polymerase 1 basic protein gene (PBl), partial cds. AY221576 Influenza A virus (A / Chicken / Hong Kong / NT873.3 / 01 (H5N1)) polymerase 1 basic protein gene (PBl), partial cds.

AY221577 Influenza A virus (A / Chicken / Hong Kong / FYl50 / 01-MB (H5N1)) polymerase 1 basic protein gene (PBl), partial cds. AY221578 Influenza A virus (A / Chicken / Hong Kong / FY150 / 01 (H5N1)) polymerase 1 basic protein gene (PBl), partial cds. AY221579 Influenza A virus (A / Pheasant / Hong Kong / PY155 / 01-MB (H5N1)) polymerase 1 basic protein gene (PBl), partial cds. AY221580 Influenza A virus (A / Pheasant / Hong Kong / PY155 / 01 (H5N1)) polymerase 1 basic protein gene (PBl), partial cds. AY221581 Influenza A virus (A / Chicken / Hong Kong / YU822.2 / 01-MB (H5N1)) polymerase 1 basic protein gene (PBl), partial cds. AY221582 Influenza A virus (A / Chicken / Hong Kong / Yü822.2 / 01 (H5N1)) polymerase 1 basic protein gene (PBl), partial cds. AY221583 Influenza A virus (A / Chicken / Hong Kong / YU562 / 01 (H5N1)) polymerase 1 basic protein gene (PBl), partial cds. AY518366 Influenza A virus (A / duck / China / E319-2 / 03 (H5N1)) PB1 polymerase subunit gene (PBl), complete cds. AY576394 Influenza A virus (A / GS / HK / 739.2 / 02 (H5N1)) polymerase gene (PBl), partial cds. AY576395 Influenza A virus (A / Eg / HK / 757.3 / 02 (H5N1)) polymerase gene (PBl), partial cds. AY576396 Influenza A virus (A / G. H / HK / 793.1 / 02 (H5N1)) polymerase gene (PBl), partial cds. AY576397 Influenza A virus (A / Dk / HK / 821/02 (H5N1)) polymerase gene (PBl), complete cds. AY576398 Influenza A virus (A / Ck / HK / 31.4 / 02 (H5N1)) polymerase gene (PBl), partial cds. AY576399 Influenza A virus (A / Ck / HK / 61.9 / 02 (H5N1)) polymerase gene (PBl), partial cds. AY576400 Influenza A virus (A / Ck / HK / YU777 / 02 (H5N1)) polymerase gene (PBl), partial cds. AY576401 Influenza A virus (A / Ck / HK / 96.1 / 02 (H5N1)) polymerase gene (PBl), partial cds. AY576402 Influenza A virus (A / Ck / HK / 409.1 / 02 (H5N1)) polymerase gene (PBl), partial cds. AY576403 Influenza A virus (A / Ph / HK / 674.15 / 02 (H5N1)) polymerase gene (PBl), partial cds. AY585483 Influenza A virus (A / duck / Fuj ian / 01/2002 (H5N1)) polymerase basic protein 1 (PBl) mRNA, complete cds.

AY585484 Influenza A virus (A / duck / Fuj ian / 13/2002 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585485 Influenza A virus (A / duck / Fuj ian / 17/2001 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585486 Influenza A virus (A / duck / Fuj ian / 19/2000 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585487 Influenza A virus (A / duck / Guangdong / Ol / 2001 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585488 Influenza A virus (A / duck / Guangdong / 07/2000 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585489 Influenza A virus (A / duck / Guangdong / 12/2000 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585490 Influenza A virus (A / duck / Guangdong / 22/2002 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585491 Influenza A virus (A / duck / Guangdong / 40/2000 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585492 Influenza A virus (A / duck / Guangxi / 07/1999 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585493 Influenza A virus (A / duck / Guangxi / 22/2001 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585494 Influenza A virus (A / duck / Guangxi / 35/2001 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585495 Influenza A virus (A / duck / Guangxi / 50/2001 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585496 Influenza A virus (A / duck / Guangxi / 53/2002 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585497 Influenza A virus (A / duck / Shanghai / 08/2001 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585498 Influenza A virus (A / duck / Shangai / 13/2001 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585499 Influenza A virus (A / duck / Shangai / 35/2002 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585500 Influenza A virus (A / duck / Shangai / 37/2002 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585501 Influenza A virus (A / duck / Shangai / 38/2001 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds.

AY585502 Influenza A virus (A / duck / Zhej iang / 11/2000 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY585503 Influenza A virus (A / duck / Zhej iang / 52/2000 (H5N1)) polymerase 1 basic protein mRNA (PBl), complete cds. AY590582 Influenza A virus (A / chicken / Nakorn-Patom / Thailand / CU-K2 / 2004 (H5N1)) polymerase 1 basic protein gene (PBP1), complete cds. AY609310 Influenza A virus (A / chicken / Guangdong / 174/04 (H5N1)) segment 2, complete sequence. AY651651 Influenza A virus (A / Ck / Indonesia / BL / 2003 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651652 Influenza A virus (A / Dk / Indonesia / MS / 2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651653 Influenza A virus (A / Ck / Indonesia / PA / 2003 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651654 Influenza A virus (A / Ck / Indonesia / 4/2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651655 Influenza A virus (A / Ck / Indonesia / 2A / 2003 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651656 Influenza A virus (A / Ck / Indonesia / 5/2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651657 Influenza A virus (A / Ck / Thailand / 1/2004 (H5N1)) basic polymerase 1 subunit gene (PBl), partial cds. AY651658 Influenza A virus (A / Ck / Thailand / 73/2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651659 Influenza A virus (A / Ck / Thailand / 9.1 / 2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651660 Influenza A virus (A / Qa / Thailand / 57/2004 (H5N1)) basic polymerase 1 subunit gene (PBl), partial cds. AY651661 Influenza A virus (A / bird / Thailand / 3.1 / 2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651662 Influenza A virus (A / Dk / Thailand / 71.1 / 2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651663 Influenza A virus (A / Gs / Thailand / 79/2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds.

AY651668 Influenza A virus (A / Ck / Vietnam / 33/2004 (H5N1)) basic polymerase 1 subunit gene (PBl), partial cds. AYS51669 Influenza A virus (A / Ck / Vietnam / 35/2004 (H5N1)) basic polymerase 1 subunit gene (PBl), partial cds. AY651670 Influenza A virus (A / Ck / Vietnam / 36/2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651671 Influenza A virus (A / Ck / Vietnam / 37/2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651672 Influenza A virus (A / Ck / Vietnam / 38/2004 (H5N1)) basic polymerase 1 subunit gene (PBl), partial cds. AY651673 Influenza A virus (A / Ck / Vietnam / 39/2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651674 Influenza A virus (A / Ck / Vietnam / C57 / 2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651675 Influenza A virus (A / Dk / Vietnam / 11/2004 (H5N1)) basic polymerase 1 subunit gene (PBl), partial cds. AY651676 Influenza A virus (A / Gf / HK / 38/2002 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds.

AY651677 Influenza A virus (A / Ck / HK / 31.2 / 2002 (H5N1)) polymerase 1 basic subunit gene, partial cds. AY651678 Influenza A virus (A / Ck / HK / 37.4 / 2002 (H5N1)) basic polymerase 1 subunit gene (PBl), partial cds. AY651679 Influenza A virus (A / SCk / HK / YU100 / 2002 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651680 Influenza A virus (A / Ck / HK / YU22 / 2002 (H5N1)) basic polymerase 1 subunit gene (PBl), partial cds. AY651681 Influenza A virus (A / Ck / HK / 3176.3 / 2002 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651682 Influenza A virus (A / Ck / HK / 3169.1 / 2002 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651683 Influenza A virus (A / Ck / HK / FY157 / 2003 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651684 Influenza A virus (A / Ck / HK / YU324 / 2003 (H5N1)) basic polymerase 1 subunit gene (PBl), partial cds. AY651685 Influenza A virus (A / Ck / HK / 2133.1 / 2003 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651686 Influenza A virus (A / Ck / HK / NT93 / 2003 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds.

AY651687 Influenza A virus (A / Ck / HK / SSP141 / 2003 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651688 Influenza A virus (A / Ck / HK / WF157 / 2003 (H5N1)) basic polymerase 1 subunit gene (PBl), partial cds. AY651689 Influenza A virus (A / gull-headed gull / HK / 12.1 / 2003 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651690 Influenza A virus (A / wild chick / HK / 862.7 / 2002 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651691 Influenza A virus (A / gray heron / HK / 861.1 / 2002 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651692 Influenza A virus (A / sparrow miller / HK / 864/2002 (H5N1)) basic polymerase 1 subunit gene (PBl), partial cds. AY651693 Influenza A virus (A / teal / China / 2978.1 / 2002 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651694 Influenza A virus (A / peregrine falcon / HK / D0028 / 2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651695 Influenza A virus (A / Dk / HN / 5806/2003 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds.

AY651696 Influenza A virus (A / Dk / ST / 4003/2003 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds.

AY651697 Influenza A virus (A / Ck / ST / 4231/2003 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651698 Influenza A virus (A / Dk / YN / 6255/2003 (H5N1)) basic polymerase 1 subunit gene (PBl), partial cds.

AY651699 Influenza A virus (A / Dk / YN / 6445/2003 (H5N1)) basic polymerase 1 subunit gene (PBl), partial cds.

AY651700 Influenza A virus (A / Ph / ST / 44/2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651701 Influenza A virus (A / Dk / HN / 303/2004 (H5N1)) basic polymerase 1 subunit gene (PBl), partial cds.

AY651702 Influenza A virus (A / Dk / HN / 101/2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds. AY651703 Influenza A virus (A / Ck / YN / 374/2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds.

AY651704 Influenza A virus (A / Ck / YN / 115/2004 (H5N1)) polymerase 1 basic subunit gene (PBl), partial cds.

AY653199 Influenza A virus (A / chicken / Jilin / 9/2004 (H5N1)) segment 2, complete sequence. AY676025 Virus strain of influence A (A / duck / Hong Kong / 821/02 (H5N1)) basic gene of polymerase 1 (PBl), complete cds. AY676026 Virus strain of influence A (A / heron / Hong Kong / 757.2 / 03 (H5N1)) basic gene of polymerase 1 (PBl), complete cds. AY676027 Strain of virus A (A / chicken / Korea / ES / 03 (H5N1)) basic gene of polymerase 1 (PBl), complete cds. AY676028 Strain of virus A (A / duck / Korea / ESDl / 03 (H5N1)) basic gene of polymerase 1 (PBl), complete cds. AY684704 Influenza A virus (A / chicken / Hubei / 327/2004 (H5N1)) polymerase 1 basic protein gene (PBl), complete cds. AY737287 Influenza A virus (A / chicken / Guangdong / 191/04 (H5N1)) segment 2, complete sequence. AY737294 Influenza A virus (A / chicken / Guangdong / 178/04 (H5N1)) segment 2, complete sequence. AY737302 Influenza A virus (A / duck / Guangdong / 173/04 (H5N1)) segment 2, complete sequence. AY770083 Influenza A virus (A / chicken / Hubei / 489/2004 (H5N1)) non-functional polymerase basic protein 1 (PBl) gene, complete sequence. AY770994 Influenza A virus (A / chicken / Ayutthaya / Thailand / CU-23/04 (H5N1)) polymerase 1 basic protein gene, partial cds. AY818130 Influenza A virus (A / chicken / Vietnam / C58 / 04 (H5N1)) polymerase protein gene PBl, complete cds. AY818131 Influenza A virus (A / quail / Vietnam / 36/04 (H5N1)) polymerase protein gene PBl, complete cds. AY856862 Influenza A virus (A / duck / Shandong / 093/2004 (H5N1)) segment 2, complete sequence. AB188822 Influenza A virus (A / chicken / Kyoto / 3/2004 (H5N1)) gene PBl for polymerase 1 basic protein, complete cds. AB189051 Influenza A virus (A / raven / Kyoto / 53/2004 (H5N1)) gene PBl for polymerase 1 basic protein, complete cds,. AB189060 Influenza A virus (A / raven / Osaka / 102/2004 (H5N1)) gene PBl for polymerase 1 basic protein, complete cds,. AF046085 Influenza A virus (A / Chicken / Hong Kong / 220/97 (H5N1)) polymerase 1 basic protein gene (PBl), complete cds. AF098590 Influenza A virus (A / Chicken / Hong Kong / 258/97 (H5N1)) protein gene PBl (PBl), cds arciales. AF098591 Influenza A virus (A / Chicken / Hong Kong / y388 / 97 (H5N1)) protein gene PBl (PBl), partial cds. AF098592 Influenza A virus (A / Chicken / Hong Kong / 728/97 (H5N1)) protein gene PBl (PBl), partial cds. AF098593 Influenza A virus (A / Chicken / Hong Kong / 786/97 (H5N1)) protein gene PBl (PBl), partial cds. AF098594 Influenza A virus (A / Chicken / Hong Kong / 915/97 (H5N1)) protein gene PBl (PBl), partial cds.

AF098595 Influenza A virus (A / Pato / Hong Kong / p46 / 97 (H5N1)) protein gene PBl (PBl), partial cds. AF098596 Influenza A virus (A / Pato / Hong Kong / y283 / 97 (H5N1)) protein gene PBl (PBl), partial cds. AF098598 Influenza A virus (A / Goose / Hong Kong / w355 / 97 (H5N1)) protein gene PBl (PBl), partial cds. AF144301 Influenza A virus (A / Goose / Guangdong / 1/96 (H5N1)) polymerase gene (PBl), complete cds. AF216716 Influenza A virus (A / Environment / Hong Kong / 437-4 / 99 (H5N1)) polymerase 1 basic protein gene, complete cds. AF216724 Influenza A virus (A / Environment / Hong Kong / 437-6 / 99 (H5N1)) polymerase 1 basic protein gene, complete cds. AF216732 Influenza A virus (A / Environment / Hong Kong / 437-8 / 99 (H5N1)) polymerase 1 basic protein gene, complete cds. AF216740 Influenza A virus (A / Environment / Hong Kong / 437-10 / 99 (H5N1)) polymerase 1 basic protein gene, complete cds. AY303663 Influenza A virus (A / chicken / Chile / 176822/02 (H7N3)) polymerase 1 basic protein gene, complete cds.

AY303664 Influenza A virus (A / chicken / Chile / 4957/02 (H7N3)) polymerase 1 basic protein gene, partial cds. AY586435 Influenza A virus (A / turkey / Italy / 214845/02 (H7N3)) gene PBl, partial cds. AY586436 Influenza A virus (A / turkey / Italy / 220158/2002 (H7N3)) gene PBl, partial cds. AY586437 Influenza A virus (A / wild turkey / Italy / 33/01 (H7N3)) PBl gene, partial cds. AY586438 Influenza A virus (A / wild turkey / Italy / 43/01 (H7N3)) PBl gene, partial cds. AY616765 Influenza A virus (A / chicken / British Columbia / 04 (H7N3)) PB1 polymerase subunit gene (PBl), complete cds. AY646084 Influenza A virus (A / chicken / British Columbia / GSC_human_B / 04 (H7N3)) polymerase 1 basic protein gene (PBl), complete cds. AY648293 Influenza A virus (A / GSC_pollo_B / British Columbia / 04 (H7N3)) PB1 polymerase subunit gene (PBl), complete cds. AY653039 Influenza A virus (A / GSC_pollo / British Columbia / 04 (H7N3)) PB1 polymerase subunit gene (PBl), complete cds. AJ620348 Influenza A virus (A / Chicken / Germany / R28 / 03 (H7N7)) PBl gene for RNA polymerase, genomic RNA. AY340080 Influenza A virus (A / Netherlands / 124/03 (H7N7)) polymerase gene (PBl), partial cds. AY340081 Influenza A virus (A / Netherlands / 126/03 (H7N7)) polymerase gene (PBl), partial cds.

AY340082 Influenza A virus (A / Netherlands / 127/03 (H7N7)) polymerase gene (PBl), partial cds. AY340083 Influenza A virus (A / Netherlands / 219/03 (H7N7)) polymerase gene (PBl), complete cds. AY340084 Influenza A virus (A / Netherlands / 033/03 (H7N7)) polymerase gene (PBl), complete cds. AY340085 Influenza A virus (A / chicken / Netherlands / 1/03 (H7N7)) polymerase gene (PBl), complete cds. AB049155 Influenza A virus (A / parakeet / Chiba / 1/97 (H9N2)) PBl gene for polymerase 1 basic protein, complete cds. AB049156 Influenza A virus (A / parakeet / Narita / 92A / 98 (H9N2)) PBl gene for polymerase 1 basic protein, complete cds. AF508618 Influenza A virus (A / Ostrich / South Africa / 9508103/95 (H9N2)) gene PBL polymerase segment 2 (PBl), partial cds. AF508619 Influenza A virus (A / Chicken / Pakistan / 4/99 (H9N2)) gene PBL polymerase segment 2 (PBl), partial cds. AF508620 Influenza A virus (A / Chicken / Pakistan / 5/99 (H9N2)) gene PBL polymerase segment 2 (PBl), partial cds. AF508621 Influenza A virus (A / Chicken / Germany / R45 / 98 (H9N2)) PBL polymerase segment 2 gene (PBl), partial cds. AF508622 Influenza A virus (A / Duck / Germany / 113/95 (H9N2)) gene PBL of polymerase segment 2 (PBl), partial cds. AF508623 Influenza A virus (A / Chicken / Iran / llT / 99 (H9N2)) gene PBL of polymerase segment 2 (PBl), partial cds. AF508624 Influenza A virus (A / Chicken / Saudi Arabia / 532/99 (H9N2)) PBL gene of polymerase segment 2 (PBl), partial cds. AP508625 Influenza A virus (A / Pheasant / Ireland / PVl8 / 97 (H9N2)) gene PBL polymerase segment 2 (PBl), partial cds. AF508626 Influenza A virus (A / Chicken / Korea / 99029/99 (H9N2)) gene PBL polymerase segment 2 (PBl), partial cds. AF508627 Influenza A virus (A / Chicken / Beij ing / 8/98 (H9N2)) gene PBL polymerase segment 2 (PBl), complete cds. AF508628 Influenza A virus (A / Chicken / Guangdong / 10/00 (H9N2)) gene PBL of polymerase segment 2 (PBl), partial cds. AF508629 Influenza A virus (A / Chicken / Guangdong / 11/97 (H9N2)) gene PBL polymerase segment 2 (PBl), complete cds.

AF508630 Influenza A virus (A / Chicken / Hebei / 4/98 (H9N2)) gene PBL polymerase segment 2 (PBl), complete cds. AF508631 Influenza A virus (A / Chicken / Heilongj iang / 10/97 (H9N2)) gene PBL of polymerase segment 2 (PBl), partial cds. AF508632 Influenza A virus (A / Chicken / Henan / 62/00 (H9N2)) gene PBL polymerase segment 2 (PBl), complete cds. AF508633 Influenza A virus (A / Chicken / Ningxia / 5/99 (H9N2)) gene PBL polymerase segment 2 (PBl), complete cds. AF508634 Influenza A virus (A / Chicken / Sichuan / 5/97 (H9N2)) gene PBL of polymerase segment 2 (PBl), partial cds. AF508635 Influenza A virus (A / Chicken / Shandong / 6/96 (H9N2)) gene PBL of polymerase segment 2 (PBl), partial cds. AF508636 Influenza A virus (A / Chicken / Shij iazhuang / 2/99 (H9N2)) gene PBL polymerase segment 2 (PBl), complete cds. AF508637 Influenza A virus (A / Chicken / Shenzhen / 9/97 (H9N2)) gene PBL polymerase segment 2 (PBl), complete cds. AF508638 Influenza A virus (A / Pato / Nanjing / 1/97 (H9N2)) gene PBL polymerase segment 2 (PBl), complete cds. AF508639 Influenza A virus (A / Quail / Shangai / 8/96 (H9N2)) gene PBL polymerase segment 2 (PBl), complete cds. AF523427 Influenza A virus (A / Pato / Shantou / 830/00 (H9N2)) polymerase gene (PBl), partial cds. AF523428 Influenza A virus (A / Pato / Shantou / 2102/00 (H9N2)) polymerase gene (PBl), partial cds. AF523429 Influenza A virus (A / Pato / Shantou / 1043/00 (H9N2)) polymerase gene (PBl), partial cds. AF523430 Influenza A virus (A / Pato / Shantou / 2134/00 (H9N2)) polymerase gene (PBl), partial cds. AP523431 Influenza A virus (A / Wild Duck / Shantou / 4808/01 (H9N2)) polymerase gene (PBl), partial cds. AF523432 Influenza A virus (A / Pato / Shantou / 2144/00 (H9N2)) polymerase gene (PBl), partial cds. AF523433 Influenza A virus (A / Pato / Shantou / 2143/00 (H9N2)) polymerase gene (PBl), partial cds. AF523434 Influenza A virus (A / Pato / Shantou / 1796/00 (H9N2)) polymerase gene (PBl), partial cds. AF523435 Influenza A virus (A / Pato / Shantou / 2088/01 (H9N2)) polymerase gene (PBl), partial cds. AF523436 Influenza A virus (A / Pato / Shantou / 1881/00 (H9N2)) polymerase gene (PBl), partial cds.

AF523437 Influenza A virus (A / Pato / Hong Kong / 366/78 (H9N2)) polymerase gene (PBl), partial cds. AF523438 Influenza A virus (A / Pato / Hong Kong / 552/79 (H9N2)) polymerase gene (PBl), partial cds. AF523439 Influenza A virus (A / Pato / Hong Kong / 86/76 (H9N2)) polymerase gene (PBl), partial cds. AF523440 Influenza A virus (A / Pato / Hong Kong / 289/78 (H9N2)) polymerase gene (PBl), partial cds. AF523441 Influenza A virus (A / Pato / Hong Kong / 610/79 (H9N2)) polymerase gene (PBl), partial cds. AF523442 Influenza A virus (A / Pato / Shantou / 1605/01 (H9N2)) polymerase gene (PBl), partial cds. AF523443 Influenza A virus (A / Pato / Shantou / 1042/00 (H9N2)) polymerase gene (PBl), partial cds. AF536659 Influenza A virus (A / Chicken / Beij ing / 1/95 (H9N2)) gene PBl, partial cds. AF536660 Influenza A virus (A / Chicken / Beij ing / 2/97 (H9N2)) PBl gene, partial cds. AF536661 Influenza A virus (A / Chicken / Beij ing / 3/99 (H9N2)) PBl gene, partial cds. AF536662 Influenza A virus (A / Chicken / Guangdong / 97 (H9N2)) gene PBl, partial cds. AF536663 Influenza A virus (A / Chicken / Hebei / 1/96 (H9N2)) gene PBl, partial cds. AF536664 Influenza A virus (A / Chicken / Hebei / 2/98 (H9N2)) gene PBl, partial cds. AF536665 Influenza A virus (A / Chicken / Hebei / 3/98 (H9N2)) gene PBl, partial cds. AF536666 Influenza A virus (A / Chicken / Henan / 98 (H9N2)) PBl gene, partial cds. AF536667 Influenza A virus (A / Chicken / Liaoning / 99 (H9N2)) gene PBl, partial cds. AF536668 Influenza A virus (A / Chicken / Shandong / 98 (H9N2)) gene PBl, partial cds. AJ291396 Influenza A virus (A / Chicken / Pakistan / 2/99 (H9N2)) PBl gene for polymerase PBl, genomic RNA. AJ427862 Influenza A virus (A / quail / Hong Kong / FY298 / 00 (H9N2)) partial pbl gene for polymerase protein PB1, genomic RNA AY180840 Influenza virus strain AA / Pichon / Nanchang / 7-058 / 2000 (H9N2 ) polymerase subunit gene PBl (PBl), partial cds. AY180843 Strain of influenza virus A A / Quail / Nanchang / 2-0460 / 2000 (H9N2) polymerase subunit gene PBl (PBl), partial cds. AY180844 Virus strain of influenza A / Pigeon / Nanchang / 2-0461 / 2000 (H9N2) polymerase subunit gene PBl (PBl), partial cds. AY180851 Virus strain of influenza A A / Pigeon / Nanchang / 11-145 / 2000 (H9N2) polymerase subunit gene PBl (PBl), partial cds. AY180852 Strain of influenza virus A A / Pato / Nanchang / 11-197 / 2000 (H9N2) polymerase subunit gene PBl (PBl), partial cds. AY180854 Strain of influenza virus A A / Pato / Nanchang / 11-290 / 2000 (H9N2) polymerase subunit gene PBl (PBl), partial cds. AY180856 Strain of influenza A virus A / Pato / Nanchang / 1-0070 / 2000 (H9N2) polymerase subunit gene PBl (PBl), partial cds. AY180866 Influenza virus strain A A / Pato / Nanchang / 7-092 / 2000 (H9N2) polymerase subunit gene PBl (PBl), partial cds. AY180867 Strain of influenza virus A A / Chicken / Nanchang / 1-0016 / 2000 (H9N2) polymerase subunit gene PBl (PBl), partial cds. AY180873 Strain of influenza A virus A / Chicken / Nanchang / 4-010 / 2000 (H9N2) polymerase subunit gene PBl (PBl), partial cds. AY180874 Virus strain of influenza A A / Chicken / Nanchang / 4-301 / 2001 (H9N2) polymerase subunit gene PBl (PBl), partial cds. AY180875 Virus strain of influenza A A / Chicken / Nanchang / 4-361 / 2001 (H9N2) polymerase subunit gene PBl (PBl), partial cds.

AY180892 Virus strain of influenza A A / Quail / Nanchang / 4-040 / 2000 (H9N2) polymerase subunit gene PBl (PBl), partial cds. AY180897 Virus strain of influenza A A / Wild duck / Nanchang / 2-0480 / 2000 (H9N2) polymerase subunit gene PBl (PBl), partial cds. AY180900 Virus strain of influenza A A / Pato / Nanchang / 10-389 / 2000 (H9N2) polymerase subunit gene PBl (PBl), partial cds. AY180901 Influenza virus strain A A / Pato / Nanchang / 11-392 / 2000 (H9N2) polymerase subunit gene PBl (PBl), partial cds. AY253751 Influenza A virus (A / Chicken / Shanghai / F / 98 (H9N2)) polymerase 1 basic protein gene (PBl), complete cds. AY307947 Influenza A virus (A / chicken / Beij ing / 1/00 (H9N2)) polymerase subunit gene (PBl), partial cds. AY307948 Influenza A virus (A / chicken / Hebei / 1/01 (H9N2)) polymerase subunit gene (PBl), partial cds. AY633170 Influenza A virus (A / wild turkey / Alberta / 17/91 (H9N2)) Pl RNA RNA polymerase subunit gene directed to RNA, partial cds. AY633282 Influenza A virus (A / wild turkey / Alberta / 321/88 (H9N2)) Pl RNA RNA polymerase subunit gene, partial cds.

AY633298 Influenza A virus (A / wild turkey / Alberta / 11/91 (H9N2)) Pl RNA RNA polymerase subunit gene directed to RNA, partial cds. AY664774 Influenza A virus (A / chicken / Hong Kong / CSW153 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY664775 Influenza A virus (A / chicken / Hong Kong / AP45 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY664776 Influenza A virus (A / chicken / Hong Kong / BD90 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY664777 Influenza A virus (A / chicken / Hong Kong / CSW291 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY664778 Influenza A virus (A / chicken / Hong Kong / CSW304 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY664779 Influenza A virus (A / chicken / Hong Kong / FY23 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY664780 Influenza A virus (A / guinea fowl / Hong Kong / NT101 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY664781 Influenza A virus (A / chicken / Hong Kong / NT142 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY664782 Influenza A virus (A / chicken / Hong Kong / SFl / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY664783 Influenza A virus (A / chicken / Hong Kong / SSP101 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY664784 Influenza A virus (A / chicken / Hong Kong / TP38 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY664785 Influenza A virus (A / chicken / Hong Kong / WF126 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY664786 Influenza A virus (A / chick / Hong Kong / WF53 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY664787 Influenza A virus (A / pheasant / Hong Kong / WF54 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY564788 Influenza A virus (A / guinea fowl / Hong Kong / NT184 / 03 (H9N2) polymerase 1 basic protein gene (PBl), partial cds AY664789 Influenza A virus (A / chicken / Hong Kong / WF120 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds AY664790 Influenza A virus (A / chicken / Hong Kong / NT366 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY664791 Influenza A virus (A / chicken / Hong Kong / YU427 / 03 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY800239 Influenza A virus (A / chicken / Korea / Sl / 2003 (H9N2)) polymerase 1 basic protein gene (PBl), partial cds. AY862694 Influenza A virus (A / silky chicken / Korea / S3 / 03 (H9N2)) PBl gene (PBl), partial cds. AY862695 Influenza A virus (A / chicken / Korea / S4 / 03 (H9N2)) PBl gene (PBl), partial cds. AY862696 Influenza A virus (A / chicken / Korea / S5 / 03 (H9N2)) PBl gene (PBl), partial cds. AY862697 Influenza A virus (A / chicken / Korea / S12 / 03 (H9N2)) PBl gene (PBl), partial cds. AY862698 Influenza A virus (A / duck / Korea / S13 / 03 (H9N2)) gene PBl (PBl), partial cds. AY862699 Influenza A virus (A / pigeon / Korea / S14 / 03 (H9N2)), PBl gene (PBl), partial cds. AY862700 Influenza A virus (A / chicken / Korea / S15 / 03 (H9N2)) PBl gene (PBl), partial cds. AY862701 Influenza A virus (A / chicken / Korea / S16 / 03 (H9N2)) gene PBl (PBl), partial cds. AY862702 Influenza A virus (A / chicken / Korea / S18 / 03 (H9N2)) PBl gene (PBl), partial cds. AF156416 Influenza A virus (A / Chicken / Hong Kong / G9 / 97 (H9N2)) polymerase subunit gene PBl segment 2 (PBl), partial cds. AF156417 Influenza A virus (A / Chicken / Hong Kong / G23 / 99 (H9N2)) segment 2 PBL polymerase subunit gene (PBl), partial cds. AF156418 Influenza A virus (A / Pigeon / Hong Kong / Y233 / 97 (H9N2)) segment 2 PBL polymerase subunit gene (PBl), partial cds. AF156419 Influenza A (A / Pato / Hong Kong / Y280 / 97 (H9N2)) polymerase subunit gene PBl segment 2 (PBl), partial cds. AF156420 Influenza A virus (A / Pato / Hong Kong / Y439 / 97 (H9N2)) segment 2 PBL polymerase subunit gene (PBl), partial cds. AF156421 Influenza A virus (A / Quail / Hong Kong / Gl / 97 (H9N2)) polymerase subunit gene PBl segment 2 (PBl), partial cds. AF156422 Influenza A virus (A / Chicken / Hong Kong / 739/94 (H9N2)) segment 2 PBL polymerase subunit gene (PBl), partial cds. AF156423 Influenza A virus (A / Chicken / Beij ing / 1/94 (H9N2)) segment 2 PBL polymerase subunit gene (PBl), partial cds. AF156424 Influenza A virus (A / Quail / Hong Kong / AF157 / 92 (H9N2)) segment 2 PBL polymerase subunit gene (PBl), partial cds. AF156425 Influenza A virus (A / Chicken / Korea / 38349-p96323 / 96 (H9N2)) segment 2 PBL polymerase subunit gene (PBl), partial cds. AF156426 Influenza A virus (A / Chicken / Korea / 25232-96006 / 96 (H9N2)) segment 2 PBL polymerase subunit gene (PBl), partial cds. AF156427 Influenza A virus (A / Beach bird / Delaware / 9/96 (H9N2)) polymerase subunit gene PBl of segment 2 (PBl), partial cds. AF156428 Influenza A virus (A / Quail / Arkansas / 29209- 1/93 (H9N2)) polymerase subunit gene PBl segment 2 (PBl), partial cds. AF156429 Influenza A virus (A / Pavo / California / 189/66 (H9N2)) polymerase subunit gene PBl segment 2 (PBl), partial cds. AF222632 Influenza A virus (A / Quail / Hong Kong / A17 / 99 (H9N2)) polymerase 1 gene from segment 2 (PBl), partial cds. AF222633 Influenza A virus (A / Pigeon / Hong Kong / FY6 / 99 (H9N2)) polymerase 1 gene from segment 2 (PBl), partial cds. AF222634 Influenza A virus (A / Chicken / Hong Kong / NT16 / 99 (H9N2)) polymerase 1 gene of segment 2 (PBl), partial cds. AF222635 Influenza A virus (A / Quail / Hong Kong / SSP10 / 99 (H9N2)) polymerase 1 gene from segment 2 (PBl), partial cds. AF222636 Influenza A virus (A / Pheasant / Hong Kong / SSPll / 99 (H9N2)) polymerase 1 gene of segment 2 (PBl), partial cds. AF222637 Influenza A virus (A / Chicken / Hong Kong / FY20 / 99 (H9N2)) polymerase 1 gene of segment 2 (PBl), partial cds. AF222638 Influenza A virus (A / Chicken / Hong Kong / KC12 / 99 (H9N2)) polymerase 1 gene from segment 2 (PBl), partial cds. AF222639 Influenza A virus (A / Quail / Hong Kong / NT2899 (H9N2)) polymerase 1 gene from segment 2 (PBl), partial cds. AF222640 Influenza A virus (A / Chicken / Hong Kong / SF2 / 99 (H9N2)) polymerase 1 gene of segment 2 (PBl), partial cds. AF222641 Influenza A virus (A / Silky chicken / Hong Kong / SF44 / 99 (H9N2)) polymerase 1 gene of segment 2 (PBl), partial cds.

Sequences used in the analysis of Influenza A Polymerase Basic Protein 2 (PB2) gi | 49356919 | AY633219 | Influenza A virus (A / wild turkey / Alberta / 211/98 (H1N1)) protein 2 basic polymerase gene (PB2), partial cds. gi | 27466107 IAY180748 | Strain of influenza A virus A / Quail / Nanchang / 12-340 / 2000 (H1N1) polymerase subunit gene PB2 (PB2), partial cds. gi | 45272173IAY422042 | Influenza A virus (A / duck / Hokkaido / 95/01 (H2N2)) polymerase subunit gene (PB2), partial cds. Gil 18091825 IAF213910 | Influenza A virus (A / Chicken / Italy / 5945/95 (H3N2)) polymerase protein gene of segment 1 PB2, partial cds. gi | 27466133 IAY1807611 | Strain of influenza A virus A / Chicken / Nanchang / 3-120 / 2001 (H3N2) polymerase subunit gene PB2 (PB2), partial cds. gil 56160002 IAY779267 | Influenza A virus (A / turkey / North Carolina / 12344/03 (H3N2)) protein 2 basic polymerase gene (PB2), partial cds. Gil 5616000 | AY779268 | Influenza A virus (A / turkey / Minnesota / 764-2 / 03 (H3N2)) protein 2 basic polymerase gene (PB2), partial cds. gi | 58429704 | AY862719 | Influenza A virus (A / chicken / Korea / S6 / 03 (H3N2)) PB2 gene (PB2), partial cds. gi | 58429706 | AY862720 | Influenza A virus (A / duck / Korea / S7 / 03 (H3N2)) gene PB2 (PB2), partial cds. gil 58429708 IAY862721 | Influenza A virus (A / duck / Korea / S8 / 03 (H3N2)) gene PB2 (PB2), partial cds. gil 58429710IAY862722 | Influenza A virus (A / duck / Korea / S9 / 03 (H3N2)) gene PB2 (PB2), partial cds. gi I 58429712 | AY862723 | Influenza A virus (A / duck / Korea / S10 / 03 (H3N2)) PB2 gene (PB2), partial cds. gi | 58429714 IAY862724 | Influenza A virus (A / pigeon / Korea / Sll / 03 (H3N2)) PB2 gene (PB2), partial cds. gi I 5805276IAF144300 | Influenza A virus (A / Goose / Guangdong / 1/96 (H5N1)) polymerase gene (PB2), complete cds. gil 3335416 | AF046086 | Influenza A virus (A / Chicken / Hong Kong / 220/97 (H5N1)) protein 2 basic polymerase gene (PB2), partial cds. gi | 6048841 IAF098577 | Influenza A virus (A / Chicken / Hong Kong / 258/97 (H5N1)) Protein gene PB2 (PB2), partial cds. Gil 60488431 AF098578 | Influenza A virus (A / Chicken / Hong Kong / y388 / 97 (H5N1)) protein gene PB2 (PB2), partial cds. gi | 6048845 I AF098579 | Influenza A virus (A / Chicken / Hong Kong / 728/97 (H5N1)) protein gene PB2 (PB2), partial cds. gi | 6048847 IAF098580 | Influenza A virus (A / Chicken / Hong Kong / 786/97 (H5N1)) protein gene PB2 (PB2), partial cds. gi | 6048849 | AF098581 | Influenza A virus (A / Chicken / Hong Kong / 915/97 (H5N1)) protein gene PB2 (PB2), partial cds. gi | 6048851 IAF098582 | Influenza A virus (A / Pato / Hong Kong / p46 / 97 (H5N1)) protein gene PB2 (PB2), partial cds. Gil 6048853 | AF0985831 Influenza A virus (A / Pato / Hong Kong / y283 / 97 (H5N1)) protein gene PB2 (PB2), partial cds. gi | 6048855 IAF098584 | Influenza A virus (A / Goose / Hong Kong / w355 / 97 (H5N1)) protein gene PB2 (PB2), partial cds. gil 14860983 IAY038798 | Influenza A virus (A / goose / Guangdong / 3/1997 (H5N1)) protein gene PB2 (PB2), complete cds. gi | 4715624 IAY585513 | Influenza A virus (A / duck / Guangxi / 07/1999 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gi | 9863884 IAF216717 | Influenza A virus (A / Environment / Hong Kong / 437-4 / 99 (H5N1)) polymerase basic protein 2 gene, partial cds. gi | 9863903 IAF216725 | Influenza A virus (A / Environment / Hong Kong / 437-6 / 99 (H5N1)) protein 2 polymerase basic gene, partial cds. gi I 9863921 | AF216733 | Influenza A virus (A / Environment / Hong Kong / 437-8 / 99 (H5N1)) polymerase basic protein 2 gene, partial cds. gi | 9863939 | AF216741 | Influenza A virus (A / Environment / Hong Kong / 437-10 / 99 (H5N1)) polymerase basic protein 2 gene, partial cds. Gil 47156264 | AY5855231 Influenza A virus (A / duck / Zhejiang / 11/2000 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gi | 47156266 | AY585524 | Influenza A virus (A / duck / Zhejiang / 52/2000 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gi 147156232 | AY585507 | Influenza A virus (A / duck / Fujian / 19/2000 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. Gil 47156236 | AY585509 | Influenza A virus (A / duck / Guangdong / 07/2000 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gi I 47156238 IAY585510 | Influenza A virus (A / duck / Guangdong / 12/2000 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gil 47156242 | AY585512 | Influenza A virus (A / duck / Guangdong / 40/2000 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. Gil 19697849 | AY059520 | Influenza A virus (A / Goose / Hong Kong / ww26 / 2000 (H5N1)) polymerase gene segment 1 (PB2), partial cds. gil 19697851 | AY059521 | Influenza A virus (A / Goose / Hong Kong / ww28 / 2000 (H5N1)) polymerase gene of segment 1 (PB2), partial cds.

Gil 19697853 | AY059522 | Influenza A virus (A / Pato / Hong Kong / ww381 / 2000 (H5N1)) polymerase gene of segment 1 (PB2), partial cds. gil 196978551 AY0595231 Influenza A virus (A / Pato / Hong Kong / ww461 / 2000 (H5N1)) polymerase gene of segment 1 (PB2), partial cds. gi | 19697857 IAY05952 | Influenza A virus (A / Goose / Hong Kong / ww491 / 2000 (H5N1)) polymerase gene segment 1 (PB2), partial cds. gi | 19697859 | AY059525 | Influenza A virus (A / Pato / Hong Kong / 2986.1 / 2000 (H5N1)) polymerase gene of segment 1 (PB2), partial cds. gi I 19697867 | AY059529 | Influenza A virus (A / Goose / Hong Kong / 3014.8 / 2000 (H5N1)) polymerase gene of segment 1 (PB2), partial cds. Gil 18092181 | AF398425 | Influenza A virus (A / Goose / Hong Kong / 385.3 / 2000 (H5N1)) polymerase gene (PB2), partial cds. Gil 18092183 | AF398426 | Influenza A virus (A / Goose / Hong Kong / 385.5 / 2000 (H5N1)) polymerase gene (PB2), partial cds. gi | 21359665 | AF468840 | Influenza A virus (A / Pato / Anyang / AVL-1/2001 (H5N1)) protein 2 basic polymerase gene (PB2), partial cds. gi | 28849606 | AF509143 | Influenza A virus (A / Chicken / Hong Kong / FY77 / 01 (H5N1)) polymerase gene (PB2), partial cds. gil 28849608 IAF509144 | Influenza A virus (A / Chicken / Hong Kong / YU562 / 01 (H5N1)) polymerase gene (PB2), partial cds. gil 28849610 | AF509145 | Influenza A virus (A / Chicken / Hong Kong / YU563 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi 128849612 IAF509146I Influenza A virus (A / Chicken / Hong Kong / FY150 / 01 (H5N1)) polymerase gene (PB2), partial cds. gil 28849614 IAF509147 | Influenza A virus (A / Pheasant / Hong Kong / FY155 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi | 28849616 | AF509148 | Influenza A virus (A / Chicken silky / Hong Kong / SF189 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi 128849618 | AF509149 | Influenza A virus (A / Quail / Hong Kong / SF203 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi | 28849620 | AF509150 I Influenza A virus (A / Pigeon / Hong Kong / SF215 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi 128849622 IAF509151 | Influenza A virus (A / Chicken / Hong Kong / SF219 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi 128849624 IAF509152 | Influenza A virus (A / Chicken / Hong Kong / 715.5 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi | 28849626 | AF509153 | Influenza A virus (A / Chicken / Hong Kong / 751.1 / 01 (H5N1)) polymerase gene (PB2), partial cds. gil 28849628 IAF50915 | Influenza A virus (A / Chicken / Hong Kong / 822.1 / 01 (H5N1)) polymerase gene (PB2), partial cds. gil 28849630 | AF509155 | Influenza A virus (A / Chicken / Hong Kong / 829.2 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi 128849632 | AF509156 | Influenza A virus (A / Chicken / Hong Kong / 830.2 / 01 (H5N1)) polymerase gene (PB2), partial cds. gil 28849634 IAF509157 | Influenza A virus (A / Chicken / Hong Kong / 858.3 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi | 28849636IAF509158 | Influenza A virus (A / Chicken / Hong Kong / 866.3 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi 128849638 | AF509159 | Influenza A virus (A / Chicken / Hong Kong / 867.1 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi 128849640 | AF509160 | Influenza A virus (A / Chicken / Hong Kong / 879.1 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi 128849642 IAF509161 | Influenza A virus (A / Chicken / Hong Kong / 873.3 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi 128849644 IAF509162 | Influenza A virus (A / Chicken / Hong Kong / 876.1 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi | 28849646 | AF509163 | Influenza A virus (A / Chicken / Hong Kong / 891.1 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi | 28849648 IAF509164 | Influenza A virus (A / Chicken / Hong Kong / 893.2 / 01 (H5N1)) polymerase gene (PB2), partial cds. Gil 28849650 | AF509165 | Influenza A virus (A / Goose / Hong Kong / 76 1/01 (H5N1)) polymerase gene (PB2), partial cds. gi | 28849652 | AF509166 | Influenza A virus (A / Goose / Hong Kong / wwl00 / 01 (H5N1)) polymerase gene (PB2), partial cds. gil 2884965 IAF509167 | Influenza A virus (A / Pato / Hong Kong / 573.4 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi | 28849656 | AF509168 | Influenza A virus (A / Pato / Hong Kong / 646.3 / 01 (H5N1)) polymerase gene (PB2), partial cds. gi 128823262 | AY221584 | Influenza A virus (A / Chicken / Hong Kong / NT873.3 / 01-MB (H5N1)) protein 2 basic polymerase gene (PB2), partial cds. gil 28823443 | AY221585 | Influenza A virus (A / Chicken / Hong Kong / NT873.3 / 01 (H5N1)) protein 2 basic polymerase gene (PB2), partial cds. gi 128823612 | AY221586 | Influenza A virus (A / Chicken / Hong Kong / FY150 / 01-MB (H5N1)) protein 2 basic polymerase gene (PB2), partial cds. gi 128823783 IAY221587 Influenza A virus (A / Chicken / Hong Kong / PY150 / 01 (H5N1)) protein 2 basic polymerase gene (PB2), partial cds. gi 128823961 IAY221588 | Influenza A virus (A / Pheasant / Hong Kong / FY155 / 01-MB (H5N1)) protein 2 basic polymerase gene (PB2), partial cds. gi | 28824143 | AY221589 | Influenza A virus (A / Pheasant / Hong Kong / FY155 / 01 (H5N1)) protein 2 basic polymerase gene (PB2), partial cds. gi 128824334 IAY221590 | Influenza A virus (A / Chicken / Hong Kong / YU822.2 / 01-MB (H5N1)) protein 2 basic polymerase gene (PB2), partial cds. gil 28824502 IAY221591 | Influenza A virus (A / Chicken / Hong Kong / YU822.2 / 01 (H5N1)) protein 2 basic polymerase gene (PB2), partial cds. gi 128824684 IAY221592 Influenza A virus (A / Chicken / Hong Kong / YU562 / 01 (H5N1)) protein 2 basic polymerase gene (PB2), partial cds. gi | 7156230 | AY585506 | Influenza A virus (A / duck / Fuj? An / 17/2001 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gi 147156234 IAY585508 | Influenza A virus (A / duck / Guangdong / 01/2001 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gi | 47156246IAY58551 | Influenza A virus (A / duck / Guangx? / 22/2001 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gil 47156248 IAY585515 | Influenza A virus (A / duck / Guangx? / 35/2001 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gi I 47156250 | AY585516 | Influenza A virus (A / duck / Guangx? / 50/2001 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gil 47156254 | AY585518 | Influenza A virus (A / duck / Shanga? / 08/2001 (H5N1)) protein polymerase 2 mRNA (PB2), complete cds. gi] 7156256 | AY585519 | Influenza A virus (A / duck / Shangai / 13/2001 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gil 47156262 IAY585522 | Influenza A virus (A / duck / Shangai / 38/2001 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gil 47156258 IAY585520 | Influenza A virus (A / duck / Shangai / 35/2002 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gil 47156260 IAY585521 | Influenza A virus (A / duck / Shangai / 37/2002 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gil 47156252 IAY585517 | Influenza A virus (A /? Ato / Guangxi / 53/2002 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gil 47156240 IAY585511 | Influenza A virus (A / duck / Guangdong / 22/2002 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds. gi 147834791 | AY576382 | Influenza A virus (A / Gs / HK / 739.2 / 02 (H5N1)) polymerase gene (PB2), partial cds. gi | 47834793 | AY576383 | Influenza A virus (A / Eg / HK / 757.3 / 02 (H5N1)) polymerase gene (PB2), partial cds. gi | 47834795 IAY576384 | Influenza A virus (A / G.H / HK / 793.1 / 02 (H5N1)) polymerase gene (PB2), partial cds. gi | 47834797 IAY576385 Influenza A virus (A / Dk / HK / 821/02 (H5N1)) polymerase gene (PB2), partial cds. gi | 47834799 | AY576386 Influenza A virus (A / Ck / HK / 31.4 / 02 (H5N1) 'polymerase gene (PB2), partial cds gi | 47834801 | AY576387 Influenza A virus (A / Ck / HK / 61.9 / 02 (H5N1) 'polymerase gene (PB2), partial cds gi | 47834803 | AY576388 Influenza A virus (A / Ck / HK / YU777 / 02 (H5N1) polymerase gene (PB2), partial cds. Gi | 47834805 | AY576389 Influenza A virus (A / Ck / HK / 96.1 / 02 (H5N1) "polymerase gene (PB2), partial cds. Gi | 47834807 IAY576390 Influenza A virus (A / Ck / HK / 409.1 / 02 ( H5N1) polymerase gene (PB2), partial cds gi | 47834809 | AY576391 Influenza A virus (A / Ph / HK / sv674.15 / 02 (H5N1)) polymerase gene (PB2), partial cds. gi | 47156226 | AY585504 | Influenza A virus (A / duck / Fujian / 01/2002 (H5N1 * polymerase basic protein 2 mRNA (PB2), complete cds, gil 47156228 | AY585505 | Influenza A virus (A / duck / Pujian / 13/2002 (H5N1)) polymerase basic protein 2 mRNA (PB2), complete cds gi 150296597 | AY651744 | Influenza A virus (A / gray heron / HK / 861.1 / 2002 (H5N1)) basic polymerase 2 subunit gene ( PB2), partial cds gi | 50296599 IAY651745 | Influenza A virus (A / wild chick / HK / 862.7 / 2002 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds gi 150296601 | AY651746 | Virus of influenza A (A / sparrow miller / HK / 864/2002 (H5N1)) gene of basic subunit of polymerase 2 (PB2), partial cds gil 50296603 | AY651747 | Influenza A virus (A / teal / China / 2978.1 / 2002 (H5N1)) polymerase 2 basic subunit gene (PB2), partial cds gi | 56548879 IAY676021 | influenza A virus (A / duck / Hong Kong / 821/02 (H5N1)) polymerase 2 basic gene (PB2 ), complete cds, gil 50296569 1 AY651730 | Influenza A virus (A / Gf / HK / 38/2002 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. gij 50296571 | AY651731 | Influenza A virus (A / Ck / HK / 31.2 / 2002 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. gi | 50296573 | AY651732 | Influenza A virus (A / Ck / HK / 37.4 / 2002 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. gi | 50296575 | AY651733 | Influenza A virus (A / SCk / HK / YU100 / 2002 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. gi I 50296577 IAY651734 | Influenza A virus (A / Ck / HK / YU22 / 2002 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. gi | 50296579 | AY651735 | Influenza A virus (A / Ck / HK / 3176.3 / 2002 (H5N1)) polymerase 2 basic subunit gene (PB2), partial cds. gi | 50296581 IAY651736 | Influenza A virus (A / Ck / HK / 3169.1 / 2002 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. gi 150296583 | AY651737 | Influenza A virus (A / Ck / HK / FY157 / 2003 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. gi | 50296585 | AY651738 | Influenza A virus (A / Ck / HK / YU324 / 2003 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. Gil 50296587 | AY651739 | Influenza A virus(A / Ck / HK / 2133.1 / 2003 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. Gil 502965891 AY651740 | Influenza A virus (A / Ck / HK / NT93 / 2003 (H5N1)) polymerase 2 basic subunit gene (PB2), partial cds. gi I 50296591 IAY651741 | Influenza A virus (A / Ck / HK / SSP141 / 2003 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. Gil 50296593 IAY651742 | Influenza A virus (A / Ck / HK / WF157 / 2003 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. Gil 50296595 | AY651743 | Influenza A virus (A / gull-headed gull / HK / 12.1 / 2003 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. Gil 50296607 | AY651749 | Virus . of influenza A (A / Dk / HN / 5806/2003 (H5N1)) polymerase 2 basic subunit gene (PB2), partial cds. Gil 502966091 AY651750 | Influenza A virus (A / Dk / ST / 4003/2003 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. Gil 50296611 | AY651751 | Influenza A virus (A / Ck / ST / 4231/2003 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. gi | 50296613 | AY651752 | Influenza A virus (A / Dk / YN / 6255/2003 (H5N1)) polymerase 2 basic subunit gene (PB2), partial cds. gil 502966151 AY6517531 Influenza A virus (A / Dk / YN / 6445/2003 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. gi | 50296529 IAY651710 | Influenza A virus (A / Ck / Indonesia / 2A / 2003 (H5N1)) polymerase 2 basic subunit gene (PB2), partial cds. Gil 56548881 | AY676022 | Influenza A virus (A / heron / Hong Kong / 757.2 / 03 (H5N1)) basic gene of polymerase 2 (PB2), complete cds. gi | 56548883 IAY676023 | Influenza A virus (A / chicken / Korea / ES / 03 (H5N1)) polymerase 2 basic gene (PB2), complete cds. gil 56548885 IAY676024 | Influenza A virus (A / duck / Korea / ESDl / 03 (H5N1)) polymerase 2 basic gene (PB2), complete cds. Gil 50296519 | AY651705 | Influenza A virus (A / Ck / Indonesia / PA / 2003 (H5N1)) basic polymerase 2 subunit gene (PB2), complete cds. gi I 50296523 IAY651707 | Influenza A virus (A / Ck / Indonesia / BL / 2003 (H5N1)) polymerase 2 basic subunit gene (PB2), complete cds. gil 412075011 AY518367 | Influenza A virus (A / duck / China / E319-2 / 03 (H5N1)) polymerase subunit gene PB2 (PB2), complete cds. gil 453593691 AY550147 | Influenza A virus (A / chicken / Nakorn-Patom Thailand / CU-K2 / 04 (H5N1)) protein 2 basic polymerase gene (PB2), partial cds. gi | 50296525 IAY651708 | Influenza A virus (A / Ck / Indonesia / 5/2004 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. Gil 50296527 | AY651709 | Influenza A virus (A / Ck / Indonesia / 4/2004 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. Gil 50296521 | AY651706 | Influenza A virus (A / Dk / Indonesia / MS / 2004 (H5N1)) polymerase 2 basic subunit gene (PB2), complete cds. gil 510941031 AY590581 | Influenza A virus (A / chicken / Nakorn-Patom / Thailand / CU-K2 / 200 (H5N1)) polymerase 2 basic protein gene (PB2), partial cds. - gi | 47716766 | AY609309 | Influenza A virus (A / chicken / Guangdong / 174/04 (H5N1)) segment 1, complete sequence. gi 158531082 | AB166859 | Influenza A virus (A / chicken / Yamaguchi / 7/2004 (H5N1)) PB2 gene for polymerase 2 basic protein, complete cds. gil 58531114 | AB1888131 Influenza A virus (A / chicken / Oita / 8/2004 (H5N1)) Gene PB2 for polymerase 2 basic protein, complete cds. Gil 50956621 | AY684703 | Influenza A virus (A / chicken / Hubei / 327/2004 (H5N1)) protein 2 polymerase basic gene (PB2), complete cds. gil 57915957 | AY7372861 Influenza A virus (A / chicken / Guangdong / 191/04 (H5N1)) segment 1, complete sequence. gi | 57916006 | AY737293 | Influenza A virus (A / chicken / Guangdong / 178/04 (H5N1)) segment 1, complete sequence. gil 57916060 IAY737301 | Influenza A virus (A / duck / Guangdong / 173/04 (H5N1)) segment 1, complete sequence. gi | 55233237 IAY770084 | Influenza A virus (A / chicken / Hubei / 489/2004 (H5N1)) protein 2 basic polymerase gene (PB2), complete cds. Gil 54873461 | AY7709931 Influenza A virus (A / chicken / Ayutthaya / Thailand / CU-23/04 (H5N1)) protein 2 polymerase basic gene, partial cds. gil 58618421 IAY818127 | Influenza A virus (A / chicken / Vietnam / C58 / 04 (H5N1)) PB2 gene of polymerase protein, complete cds. gi | 58618423 | AY818128 | Influenza A virus (A / quail / Vietnam / 36/04 (H5N1)) PB2 gene of polymerase protein, complete cds. gil 58374183IAY856861 | Influenza A virus (A / duck / Shandong / 093/2004 (H5N1)) segment 1, complete sequence. gil 58531132 IAB188821 | Influenza A virus (A / chicken / Kyoto / 3/2004 (H5N1)) PB2 gene for polymerase 2 basic protein, complete cds. gi | 58531150 IAB189050 | Influenza A virus (A / raven / Kyoto / 53/2004 (H5N1)) PB2 gene for polymerase 2 basic protein, complete cds. gi I 58531168 IAB189058 | Influenza A virus (A / raven / Osaka / 102/2004 (H5N1)) PB2 gene for polymerase 2 basic protein, complete cds ,. gi | 50296605 IAY651748 | Influenza A virus (A / hawk-peregrine / HK / D0028 / 2004 { H5Nl)) basic polymerase 2 subunit gene (PB2), complete cds. gi | 50296531 IAY651711 | Influenza A virus (A / Ck / Thailand / 1/2004 (H5N1)) polymerase 2 basic subunit gene (PB2), partial cds. Gil 502965331 AY651712 | Influenza A virus (A / Ck / Thailand / 73/2004 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. gi | 50296535 IAY651713 | Influenza A virus (A / Ck / Thailand / 9.1 / 2004 (H5N1)) basic polymerase 2 subunit gene (PB2), complete cds. Gil 50296537 | AY651714 | Influenza A virus (A / Qa / Thailand / 57/2004 (H5N1)) basic polymerase 2 subunit gene (PB2), complete cds. gi | 50296539 | AY651715 | Influenza A virus (A / bird / Thailand / 3.1 / 2004 (H5N1)) polymerase 2 basic subunit gene (PB2), complete cds. gi | 50296541 | AY651716 | Influenza A virus (A / Dk / Thailand / 71.1 / 2004 (H5N1)) basic polymerase 2 subunit gene (PB2), complete cds. gi 150296543 | AY651717 | Influenza A virus (A / Gs / Thailand / 79/2004 (H5N1)) polymerase 2 basic subunit gene (PB2), partial cds. Gil 502965531 AY651722 | Influenza A virus (A / Ck / Vietnam / 33/2004 (H5N1)) basic polymerase 2 subunit gene (PB2), complete cds. gil 502965551 AY6517231 Influenza A virus (A / Ck / Vietnam / 35/2004 (H5N1)) basic polymerase 2 subunit gene (PB2), complete cds. Gil 50296557 | AY651724 | Influenza A virus (A / Ck / Vietnam / 36/2004 (H5N1)) basic polymerase 2 subunit gene (PB2), complete cds. Gil 5029S559 | AY651725 | Influenza A virus (A / Ck / Vietnam / 37/2004 (H5N1)) basic polymerase 2 subunit gene (PB2), complete cds. gi 150296561 IAY651726I Influenza A virus (A / Ck / Vietnam / 38/2004 (H5N1)) polymerase 2 basic subunit gene (PB2), complete cds. Gil 502965631 AY651727 | Influenza A virus (A / Ck / Vietnam / 39/2004 (H5N1)) polymerase 2 basic subunit gene (PB2), complete cds. gi | 50296565 | AY651728 | Influenza A virus (A / Ck / Vietnam / C57 / 2004 (H5N1)) basic polymerase 2 subunit gene (PB2), complete cds. Gil 50296567 | AYS517291 Influenza A virus (A / Dk / Vietnam / 11/2004 (H5N1)) polymerase 2 basic subunit gene (PB2), complete cds. gi 150296617 | AY651754 | Influenza A virus (A / Ck / YN / 374/2004 (H5N1)) polymerase 2 basic subunit gene (PB2), partial cds. Gil 502966191 AY651755 | Influenza A virus (A / Ck / YN / 115/2004 (H5N1)) polymerase 2 basic subunit gene (PB2), partial cds. gi 150296621 | AY651756 | Influenza A virus (A / Ph / ST / 44/2004 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. gi 1502966231 AY651757 | Influenza A virus (A / Dk / HN / 303/2004 (H5N1)) basic polymerase 2 subunit gene (PB2), partial cds. Gil 502966251 AY651758 | Influenza A virus (A / Dk / HN / 101/2004 (H5N1)) polymerase 2 basic subunit gene (PB2), partial cds. Gil 50365712 | AY6531931 Influenza A virus (A / chicken / Jilin / 9/2004 (H5N1)) segment 1, complete sequence. Gil 47680940 | AY5864451 Influenza A virus (A / wild turkey / Italy / 43/01 (H7N3)) PB2 gene, partial cds. gi 147680930 IAY5864401 Influenza A virus (A / wild turkey / Italy / 33/01 (H7N3)) PB2 gene, partial cds. gi | 47680932 IAY586441 | Influenza A virus (A / turkey / Italy / 220158/2002 (H7N3)) gene PB2, partial cds. gi | 45124743 IAJ627485 | Influenza A virus (A / turkey / Italy / 214845/2002 (H7N3)) PB2 gene for RNA polymerase, genomic RNA. gi I 45124767 | AJ627496 | Influenza A virus (A / turkey / Italy / 220158/2002 (H7N3)) PB2 gene for RNA polymerase, genomic RNA. gi 134597782 | AY303665 | Influenza A virus (A / chicken / Chile / 176822/02 (H7N3)) protein 2 basic polymerase gene, partial cds. gi 134597784 | AY303666 | Influenza A virus (A / chicken / Chile / 4957/02 (H7N3)) protein 2 basic polymerase gene, partial cds. gi | 47680928 IAY586439 | Influenza A virus (A / turkey / Italy / 214845/02 (H7N3)) PB2 gene, partial cds. gi | 7834374 | AY616766I Influenza A virus (A / chicken / British Columbia / 04 (H7N3)) PB2 gene of polymerase subunit (PB2), complete cds. Gil 50542651 | AY6460851 Influenza A virus (A / chicken / British Columbia / GSC_human_B / 04 (H7N3)) protein 2 basic polymerase gene (PB2), complete cds. gi | 50083053 | AY64829 | Influenza A virus (A / GSC_pollo_B / British Columbia / 04 (H7N3)) PB2 gene of polymerase subunit (PB2), complete cds.

Gil 50059194 | AY650276 | Influenza A virus (A / GSC_pollo / British Columbia / 04 (H7N3)) PB2 gene of polymerase subunit (PB2), complete cds. gil 607001X586911 Influenza A virus (A / FPV / Dobson / 27 (H7N7)) gene for upper binding protein PB2, genomic RNA gi I 325001 IM38291 | Influenza A virus / FPV / Weybridge polymerase basic protein 2 (PB2) gene (sec3), complete cds. gi I 9988661 IAF268120 | Influenza A virus (A / Red-cheeked / Delaware / 259/94 (H7N7)) PB2 gene of polymerase protein, partial cds. gil 40732893 | AJ620347 | Influenza A virus ((A / Chicken / Germany / R28 / 03 (H7N7)) A / Chicken / Germany / R28 / 03 (H7N7)) PB2 gene for RNA polymerase, genomic RNA. gi 137813157 | AY342410 | Influenza A virus (A / Netherlands / 124/03 (H7N7)) gene 2 polymerase protein, partial cds. gi | 37813159 IAY342411 | Influenza A virus (A / Netherlands / 126/03 (H7N7)) gene 2 polymerase protein, partial cds. gi | 37813161 IAY342412 | Influenza A virus (A / Netherlands / 127/03 (H7N7)) gene 2 polymerase protein, partial cds. gi | 37813163 | AY342413 | Influenza A virus (A / Netherlands / 219/03 (H7N7)) polymerase protein 2 gene, partial cds. gil 37813165IAY34241 | Influenza A virus (A / chicken / Netherlands / 1/03 (H7N7)) polymerase protein 2 gene, partial cds. gi I 5732354 IAF156443I Influenza A virus (A / Pavo / California / 189/66 (H9N2)) PB2 polymerase subunit gene of segment 1 (PB2), partial cds. gi | 31339587 IAF523469 | Influenza A virus (A / Pato / Hong Kong / 86/76 (H9N2)) polymerase gene (PB2), partial cds. gi | 31339583 | AF523467 | Influenza A virus (A / Pato / Hong Kong / 366/78 (H9N2)) polymerase gene (PB2), partial cds. Gil 313396051 AF523478 | Influenza A virus (A / Pato / Hong Kong / 289/78 (H9N2)) polymerase gene (PB2), partial cds. gi | 31339585 | AF523468 | Influenza A virus (A / Pato / Hong Kong / 552/79 (H9N2)) polymerase gene (PB2), partial cds. Gil 31339589 | AF523470 | Influenza A virus (A / Pato / Hong Kong / 610/79 (H9N2)) polymerase gene (PB2), partial cds. gil 493569351 AY633283 | Influenza A virus (A / wild turkey / Alberta / 321/88 (H9N2)) protein 2 basic polymerase gene (PB2), partial cds. gi | 9356939 IAY633299 | Influenza A virus (A / wild turkey / Alberta / 11/91 (H9N2)) protein 2 basic polymerase gene (PB2), partial cds. gi I 49356907 IAY633171 | Influenza A virus. { A / wild turkey / Alberta / 17/91 (H9N2)) protein 2 basic polymerase gene (PB2), partial cds. gi | 5732342 | AF156437 | Influenza A virus (A / Quail / Hong Kong / AF157 / 92 (H9N2)) PB2 polymerase subunit gene of segment 1 (PB2), partial cds. gi I 5732352 IAF156442 | Influenza A virus (A / Quail / Arkansas / 29209-1 / 93 (H9N2)) PB2 polymerase subunit gene of segment 1 (PB2), partial cds. gi | 5732340 | AF156436 | Influenza A virus (A / Chicken / Hong Kong / 739/94 (H9N2)) PB2 polymerase subunit gene of segment 1 (PB2), partial cds. gi 15732344 | AF156438 | Influenza A virus (A / Chicken / Beijing / 1/94 (H9N2)) PB2 polymerase subunit gene of segment 1 (PB2), partial cds. gi 122759060 IAF536679 Influenza A virus (A / Chicken / Beijing / 1/95 (H9N2)) PB2 gene, partial cds. Gil 33318110 | AF5086401 Influenza A virus (A / Ostrich / South Africa / 9508103/95 (H9N2)) PB2 polymerase gene of segment 1 (PB2), complete cds. gi | 33318118 IAF508644 | Influenza A virus (A / Pato / Germany / 113/95 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. gi 133318144 | AF508657 | Influenza A virus (A / Chicken / Shandong / 6/96 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. gi 133318152 | AF508661 | Influenza A virus (A / Quail / Shangai / 8/96 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. gil 5732346 | AF156439 | Influenza A virus (A / Chicken / Korea / 38349-p96323 / 96 (H9N2)) PB2 polymerase subunit gene of segment 1 (PB2), partial cds. gi 15732348 IAF156440 | Influenza A virus (A / Chicken / Korea / 25232-96006 / 96 (H9N2)) PB2 polymerase subunit gene of segment 1 (PB2), partial cds. gil 5732350 | AF156441 | Influenza A virus (A / Beach bird / Delaware / 9/96 (H9N2)) PB2 polymerase subunit gene of segment 1 (PB2), partial cds. gi 122759068 IAF536683 | Influenza A virus (A / Chicken / Hebei / 1/96 (H9N2)) PB2 gene, partial cds. gil 5732328 | AF156430 | Influenza A virus (A / Chicken / Hong Kong / G9 / 97 (H9N2)) PB2 polymerase subunit gene of segment 1 (PB2), complete cds. gi | 5732330 | AF156431 | Influenza A virus (A / Chicken / Hong Kong / G23 / 97 (H9N2)) PB2 polymerase subunit gene of segment 1 (PB2), partial cds. gi 15732332 | AF156432 | Influenza A virus (A / Pigeon / Hong Kong / Y233 / 97 (H9N2)) PB2 polymerase subunit gene of segment 1 (PB2), partial cds. gil 5732334 | AF156433 | Influenza A virus (A / Pato / Hong Kong / Y280 / 97 (H9N2)) PB2 polymerase subunit gene of segment 1 (PB2), partial cds. gi | 5732336IAF156434 | Influenza A virus (A / Pato / Hong Kong / Y439 / 97 (H9N2)) PB2 polymerase subunit gene of segment 1 (PB2), partial cds. gil 5732338 IAF156435 | Influenza A virus (A / Quail / Hong Kong / Gl / 97 (H9N2)) PB2 polymerase subunit gene of segment 1 (PB2), partial cds. Gil 33318148 | AF508659 | Influenza A virus (A / Chicken / Shenzhen / 9/97 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. gi | 33318150 | AF508660 | Influenza A virus (A / Pato / Nanjing / 1/97 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. gi 133318124 IAF508647 | Influenza A virus (A / Pheasant / Ireland / PV18 / 97 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. gi | 13383266 | AB049153 | Influenza A virus (A / perico / Chiba / 1/97 (H9N2)) PB2 gene for polymerase 2 basic protein, complete cds. gi 133318132 | AF508651 | Influenza A virus (A / Chicken / Guangdong / 11/97 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. Gil 333181361 AF508653 | Influenza A virus (A / Chicken / Heilongjiang / 10/97 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. gil 22759062 IAF536680 | Influenza A virus (A / Chicken / Beijing / 2/97 (H9N2)) PB2 gene, partial cds. gi | 33318142 | AF508656 | Influenza A virus (A / Chicken / Sichuan / 5/97 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. gi | 22759066 | AF536682 | Influenza A virus (A / Chicken / Guangdong / 97 (H9N2)) PB2 gene, partial cds. gi | 22759078 IAF536688 | Influenza A virus (A / Chicken / Shandong / 98 (H9N2)) PB2 gene, partial cds. Gil 33318116IAF508643I Influenza A virus (A / Chicken / Germany / R45 / 98 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. gi | 33318134 IAF508652 | Influenza A virus (A / Chicken / Hebei / 4/98 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. gi 133318128 | AF508649 | Influenza A virus (A / Chicken / Beijing / 8/98 (H9N2)) PB2 polymerase gene of segment 1 (PB2), complete cds. gil 13383268 | AB049154 | Influenza A virus (A / parakeet / Narita / 92A / 98 (H9N2)) PB2 gene for polymerase 2 basic protein, complete cds. gil 22759070 IAF536684 | Influenza A virus (A / Chicken / Hebei / 2/98 (H9N2)) PB2 gene, partial cds. Gil 22759072 | AF5366851 Influenza A virus (A / Chicken / Hebei / 3/98 (H9N2)) PB2 gene, partial cds. gi 122759074 | AF536686 | Influenza A virus (A / Chicken / Henan / 98 (H9N2)) PB2 gene, partial cds.

Gil 30025722 | AY253750 | Influenza A virus (A / Chicken / Shangai / F / 98 (H9N2)) RNA polymerase gene (PB2), complete cds. gil 12060631 | AF222622 | Influenza A virus (A / Quail / Hong Kong / A17 / 99 (H9N2)) polymerase 2 gene from segment 1 (PB2), partial cds. gi | 12060633 IAF222623 | Influenza A virus (A / Pigeon / Hong Kong / FY6 / 99 (H9N2)) polymerase 2 gene from segment 1 (PB2), partial cds. Gil 12060635 | AF222624 | Influenza A virus (A / Chicken / Hong Kong / NT16 / 99 (H9N2)) polymerase 2 gene from segment 1 (PB2), partial cds. gi I 12060637 IAF222625 | Influenza A virus (A / Quail / Hong Kong / SSP10 / 99 (H9N2)) polymerase 2 gene from segment 1 (PB2), partial cds. gi | 12060639 | AF222626 | Influenza A virus (A / Pheasant / Hong Kong / SSPll / 99 (H9N2)) polymerase 2 gene from segment 1 (PB2), partial cds. Gil 12060641 | AF222627 | Influenza A virus (A / Chicken / Hong Kong / FY20 / 99 (H9N2)) polymerase 2 gene from segment 1 (PB2), partial cds. gi | 12060643 | AF222628 | Influenza A virus (A / Chicken / Hong Kong / KC12 / 99 (H9N2)) polymerase 2 gene from segment 1 (PB2), partial cds. gi | 12060645 | AF222629 | Influenza A virus (A / Quail / Hong Kong / NT28 / 99 (H9N2)) polymerase 2 gene from segment 1 (PB2), partial cds. gil 12060647 | AF222630 | Influenza A virus (A / Chicken / Hong Kong / SF2 / 99 (H9N2)) polymerase 2 gene from segment 1 (PB2), partial cds. gi | 120606491 AF222631 | Influenza A virus (A / Silky chicken / Hong Kong / SF44 / 99 (H9N2)) polymerase 2 gene of segment 1 (PB2), partial cds. gi | 22759076 | AF536687 | Influenza A virus (A / Chicken / Liaoning / 99 (H9N2)) PB2 gene, partial cds. gi | 33318112 IAF508641] Influenza A virus (A / Chicken / Pakistan / 4/99 (H9N2)) polymerase gene PB2 segment 1 (PB2), complete cds. Gil 33318114 | AF508642 | Influenza A virus (A / Chicken / Pakistan / 5/99 (H9N2)) PB2 polymerase gene of segment 1 (PB2), complete cds. Gil 33318126IAF508648 | Influenza A virus (A / Chicken / Korea / 99029/99 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. Gil 33318120 | AF508645 | Influenza A virus (A / Chicken / Iran / llT / 99 (H9N2)) PB2 polymerase gene of segment 1 (PB2), complete cds. gi I 33318122 IAF508646I Influenza A virus (A / Chicken / Saudi Arabia / 532/99 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. gi | 33318140 | AF508655 | Influenza A virus (A / Chicken / Ningxia / 5/99 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. gi | 33318146 | AF508658 | Influenza A virus (A / Chicken / Shijiazhuang / 2/99 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. gi | 12038893 IAJ291395 | Influenza A virus (A / Chicken / Pakistan / 2/99 (H9N2)) PB2 gene for PB2 polymerase, genomic RNA. gi 122759064 IAF536681 | Influenza A virus (A / Chicken / Beijing / 3/99 (H9N2)) PB2 gene, partial cds. gi 131339607 | AF523479 I Influenza A virus (A / Pato / Shantou / 1881/00 (H9N2)) polymerase gene (PB2), partial cds. Gil 31339601 | AF5234761 Influenza A virus (A / Pato / Shantou / 830/00 (H9N2)) polymerase gene (PB2), partial cds. gi I 31339603 IAF523477 | Influenza A virus (A / Pato / Shantou / 1796/00 (H9N2)) polymerase gene (PB2), partial cds. gi | 18496117 IAJ427861 | Influenza A virus (A / quail / Hong Kong / FY298 / 00 (H9N2)) partial PB2 gene for polymerase protein PB2, genomic RNA gi I 27466041 IAY180715 | Flu virus strain A A / Wild Duck / Nanchang / 2-0480 / 2000 (H9N2) polymerase subunit gene PB2 (PB2), partial cds. gi | 27466043 | Y180716 j Virus strain of influenza A A / Pigeon / Nanchang / 2-0461 / 2000 (H9N2) polymerase subunit gene PB2 (PB2), partial cds. gi | 27466045 | AY180717 | Strain of influenza virus A A / Pato / Nanchang / 1-0070 / 2000 (H9N2) gene of polymerase subunit PB2 (PB2), partial cds. gi 127466055 IAY180722 | Strain of influenza virus A A / Pato / Nanchang / 10-389 / 2000 (H9N2) gene of polymerase subunit PB2 (PB2), partial cds. gil 27466057 IAY180723 | Strain of influenza virus A A / Pigeon / Nanchang / 7-058 / 2000 (H9N2) gene of polymerase subunit PB2 (PB2), partial cds. gil 27466067 IAY180728 | Strain of influenza A virus / Quail / Nanchang / 2-0460 / 2000 (H9N2) polymerase subunit gene PB2 (PB2), partial cds. gi | 27466085 | AY180737 | Strain of influenza A virus / Pichón / Nanchang / 11-145 / 2000 (H9N2) gene of polymerase subunit PB2 (PB2), partial cds. gi | 27466087 IAY180738 | Strain of influenza virus A / Pato / Nanchang / 11-197 / 2000 (H9N2) gene of polymerase subunit PB2 (PB2), partial cds. gi 127466091 IAY180740 | Strain of influenza virus A A / Pato / Nanchang / 11-290 / 2000 (H9N2) gene of polymerase subunit PB2 (PB2), partial cds. gil 274660931 AY180741 | Strain of influenza A virus A / Pato / Nanchang / 11-392 / 2000 (H9N2) gene - of polymerase subunit PB2 (PB2), partial cds. gi 131339575 | AF523463 | Influenza A virus (A / Pato / Shantou / 2134/00 (H9N2)) polymerase gene (PB2), partial cds. gi | 31339579 IAF523465 | Influenza A virus (A / Pato / Shantou / 1043/00 (H9N2)) polymerase gene (PB2), partial cds. gi 131339581 | AF5234661 Influenza A virus (A / Pato / Shantou / 1042/00 (H9N2)) polymerase gene (PB2), partial cds. gi | 31339593 IAF523472 | Influenza A virus (A / Pato / Shantou / 2102/00 (H9N2)) polymerase gene (PB2), partial cds. gi | 31339595 | AF523473 | Influenza A virus (A / Pato / Shantou / 2144/00 (H9N2)) polymerase gene (PB2), partial cds. Gil 31339597 | AF523474 | Influenza A virus (A / Pato / Shantou / 2143/00 (H9N2)) polymerase gene (PB2), partial cds. gi | 33318138 IAF508654 | Influenza A virus (A / Chicken / Henan / 62/00 (H9N2)) polymerase gene PB2 of segment 1 (PB2), partial cds. gi 133318130 | AF5086501 Influenza A virus (A / Chicken / Guangdong / 10/00 (H9N2)) PB2 polymerase gene of segment 1 (PB2), partial cds. gi 127466121 | AY1807551 Flu virus strain A A / Pato / Nanchang / 7-092 / 2000 (H9N2) polymerase subunit gene PB2 (PB2), partial cds. gil 274661411 AY1807651 Flu virus strain A A / Chicken / Nanchang / 4-010 / 2000 (H9N2) polymerase subunit gene PB2 (PB2), partial cds. gil 27466157 | AY1807731 Strain of influenza A virus / Quail / Nanchang / 4-040 / 2000 (H9N2) polymerase subunit gene PB2 (PB2), partial cds. gi | 27466159 IAY180774 | Strain of influenza A virus A / Chicken / Nanchang / 1-0016 / 2000 (H9N2) polymerase subunit gene PB2 (PB2), partial cds. gi | 55469788 IAY768575 | Influenza A virus (A / chicken / Korea / SNU0028 / 00 (H9N2)) basic polymerase 2 subunit gene (PB2), partial cds. gi | 55469790 | AY768576 | Influenza A virus (A / chicken / Korea / SNU0037 / 00 (H9N2)) basic polymerase 2 subunit gene (PB2), partial cds. gi 155469792 | AY768577 | Influenza A virus (A / chicken / Korea / SNU0073 / 00 (H9N2)) polymerase 2 basic subunit gene (PB2), partial cds. gi | 55469794 IAY768578 | Influenza A virus (A / chicken / Korea / SNU0091 / 00 (H9N2)) basic polymerase 2 subunit gene (PB2), partial cds. Gil 55469796 | AY768579 | Influenza A virus (A / chicken / Korea / SNU0140 / 00 { H9N2)) polymerase 2 basic subunit gene (PB2), partial cds. gi | 55469798 IAY768580 | Influenza A virus (A / chicken / Korea / SNU0146 / 00 (H9N2)) polymerase 2 basic subunit gene (PB2), partial cds. Gil 55469800 IAY768581 | Influenza A virus (A / chicken / Korea / SNU1035C / 00 (H9N2)) basic polymerase 2 subunit gene (PB2), partial cds. gi 127466143 | AY180766 | Strain of influenza virus A A / Chicken / Nanchang / 4-301 / 2001 (H9N2) gene of polymerase subunit PB2 (PB2), partial cds. gi | 31339599 | AF523475 | Influenza A virus (A / Pato / Shantou / 2088/01 (H9N2)) polymerase gene (PB2), partial cds. Gil 31339591 | AF523471 | Influenza A virus (A / Pato / Shantou / 1605/01 (H9N2)) polymerase gene (PB2), partial cds. Gil 31339577 IAF523464 | Influenza A virus (A / Duck Wild / Shantou / 4808/01 (H9N2)) polymerase gene (PB2), partial cds. gi 127466097 IAY180743 | Strain of influenza A virus A / Chicken / Nanchang / 4-361 / 2001 (H9N2) polymerase subunit gene PB2 (PB2), partial cds. gi | 54398631 IAY664792 | Influenza A virus (A / chicken / Hong Kong / CSW153 / 03 (H9N2)) protein 2 basic polymerase gene (PB2), partial cds. Gil 54398633 | AY664793 | Influenza A virus (A / chicken / Hong Kong / AP45 / 03 (H9N2)) protein 2 basic polymerase gene (PB2), partial cds. gi | 54398635 | AY664794 | Influenza A virus (A / chicken / Hong Kong / BD90 / 03 (H9N2)) protein 2 basic polymerase gene (PB2), partial cds. gi | 54398637 IAY664795 | Influenza A virus (A / chicken / Hong Kong / CSW291 / 03 (H9N2)) non-functional polymerase basic protein 2 (PB2) gene, partial sequence. gi I 54398638 IAY664796 | Influenza A virus (A / chicken / Hong Kong / CSW304 / 03 (H9N2)) non-functional polymerase basic protein 2 (PB2) gene, partial sequence. gi I 54398639 | AY664797 i 'Influenza A virus (A / chicken / Hong Kong / FY23 / 03 (H9N2)) non-functional polymerase basic protein 2 (PB2) gene, partial sequence. gi 154398640 | AY664798 | Influenza A virus (A / guinea fowl / Hong Kong / NT101 / 03 (H9N2)) protein 2 basic polymerase gene (PB2), partial cds. Gil 54398642 | AY664799 | Influenza A virus (A / chicken / Hong Kong / NT142 / 03 (H9N2)) protein 2 basic polymerase gene (PB2), partial cds. gi | 54398644 IAY664800 | Influenza A virus (A / chicken / Hong Kong / SFl / 03 (H9N2)) non-functional polymerase basic protein 2 (PB2) gene, partial sequence. Gil 54398645 | AY664801 I Influenza A virus (A / chicken / Hong Kong / SSP101 / 03 (H9N2)) non-functional polymerase basic protein 2 (PB2) gene, partial sequence. Gil 54398646 | AY664802 | Influenza A virus (A / chicken / Hong Kong / TP38 / 03 (H9N2)) protein 2 basic polymerase gene (PB2), partial cds. Gil 54398648 | AY664803 | Influenza A virus (A / chicken / Hong Kong / WF126 / 03 (H9N2)) non-functional polymerase basic protein 2 (PB2) gene, partial sequence. Gil 54398649 | AY664804 | Influenza A virus (A / pigeon / Hong Kong / WF53 / 03 (H9N2)) non-functional polymerase basic protein 2 (PB2) gene, partial sequence. gi | 54398650 IAY664805 | Influenza A virus (A / pheasant / Hong Kong / WF54 / 03 (H9N2)) non-functional polymerase basic protein 2 (PB2) gene, partial sequence. gi | 54398651 | AY664806 | Influenza A virus (A / guinea fowl / Hong Kong / NT184 / 03 (H9N2)) protein 2 basic polymerase gene (PB2), partial cds. gi | 54398653 | AY664807 | Influenza A virus (A / chicken / Hong Kong / WF120 / 03 (H9N2)) non-functional polymerase basic protein 2 (PB2) gene, partial sequence. Gil 54398654 | AY664808 | Influenza A virus (A / chicken / Hong Kong / NT366 / 03 (H9N2)) protein 2 basic polymerase gene (PB2), partial cds. Gil 54398656 | AY664809 | Influenza A virus (A / chicken / Hong Kong / SSP418 / 03 (H9N2)) protein 2 basic polymerase gene (PB2), partial cds. Gil 54398658 | AY664810 | Influenza A virus (A / chicken / Hong Kong / YU427 / 03 (H9N2)) protein 2 basic polymerase gene (PB2), partial cds. gi I 55793686IAY800240 | Influenza A virus (A / chicken / Korea / Sl / 2003 (H9N2)) protein 2 basic polymerase gene (PB2), partial cds. gi I 58429686IAY862710 | Influenza A virus (A / chicken silky / Korea / S3 / 03 (H9N2)) gene PB2 (PB2), partial cds. gi | 58429688 IAY862711 | Influenza A virus (A / chicken / Korea / S4 / 03 (H9N2)) PB2 gene (PB2), partial cds. gil 58429690 IAY862712 | Influenza A virus (A / chicken / Korea / S5 / 03 (H9N2)) PB2 gene (PB2), partial cds. gi 158429692 | AY862713 | Influenza A virus (A / chicken / Korea / S12 / 03 (H9N2)) PB2 gene (PB2), partial cds. gi 158429694 | AY862714 | Influenza A virus (A / duck / Korea / S13 / 03 (H9N2)) gene PB2 (PB2), partial cds .. gil 584296961 AY862715 | Influenza A virus (A / pigeon / Korea / S14 / 03 (H9N2)) PB2 gene (PB2), partial cds. gi | 58429698 | AY862716 | Influenza A virus (A / chicken / Korea / S15 / 03 (H9N2)) PB2 gene (PB2), partial cds. Gil 58429700 | AY862717 | Influenza A virus (A / chicken / Korea / S16 / 03 (H9N2)) PB2 gene (PB2), partial cds. gi I 58429702 IAY862718 | Influenza A virus (A / chicken / Korea / S18 / 03 (H9N2)) PB2 gene (PB2), partial cds. Sequences used in protein analysis Influenza A Polymerase Acid (PA) gi | 27465935 | AY180662 | Strain of influenza virus A A / Quail / Nanchang / 12-340 / 2000 (H1N1) polymerase subunit gene PA (PA), partial cds. gil 493570631 AY633217 | Influenza A virus (A / wild turkey / Alberta / 211/98 (H1N1)) polymerase protein A (PA) gene, partial cds. Gil 59181951 AJ24399 | Influenza A virus (CEPA A / TURKEY SILVESTRE / NEW YORK / 6750/78) partial mRNA for PA protein. gi 145272157 | AY422034 | Influenza A virus (A / duck / Hokkaido / 95/01 (H2N2)) PA protein gene (PA), partial cds. gi I27465965IAY180677 | Strain of influenza A virus A / Pollo / Nanchang / 3-120 / 2001 (H3N2) PA polymerase subunit gene (PA), partial cds. gi | 56159994 IAY779263 | Influenza A virus (A / Turkey / North Carolina / 12344/03 (H3N2)) polymerase acid protein (PA) gene, partial cds. gil 561599961 AY77926 | Influenza A virus (A / turkey / Minnesota / 764-2 / 03 (H3N2)) polymerase acid protein (PA) gene, partial cds. gi I58429736IAY862687 | - Influenza A virus (A / chicken / Korea / S6 / 03 (H3N2)) PA gene (PA), partial cds. gi I 58429738 IAY862688 | Influenza A virus (A / duck / Korea / S7 / 03 (H3N2)) PA gene (PA), partial cds. Gil 58429740 | AY8626891 Influenza A virus (A / duck / Korea / S8 / 03 (H3N2)) PA gene (PA), partial cds. Gil 58429742 | AY862690 | Influenza A virus (A / duck / Korea / S9 / 03 (H3N2)) PA gene (PA), partial cds. gil 58429744 IAY862691 | Influenza A virus (A / duck / Korea / S10 / 03 (H3N2)) PA gene (PA), partial cds. gi I 58429746IAY862692 | Influenza A virus (A / pigeon / Korea / Sll / 03 (H3N2)) PA gene (PA), partial cds. Gil 18091833 | AF213914 | Influenza A virus (A / Chicken / Italy / 5945/95 (H3N2)) polymerase protein gene PA segment 3, partial cds. gi I 58531086IAB1668611 Influenza A virus (A / chicken / Yamaguchi / 7/2004 (H5N1)) PA gene for polymerase acid protein, complete cds. gi I 58531118 IAB1888151 Influenza A virus (A / chicken / Oita / 8/2004 (H5N1)) PA gene for polymerase acid protein, complete cds. gil 9863935 | AF216739 | Influenza A virus (A / Environment / Hong Kong / 437-10 / 99 (H5N1)) polymerase acid protein gene, complete cds. gil 14165201 | AF380163 | Influenza A virus (A / Goose / Guangdong / 3/97 (H5N1)) polymerase gene segment 3 (PA), complete cds. gi I 18092185 IAF398427 | Influenza A virus (A / Goose / Hong Kong / 385.3 / 2000 (H5N1)) polymerase gene (PA), partial cds. gi | 18092187 IAF398428 | Influenza A virus (A / Goose / Hong Kong / 385.5 / 2000 (H5N1)) polymerase gene (PA), partial cds. gi | 21359667 IAF468841 | Influenza A virus (A / Pato / Anyang / AVL-1/2001 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi 128849710 | AF509195 | Influenza A virus (A / Chicken / Hong Kong / FY77 / 01 (H5N1)) polymerase gene (PA), partial cds. gi | 28849712 IAF509196I Influenza A virus (A / Chicken / Hong Kong / YU562 / 01 (H5N1)) polymerase gene (PA), partial cds. gi | 28849714 IAF509197 | Influenza A virus (A / Chicken / Hong Kong / YU563 / 01 (H5N1)) polymerase gene (PA), complete cds. gi | 28849716 | AF509198 | Influenza A virus (A / Chicken / Hong Kong / FY150 / 01 (H5N1)) polymerase gene (PA), partial cds. gi | 28849718 IAF509199 | Influenza A virus (A / Pheasant / Hong Kong / FY155 / 01 (H5N1)) polymerase gene (PA), partial cds. gi | 28849720 | AF509200 | Influenza A virus (A / Chicken silky / Hong Kong / SF189 / 01 (H5N1)) polymerase gene (PA), partial cds. gi 128849722 IAF509201 | Influenza A virus (A / Quail / Hong Kong / SF203 / 01 (H5N1)) polymerase gene (PA), partial cds. gi | 28849724 | AF509202 | Influenza A virus (A / Pigeon / Hong Kong / SF215 / 01 (H5N1)) polymerase gene (PA), partial cds. gi | 28849726 | AF509203 | Influenza A virus (A / Chicken / Hong Kong / SF219 / 01 (H5N1)) polymerase gene (PA), partial cds. gil 28849728 IAF509204 | Influenza A virus (A / Chicken / Hong Kong / 715.5 / 01 (H5N1)) polymerase gene (PA), partial cds. gi | 28849730 IAF509205 | Influenza A virus (A / Chicken / Hong Kong / 751.1 / 01 (H5N1)) polymerase gene (PA), partial cds. gi | 28849732 | AF509206 | Influenza A virus (A / Chicken / Hong Kong / 822.1 / 01 (H5N1)) polymerase gene (PA), partial cds. gi 128849734 IAF509207 | Influenza A virus (A / Chicken / Hong Kong / 829.2 / 01 (H5N1)) polymerase gene (PA), partial cds .. gi | 28849736 | AF509208 | Influenza A virus (A / Chicken / Hong Kong / 830.2 / 01 (H5N1)) polymerase gene (PA), partial cds. gi 128849738 I AF509209 | Influenza A virus (A / Chicken / Hong Kong / 858.3 / 01 (H5N1)) polymerase gene (PA), partial cds. gi 128849740 IAF509210I Influenza A virus (A / Chicken / Hong Kong / 866.3 / 01 (H5N1)) polymerase gene (PA), partial cds. gil 28849742 IAF509211 | Influenza A virus (A / Chicken / Hong Kong / 867.1 / 01 (H5N1)) polymerase gene (PA), partial cds. gi 128849744 IAF509212 | Influenza A virus (A / Chicken / Hong Kong / 879.1 / 01 (H5N1)) polymerase gene (PA), partial cds. gi | 28849746 | AF509213 | Influenza A virus (A / Chicken / Hong Kong / 873.3 / 01 (H5N1)) polymerase gene (PA), partial cds. gi 128849748 IAF509214 | Influenza A virus (A / Chicken / Hong Kong / 876.1 / 01 (H5N1)) polymerase gene (PA), partial cds. gi 128849750 IAF509215I Influenza A virus (A / Chicken / Hong Kong / 891.1 / 01 (H5N1)) polymerase gene (PA), partial cds. gi 128849752 IAF509216I Influenza A virus (A / Chicken / Hong Kong / 893.1 / 01 (H5N1)) polymerase gene (PA), partial cds. gi 128849754 IAF509217 | Influenza A virus (A / Goose / Hong Kong / 76.1 / 01 (H5N1)) polymerase gene (PA), partial cds. gi | 28849756 | AF509218 | Influenza A virus (A / Goose / Hong Kong / wwl00 / 01 (H5N1)) polymerase gene (PA), partial cds. gi | 28849758 | AF509219) Influenza A virus (A / Duck / Hong Kong / 573.4 / 01 (H5N1)) polymerase gene (PA), partial cds. gi 128849760 IAF509220 | Influenza A virus (A / Pato / Hong Kong / 646.3 / 01 (H5N1)) polymerase gene (PA), partial cds. gi I 19697861 | AY059526 | Influenza A virus (A / Goose / Hong Kong / ww26 / 2000 (H5N1)) polymerase gene segment 3 (PA), partial cds. gil 196978631 AY059527 | Influenza A virus (A / Goose / Hong Kong / ww28 / 2000 (H5N1)) polymerase gene segment 3 (PA), partial cds. gi | 19697865 IAY059528 | Influenza A virus (A / Pato / Hong Kong / ww381 / 2000 (H5N1)) polymerase gene segment 3 (PA), partial cds. gi | 19697869 | AY059530 | Influenza A virus (A / Pato / Hong Kong / ww461 / 2000 (H5N1)) polymerase gene segment 3 (PA), partial cds.

Gil 19697871 | AY059531 | Influenza A virus (A / Goose / Hong Kong / ww491 / 2000 (H5N1)) polymerase gene segment 3 (PA), partial cds. gi I 19697873 IAY059532 | Influenza A virus (A / Pato / Hong Kong / 2986.1 / 2000 (H5N1)) polymerase gene segment 3 (PA), partial cds. gi | 19697875 IAY059533 | Influenza A virus (A / Goose / Hong Kong / 3014.8 / 2000 (H5N1)) polymerase gene segment 3 (PA), partial cds. gi 128821204 | AY221566 | Influenza A virus (A / Chicken / Hong Kong / NT873.3 / 01-MB (H5Nl)) polymerase gene (PA), partial cds. gi | 28821206 | AY221567 | Influenza A virus (A / Chicken / Hong Kong / NT873.3 / 01 (H5N1)) polymerase gene (PA), partial cds. gi | 28821208 IAY221568 | Influenza A virus (A / Chicken / Hong Kong / PYl50 / 01-MB (HSN1)) polymerase gene (PA), partial cds. gi 128821210 | AY221569 | Influenza A virus (A / Chicken / Hong Kong / FY150 / 01 (H5N1)) polymerase gene (PA), partial cds. gi 128821212 | Y221570 | Influenza A virus (A / Pheasant / Hong Kong / FYl55 / 01-MB (H5Nl)) polymerase gene (PA), partial cds. gil 28821214 IAY221571 | Influenza A virus (A / Pheasant / Hong Kong / FY155 / 01 (H5N1)) polymerase gene (PA), partial cds. gi | 28821216 | AY221572 | Influenza A virus (A / Chicken / Hong Kong / YU822.2 / 01-MB (H5Nl)) polymerase gene (PA), partial cds. gil 28821218 IAY221573 | Influenza A virus (A / Chicken / Hong Kong / YU822.2 / 01 (H5N1)) polymerase gene (PA), partial cds, gi 128821220 IAY221574 | Influenza A virus (A / Chicken / Hong Kong / YU562 / 01 (H5N1)) polymerase gene (PA), partial cds. gi | 41207483 | AY518365 | Influenza A virus (A / duck / China / E319-2 / 03 (H5N1)) polymerase gene (PA), complete cds. gi I 5109411 IAY551934 | Influenza A virus (A / chicken / Nakorn-Patom Thailand / CU-K2 / 04 (H5N1)) polymerase gene (PA), complete cds. gi | 47834839 | AY576406 | Influenza A virus (A / GS / HK / 739.2 / 02 (H5N1)) polymerase gene (PA), partial cds. gi | 47834841 IAY576407 | Influenza A virus (A / Eg / HK / 757.3 / 02 (H5N1)) polymerase gene (PA), partial cds. gil 47834843IAY576408 | Influenza A virus (A / G.H / HK / 793.1 / 02 (H5N1)) polymerase gene (PA), partial cds. gi | 47834845 IAY576409 | Influenza A virus (A / Dk / HK / 821/02 (H5N1)) polymerase gene (PA), partial cds. gi | 47834847 IAY576410 | Influenza A virus (A / Ck / HK / 31.4 / 02 (H5N1)) polymerase gene (PA), complete cds. gi | 47834849 IAY576411 | Influenza A virus (A / Ck / HK / 61.9 / 02 (H5N1)) polymerase gene (PA), complete cds. gi 147834851 IAY576412 | Influenza A virus (A / Ck / HK / YU777 / 02 (H5N1)) polymerase gene (PA), complete cds. Gil 47834853 | AY5764131 Influenza A virus (A / Ck / HK / 96.1 / 02 (H5N1)) polymerase gene (PA), partial cds. gi | 47834855 | AY576414 | Influenza A virus (A / Ck / HK / 409.1 / 02 (H5N1)) polymerase gene (PA), partial cds. Gil 47834857 | AY576415 | Influenza A virus (A / Ph / HK / sv674.15 / 02 (H5N1)) polymerase gene (PA), complete cds. gi 147156478 IAY585462 | Influenza A virus (A / duck / Fujian / 01/2002 (H5N1)) polymerase mRNA (PA), complete cds. gil 47156480 | AY5854631 Influenza A virus (A / duck / Fujian / 13/2002 (H5N1)) polymerase mRNA (PA), complete cds. gi I 47156482 IAY585464 | Influenza A virus (A / duck / Fujian / 17/2001 (H5N1)) polymerase mRNA (PA), complete cds. gi | 47156484 IAY585465 | Influenza A virus (A / duck / Fujian / 19/2000 (H5N1)) polymerase mRNA (PA), complete cds. Gil 47156486 | AY585466 | Influenza A virus (A / duck / Guangdong / 01/2001 (H5N1)) polymerase mRNA (PA), complete cds. gi | 47156488 IAY585467 | Influenza A virus (A / duck / Guangdong / 07/2000 (H5N1)) polymerase mRNA (PA), complete cds. gil 47156490 IAY585468 | Influenza A virus (A / duck / Guangdong / 12/2000 (H5N1)) polymerase mRNA (PA), complete cds. gi | 47156492 | AY585469 | Influenza A virus (A / duck / Guangdong / 22/2002 (H5N1)) polymerase mRNA (PA), complete cds. gi | 47156494 | AY585470 | Influenza A virus (A / duck / Guangdong / 40/2000 (H5N1)) polymerase mRNA (PA), complete cds. gi | 47156496 | AY585471 | Influenza A virus (A / duck / Guangxi / 07/1999 (H5N1)) polymerase mRNA (PA), complete cds. gi | 47156498 IAY585472 | Influenza A virus (A / duck / Guangxi / 22/2001 (H5N1)) polymerase mRNA (PA), complete cds. gi 147156500 IAY5854731 Influenza A virus (A / duck / Guangxi / 35/2001 (H5N1)) polymerase mRNA (PA), complete cds. gi | 47156502 IAY58547 | Influenza A virus (A / duck / Guangxi / 50/2001 (H5N1)) polymerase mRNA (PA), complete cds. gi 147156504 | AY585475 | Influenza A virus (A / duck / Guangxi / 53/2002 (H5N1)) polymerase mRNA (PA), complete cds. gi I 47156506 | AY585476 | Influenza A virus (A / duck / Shanghai / 08/2001 (H5N1)) polymerase mRNA (PA), complete cds. gi 147156508 IAY585477 | Influenza A virus (A / duck / Shangai / 13/2001 (H5N1)) polymerase mRNA (PA), complete cds. gi I 47156510 IAY585478 | Influenza A virus (A / duck / Shangai / 35/2002 (H5N1)) polymerase mRNA (PA), complete cds. Gil 47156512 | Y585479 | Influenza A virus (A / duck / Shangai / 37/2002 (H5N1)) polymerase mRNA (PA), complete cds. Gil 47156514 | AY58548T | Influenza A virus (A / duck / Shangai / 38/2001 (H5N1)) polymerase mRNA (PA), complete cds. gi | 47156516 IAY585481 | Influenza A virus (A / duck / Zhejiang / 11/2000 (H5N1)) Polymerase mRNA (PA), complete cds. gi 147156518 IAY585482 | Influenza A virus (A / duck / Zhejiang / 52/2000 (H5N1)) polymerase mRNA (PA), complete cds. gi 147716770 IAY609311 | Influenza A virus (A / chicken / Guangdong / 174/04 (H5N1)) segment 3, complete sequence. gi | 50313026IAY651597 | Influenza A virus (A / Ck / Indonesia / 4/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313028 | AY651598 | Influenza A virus (A / Ck / Indonesia / 5/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi 150313030 | AY651599 | Influenza A virus (A / Ck / Indonesia / 2A / 2003 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313032 | AY651600 | Influenza A virus (A / Dk / Indonesia / MS / 2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313034 | AY6516011 Influenza A virus (A / Ck / Indonesia / BL / 2003 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 503130361 AY651602 | Influenza A virus (A / Ck / Indonesia / PA / 2003 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313038 | AY6516031 Influenza A virus (A / Ck / Thailand / 1/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313040 | AY651604 | Influenza A virus (A / Ck / Thailand / 73/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313042 | AY6516051 Influenza A virus (A / Ck / Thailand / 9.1 / 2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313044 | AY651606 | Influenza A virus (A / Qa / Thailand / 57/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313046IAY651607 | Influenza A virus (A / bird / Thailand / 3.1 / 2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313048 | AY651608 | Influenza A virus (A / Dk / Thailand / 71.1 / 2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi 150313050 | AY651609 | Influenza A virus (A / Gs / Thailand / 79/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi | 50313060 IAY651614 | Influenza A virus (A / Ck / Vietnam / 33/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313062 | AY551615 | Influenza A virus (A / Ck / Vietnam / 35/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi | 50313064 IAY651616 | Influenza A virus (A / Ck / Vietnam / 36/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313066IAY651617 | Influenza A virus (A / Ck / Vietnam / 37/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi | 50313068 IAY651618 | Influenza A virus (A / Ck / Vietnam / 38/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313070 | AY651619 | Influenza A virus (A / Ck / Vietnam / 39/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313072 | AY6516201 Influenza A virus (A / Ck / Vietnam / C57 / 2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313074 | AY651621 | Influenza A virus (A / Dk / Vietnam / 11/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313076IAY651622 | Influenza A virus (A / Gf / HK / 38/2002 (H5N1)) polymerase acid protein (PA) gene, complete cds. Gil 50313078 | AY651623 | Influenza A virus (A / Ck / HK / 31.2 / 2002 (H5N1)) polymerase acid protein (PA) gene, complete cds. Gil 50313080 | AY65162 | Influenza A virus (A / Ck / HK / 37.4 / 2002 (H5N1)) polymerase acid (PA) protein gene, partial cds. Gil 50313082 | AY6516251 Influenza A virus (A / SCk / HK / YU100 / 2002 (H5N1)) polymerase acid protein (PA) gene, complete cds. Gil 50313084 | AY651626 | Influenza A virus (A / Ck / HK / YU22 / 2002 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi I 50313086IAY651627 | Influenza A virus (A / Ck / HK / 3176.3 / 2002 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313088 | AY651628 | Influenza A virus (A / Ck / HK / 3169.1 / 2002 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi | 50313090 IAY651629I Influenza A virus (A / Ck / HK / FY157 / 2003 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi I 50313092 IAY651630I Influenza A virus (A / Ck / HK / YU324 / 2003 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi I 50313094 IAY651631 | Influenza A virus (A / Ck / HK / 2133.1 / 2003 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi I 50313096 IAY651632 | Influenza A virus (A / Ck / HK / NT93 / 2003 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313098 | AY651633 | Influenza A virus (A / Ck / HK / SSP141 / 2003 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi 150313100 | AY651634 | Influenza A virus (A / Ck / HK / WF157 / 2003 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi 150313102 IAY6516351 Influenza A virus (A / gull-headed gull / HK / 12.1 / 2003 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 5031310 | AY651636 | Influenza A virus (A / Gray Heron / HK / 861.1 / 2002 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi | 50313106 | AY651637 | Influenza A virus (A / wild pigeon / HK / 862.7 / 2002 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi I 50313108 IAY651638 | Influenza A virus (A / sparrow miller / HK / 864/2002 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi | 50313110 IAY651639 | Influenza A virus (A / teal / China / 2978.1 / 2002 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313112 | AY651640 | Influenza A virus (A / peregrine falcon / HK / D0028 / 2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi 15031311 IAY651541 | Influenza A virus (A / Dk / HN / 5806/2003 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi | 50313116IAY651642 | Influenza A virus (A / Dk / HN / 303/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi | 50313118 IAY651643 | Influenza A virus (A / Dk / HN / 101/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi | 50313120IAY651644 | Influenza A virus (A / Dk / ST / 4003/2003 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313122 | AY6516451. Influenza A virus (A / Ph / ST / 44/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi I 50313124 IAY6516461 Influenza virus A (A / Ck / ST / 4231/2003 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi I 50313126IAY651647 | Influenza A virus (A / Dk / YN / 6255/2003 (H5N1)) polymerase acid (PA) protein gene, partial cds. gi I 50313128 IAY651648 | Influenza A virus (A / Dk / YN / 6445/2003 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi | 50313130 | AY651649 | Influenza A virus (A / Ck / YN / 115/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. Gil 50313132 | AY651650 | Influenza A virus (A / Ck / YN / 374/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi 150365724 | AY653198 | Influenza A virus (A / chicken / Jilin / 9/2004 (H5N1)) segment 3, complete sequence. Gil 56548923 | AY676029 | Influenza A virus (A / duck / Hong Kong / 821/02 (H5N1)) polymerase gene (PA), complete cds. gi | 56548925 IAY676030 | Influenza A virus (A / heron / Hong Kong / 757.2 / 03 (H5N1)) polymerase gene (PA), complete cds. gi I 56548927 IAY676031 | Influenza A virus (A / chicken / Korea / ES / 03 (H5N1)) polymerase gene (PA), complete cds. gil 56548929IAY676032 | Influenza A virus (A / duck / Korea / ESDl / 03 (H5N1)) polymerase gene (PA), complete cds. gi | 50956625 | AY684705 | Influenza A virus (A / chicken / Hubei / 327/2004 (H5N1)) polymerase gene (PA), complete cds. gi | 56119221 IAY720944 | Influenza A virus (A / chicken / Vietnam / DT-171/2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi 156119227 | AY720947 | Influenza A virus (A / duck / Vietnam / TG-007A / 2004 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi | 57924419 | AY724784 | Influenza A virus (A / chicken / Vietnam / HCM-022/2004 (H5N1)) polymerase gene (PA), partial cds. gil 57924480 | AY7247861 Influenza A virus (A / chicken / Vietnam / DN-045/2004 (H5N1)) polymerase gene (PA), partial cds. gil 57924569] AY724788 | Influenza A virus (A / chicken / Vietnam / VL-008/2004 (H5N1)) polymerase gene (PA), partial cds. gi I 57924680 IAY724790 | Influenza A virus (A / chicken / vietnam / AG-010/2004 (H5N1)) polymerase gene (PA), partial cds. gi | 57924765 | AY724792 | Influenza A virus (A / chicken / Vietnam / DT-015/2004 (H5N1)) polymerase gene (PA), partial cds. gil 57924882 | AY724796 | Influenza A virus (A / chicken / Vietnam / LA-024/2004 (H5N1)) polymerase gene (PA), partial cds. gi | 57915971 | AY737288 | Influenza A virus (A / chicken / Guangdong / 191/04 (H5N1)) segment 3, complete sequence. gi 157916018 | AY737295 Influenza A virus (A / chicken / Guangdong / 178/04 (H5N1)) segment 3, complete sequence. gi 157916074 | AY737303 | Influenza A virus (A / duck / Guangdong / 173/04 (H5N1)) segment 3, complete sequence. Gil 55233234 | AY770082 | Influenza A virus (A / chicken / Hubei / 489/2004 (H5N1)) polymerase gene (PA), complete cds. gil 54873465 IAY770995 | Influenza A virus (A / chicken / Ayutthaya / Thailand / CU-23/04 (H5N1)) polymerase gene, partial cds. gil 58618433IAY818133 | Influenza A virus (A / chicken / Vietnam / C58 / 04 (H5N1)) PA polymerase protein gene, complete cds. gi | 58618435 IAY818134 | Influenza A virus (A / quail / Vietnam / 36/04 (H5N1)) PA polymerase protein gene, complete cds. gil 58374187 IAY856863 | Influenza A virus (A / pato / Shandong / 093/2004 (H5N1)) segment 3, complete sequence. gi | 58531136 | AB188823 | Influenza A virus (A / chicken / Kyoto / 3/2004 (H5N1)) PA gene for polymerase acid protein, complete cds. gil 58531154 | AB189052 | k Influenza A virus (A / raven / Kyoto / 53/2004 (H5N1)) PA gene for polymerase acid protein, complete cds ,. gi 158531170 IAB189059) Influenza A virus (A / raven / Osaka / 102/2004 (H5N1)) PA gene for polymerase acid protein, complete cds,. gil 3335418 IAF046087 | Influenza A virus (A / Chicken / Hong Kong / 220/97 (H5N1)) polymerase acid protein (PA) gene, partial cds. gi I 6048895 IAF098604 | Influenza A virus (A / Chicken / Hong Kong / 258/97 (H5N1)) PA protein gene (PA), complete cds. gi | 6048897 IAF098605 | Influenza A virus (A / Chicken / Hong Kong / y388 / 97 (H5N1)) PA protein gene (PA), complete cds. Gil 6048899 | AF098606 | Influenza A virus (A / Chicken / Hong Kong / 728/97 (H5N1)) PA protein gene (PA), complete cds. gi I 6048901 IAF098607 | Influenza A virus (A / Chicken / Hong Kong / 786/97 (H5N1)) PA protein gene (PA), complete cds. gi | 6048903 IAF098608 | Influenza A virus (A / Chicken / Hong Kong / 915/97 (H5N1)) PA protein gene (PA), complete cds. gi | 6048905 IAF098609 | Influenza A virus (A / Pato / Hong Kong / p46 / 97 (H5N1)) PA protein gene (PA), complete cds. gi I 6048907 IAF098610 | Influenza A virus (A / Pato / Hong Kong / y283 / 97 (H5N1)) PA protein gene (PA), complete cds. gi | 6048909 IAF098611 | Influenza A virus (A / Goose / Hong Kong / w355 / 97 (H5N1)) PA protein gene (PA), complete cds. Gil 5805280 IAF144302 | Influenza A virus (A / Goose / Guangdong / 1/96 (H5N1)) polymerase gene (PA), complete cds. gi | 9863880 | AF216715 | Influenza A virus (A / Environment / Hong Kong / 437-4 / 99 (H5N1)) polymerase acid protein gene, complete cds. gil 98638991 AF216723 | Influenza A virus (A / Environment / Hong Kong / 437-6 / 99 (H5N1)) polymerase acid protein gene, complete cds. gi I 9863917 IAF216731 | Influenza A virus (A / Environment / Hong Kong / 437-8 / 99 (H5N1)) polymerase acid protein gene, complete cds. gi | 34597776 | AY303660 | Influenza A virus (A / chicken / Chile / 176822/02 (H7N3)) polymerase acid prbtein gene, complete cds. Gil 34597778 IAY303661 | Influenza A virus (A / chicken / Chile / 4957/02 (H7N3)) polymerase acid protein gene, complete cds. Gil 34597780 | AY303662 | Influenza A virus (A / chicken / Chile / 4322/02 (H7N3)) polymerase acid protein gene, partial cds. gil 47680912 | AY586431 | Influenza A virus (A / wild turkey / Italy / 43/01 (H7N3)) PA gene, partial cds. gi | 47680914 IAY586432 | Influenza A virus (A / wild turkey / Italy / 33/01 (H7N3)) PA gene, partial cds. gi | 47680916 | AY586433 | Influenza A virus (A / turkey / Italy / 220158/2002 (H7N3)) PA gene, partial cds. gi | 47680918 IAY58643 | Influenza A virus (A / turkey / Italy / 214845/02 (H7N3)) PA gene, partial cds. gi | 47834370 | AY616764 | Influenza A virus (A / chicken / British Columbia / 04 (H7N3)) protein polymerase 2 (PA) gene, complete cds. gi | 50542647 | AY646083 | Influenza A virus (A / chicken / British Columbia / GSC_human_B / 04 (H7N3)) protein polymerase 2 (PA) gene, complete cds. gi | 50083049 IAY648292 | Influenza A virus (A / GSC_pollo_B / British Columbia / 04 (H7N3)) polymerase 2 acid protein (PA) gene, complete cds. Gil 50059192 | AY6502751 Influenza A virus (A / GSC_pollo / British Columbia / 04 (H7N3)) polymerase 2 acid protein (PA) gene, complete cds. gi I 9988639 | AF268109 | Influenza A virus (A / Red-cheeked / Delaware / 259/94 (H7N7)) PA polymerase protein gene, partial cds. gi | 40353080 IAJ619677 | Influenza A virus (A / chicken / Germany / R28 / 03 (H7N7)) PA gene for PA polymerase complex subunit, genomic RNA. gil 37813167 | AY3424151 Influenza A virus (A / Netherlands / 124/03 (H7N7)) gene A polymerase protein, partial cds. gi | 37813169 | AY342416 | Influenza A virus (A / Netherlands / 126/03 (H7N7)) gene A polymerase protein, partial cds. gi 137813171 | AY342417 | Influenza A virus (A / Netherlands / 127/03 (H7N7)) gene A polymerase protein, partial cds. gi I 37813173IAY342418 | Influenza A virus (A / Netherlands / 219/03 (H7N7)) gene A polymerase protein, complete cds. gil 37813175 | AY342419 | Influenza A virus (A / Netherlands / 033/03 (H7N7)) gene A polymerase protein, complete cds. gi 137813177 IAY342420 | Influenza A virus (A / chicken / Netherlands / 1/03 (H7N7)) gene A polymerase protein, complete cds. gi | 13383274 IAB049157 | Influenza A virus (A / parakeet / Chiba / 1/97 (H9N2)) PA gene for polymerase acid protein, complete cds. gi | 13383276IAB049158 | Influenza A virus (A / parakeet / Narita / 92A / 98 (H9N2)) PA gene for polymerase acid protein, complete cds. gi | 33318154 IAF508662 | Influenza A virus (A / Ostrich / South Africa / 9508103/95 (H9N2)) gene PA polymerase segment 3 (PA), complete cds. Gil 33318156 | AF508663 | Influenza A virus (A / Chicken / Pakistan / 4/99 (H9N2)) polymerase segment PA gene (PA), complete cds. Gil 33318158 | AF508664 | Influenza A virus (A / Chicken / Pakistan / 5/99 (H9N2)) polymerase segment PA gene (PA), partial cds. gi | 33318160 | AF508665 | Influenza A virus (A / Chicken / Germany / R45 / 98 (H9N2)) polymerase segment PA gene (PA), complete cds. gi | 33318162 | AF508666 | Influenza A virus (A / Pato / Germany / 113/95 (H9N2)) polymerase segment PA gene (PA), complete cds. Gil 33318164 | AF508667 | Influenza A virus (A / Chicken / Iran / llT / 99 (H9N2)) polymerase segment PA gene (PA), partial cds. Gil 333181661 AF508668 | Influenza A virus (A / Chicken / Saudi Arabia / 532/99 (H9N2)) polymerase segment PA gene (PA), complete cds. gi I 33318168 | AF5086691 Influenza A virus (A / Pheasant / Ireland / PV18 / 97 (H9N2)), polymerase segment 3 gene (PA), complete cds. Gil 333181701 AF508670 | Influenza A virus (A / Chicken / Korea / 99029/99 (H9N2)) polymerase segment 3 PA gene (PA), complete cds. gi | 33318172 | AF508671 | Influenza A virus (A / Chicken / Beijing / 8/98 (H9N2)) polymerase segment PA gene (PA), complete cds. Gil 3331817 IAF508672 | Influenza A virus (A / Chicken / Guangdong / 10/00 (H9N2)) polymerase segment PA gene (PA), complete cds. gi | 33318176 | AF508673 | Influenza A virus (A / Chicken / Guangdong / 11/97 (H9N2)) polymerase segment PA gene (PA), complete cds. gi | 33318178 IAF508674 | Influenza A virus (A / Chicken / Hebei / 4/98 (H9N2)) polymerase segment PA gene (PA), complete cds. Gil 33318180 | AF508675 | Influenza A virus (A / Chicken / Heilongjiang / 10/97 (H9N2)) polymerase segment PA gene (PA), complete cds. gi 133318182 | AF508676 | Influenza A virus (A / Chicken / Henan / 62/00 (H9N2)) polymerase segment PA gene (PA), partial cds. gi | 33318184 IAF508677 | Influenza A virus (A / Chicken / Ningxia / 5/99 (H9N2)) polymerase segment PA gene (PA), complete cds. gi | 33318186IAF508678 | Influenza A virus (A / Chicken / Sichuan / 5/97 (H9N2)) polymerase segment PA gene (PA), complete cds. Gil 33318188 | AF5086791 Influenza A virus (A / Chicken / Shandong / 6/96 (H9N2)) polymerase segment PA gene (PA), partial cds. gi 133318190 | AF508680 | Influenza A virus (A / Chicken / Shijiazhuang / 2/99 (H9N2)) polymerase segment PA gene (PA), partial cds. gi 133318192 | AF508681 | Influenza A virus (A / Chicken / Shenzhen / 9/97 (H9N2)) polymerase segment PA gene (PA), complete cds. gi | 33318194 IAF508682 | Influenza A virus (A / Pato / Nanjing / 1/97 (H9N2)) polymerase segment PA gene (PA), complete cds. Gil 33318196IAF508683 | Influenza A virus (A / Quail / Shangai / 8/96 (H9N2)) polymerase gene PA segment 3 (PA), partial cds. Gil 31339541 IAF523446I Influenza A virus (A / Pato / Shantou / 1043/00 (H9N2)) polymerase gene (PA), partial cds. gi I 31339543IAF523447 | Influenza A virus (A / Pato / Shantou / 1042/00 (H9N2)) polymerase gene (PA), partial cds. Gil 31339545 IAF523448 | Influenza A virus (A / Pato / Shantou / 2088/01 (H9N2)) polymerase gene (PA), partial cds. gi 131339547 | AF523449 | Influenza A virus (A / Pato / Shantou / 830/00 (H9N2)) polymerase gene (PA), partial cds. Gil 31339549 | AF523450 | Influenza A virus (A / Pato / Shantou / 1796/00 (H9N2)) polymerase gene (PA), partial cds. Gil 31339551 | AF523451 | Influenza A virus (A / Pato / Shantou / 2143/00 (H9N2)) polymerase gene (PA), partial cds. Gil 31339553 | AF523452 | Influenza A virus (A / Pato / Shantou / 2134/00 (H9N2)) polymerase gene (PA), partial cds. Gil 313395551 AF5234531 Influenza A virus (A / Pato / Shantou / 2144/00 (H9N2)) polymerase gene (PA), partial cds gi31339557 IAF523454 | Influenza A virus (A / wild duck / Shantou / 4808/01 (H9N2)) polymerase gene (PA), partial cds. gil 313395591 AF5234551 Influenza A virus (A / Pato / Shantou / 1881/00 (H9N2)) polymerase gene (PA), partial cds. Gil 31339561 | AF523456 | Influenza A virus (A / Pato / Shantou / 2102/00 (H9N2)) polymerase gene (PA), partial cds. Gil 313395631 AF523457 | Influenza A virus (A / Pato / Hong Kong / 289/78 (H9N2)) polymerase gene (PA), partial cds. gi | 31339565 | AF523458 I Influenza A virus (A / Pato / Hong Kong / 610/79 (H9N2)) polymerase gene (PA), partial cds. gi 131339567 | AF523459 | Influenza A virus (A / Pato / Hong Kong / 86/76 (H9N2)) polymerase gene (PA), partial cds. gi | 31339569 | AF523460 | Influenza A virus (A / Pato / Hong Kong / 366/78 (H9N2)) polymerase gene (PA), partial cds. gi 122759040 | AF536669 | Influenza A virus (A / Chicken / Beijing / 1/95 (H9N2)) PA gene, partial cds. gil 22759042 | AF536670 | Influenza A virus (A / Chicken / Beijing / 2/97 (H9N2)) PA gene, partial cds. gi 122759044 IAF536671 | Influenza A virus (A / Chicken / Beijing / 3/99 (H9N2)) PA gene, partial cds. gi | 22759046 | AF536672 | Influenza A virus (A / Chicken / Guangdong / 97 (H9N2)) PA gene, partial cds. gi 122759048 | AF536673 | Influenza A virus (A / Chicken / Hebei / 1/96 (H9N2)) PA gene, partial cds. gi | 22759050 IAF536674 | Influenza A virus (A / Chicken / Hebei / 2/98 (H9N2)) PA gene, partial cds. gi 122759052 | AF536675 | Influenza A virus (A / Chicken / Hebei / 3/98 (H9N2)) PA gene, partial cds. gi 122759054 | AF536676 | Influenza A virus (A / Chicken / Henan / 98 (H9N2)) PA gene, partial cds. gi | 22759056 | AF536677 | Influenza A virus (A / Chicken / Liaoning / 99 (H9N2)) PA gene, partial cds. gi 122759058 IAF536678 | Influenza A virus (A / Chicken / Shandong / 98 (H9N2)) PA gene, partial cds. gi | 12038897 IAJ291397 | Influenza A virus (A / Chicken / Pakistan / 2/99 (H9N2)) PA gene for PA polymerase, genomic RNA. gi I 18496121 IAJ427863 | Influenza A virus (A / quail / Hong Kong / FY298 / 00 (H9N2)) partial PA gene for PA polymerase protein, genomic RNA gi27465911 IAY180650 | Strain of influenza A virus A / Pato / Nanchang / 11-392 / 2000 (H9N2) PA polymerase subunit gene (PA), partial cds. gil 27465913 IAY180651 | Strain of influenza virus A A / Pato / Nanchang / 11-290 / 2000 (H9N2) PA polymerase subunit gene (PA), partial cds. gi 127465915 IAY180652 | Strain of influenza A virus A / Chicken / Nanchang / 1-0016 / 2000 (H9N2) PA polymerase subunit gene (PA), partial cds. gi 127465917 IAY180653 | Strain of influenza A virus A / Pato / Nanchang / 11-197 / 2000 (H9N2) PA polymerase subunit gene (PA), partial cds. gil 27465937 | AY180663 | Strain of influenza A virus A / Pichón / Nanchang / 2-0461 / 2000 (H9N2) PA polymerase subunit gene (PA), partial cds. gi 127465941 IAY180665 | Strain of influenza A virus A / Pollo / Nanchang / 4-301 / 2001 (H9N2) PA polymerase subunit gene (PA), partial cds. gi | 27465943 | AY180666 | Strain of influenza virus A A / Chicken / Nanchang / 4-361 / 2001 (H9N2) polymerase subunit gene PA (PA), partial cds. gi 127465961 IAY180675 | Strain of influenza A / Duck virus Wild / Nanchang / 2-0480 / 2000 (H9N2) PA polymerase subunit gene (PA), partial cds. gi | 27465983 | AY180686 | Strain of influenza A virus A / Pato / Nanchang / 1-0070 / 2000 (H9N2) PA polymerase subunit gene (PA), partial cds. gi | 27465989 | AY180689 | Strain of influenza A virus A / Pato / Nanchang / 10-389 / 2000 (H9N2) PA polymerase subunit gene (PA), partial cds. gi 127465993 IAY180691 | Strain of influenza A virus A / Pichón / Nanchang / 11-145 / 2000 (H9N2) PA polymerase subunit gene (PA), partial cds. gi 127466001 IAY180695I Influenza virus strain A / Quail / Nanchang / 2-0460 / 2000 (H9N2) PA polymerase subunit gene (PA), partial cds. gi | 27466003 | AY180696 | Flu virus strain A / Quail / Nanchang / 4-040 / 2000 (H9N2) PA polymerase subunit gene (PA), partial cds. gi | 27466009 | AY180699 | Strain of influenza A virus A / Chicken / Nanchang / 4-010 / 2000 (H9N2) PA polymerase subunit gene (PA), partial cds. gi 127466015 IAY180702 | Strain of influenza A virus A / Pato / Nanchang / 7-092 / 2000 (H9N2) PA polymerase subunit gene (PA), partial cds. gi | 27466019 | AY180704 | Flu virus strain A / Pichón / Nanchang / 7-058 / 2000 (H9N2) PA polymerase subunit gene (PA), partial cds. gi 130025973 | Y253752 | Influenza A virus (A / Chicken / Shangai / F / 98 (H9N2)) polymerase acid protein (PA) gene, complete cds. gil 49357051 | AY6331691 Influenza A virus (A / wild turkey / Alberta / 17/91 (H9N2)) polymerase protein A (PA) gene, partial cds. gil 493570791 AY633281 | Influenza A virus (A / wild turkey / Alberta / 321/88 (H9N2)) polymerase protein A (PA) gene, partial cds. gi I 49357083 IAY633297 | Influenza A virus (A / wild turkey / Alberta / 11/91 (H9N2)) polymerase protein A (PA) gene, partial cds. gi I 54301528 IAY664755I Influenza A virus (A / chicken / Hong Kong / CSW153 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. gi I 54301530 | AY664756 | Influenza A virus (A / chicken / Hong Kong / AP45 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. gi | 54301532 IAY664757 | Influenza A virus (A / chicken / Hong Kong / BD90 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. gi | 54301534 IAY664758 | Influenza A virus (A / chicken / Hong Kong / CSW291 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. gi | 54301536 | AY664759 | Influenza A virus (A / chicken / Hong Kong / CSW304 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. gi I 54301538 IAY664760 | Influenza A virus (A / chicken / Hong Kong / PY23 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. Gil 543015401 AY664761 | Influenza A virus. { A / guinea fowl / Hong Kong / NT101 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. Gil 54301542 | AY664762 | Influenza A virus (A / chicken / Hong Kong / NT142 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. Gil 54301544 | AY664763 | Influenza A virus (A / chicken / Hong Kong / SFl / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. Gil 54301546IAY664764 | Influenza A virus (A / chicken / Hong Kong / SSP101 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. gi | 54301548 IAY664765 | Influenza A virus (A / chicken / Hong Kong / TP38 / 03 (H9N2)) similar gene of polymerase acid (PA) protein, complete sequence. gi | 54301549 | AY664766 | Influenza A virus (A / chicken / Hong Kong / WF126 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. gi | 54301551 | AY664767 | Influenza A virus (A / chick / Hong Kong / WF53 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. gi | 54301553 IAY664768 | Influenza A virus (A / pheasant / Hong Kong / WF54 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. gil 543015551 AY6647691 Influenza A virus (A / guinea fowl / Hong Kong / NT184 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. Gil 54301557 | AY664770 | Influenza A virus (A / chicken / Hong Kong / WF120 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. gi | 54301559 | AY664771 | Influenza A virus (A / chicken / Hong Kong / NT366 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. gi | 54301561 | AY664772 | Influenza A virus (A / chicken / Hong Kong / SSP418 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. gi | 54301563 | AY664773 I Influenza A virus (A / chicken / Hong Kong / YU427 / 03 (H9N2)) polymerase acid protein (PA) gene, partial cds. gi | 55793682 IAY800238 | Influenza A virus A / chicken / Korea / Sl / 2003 (H9N2)) polymerase acid (PA) protein gene, complete cds. gi 158429718 | AY862678 | Influenza A virus (A / silky chicken / Korea / S3 / 03 (H9N2)) PA gene (PA), partial cds. Gil 58429720 | AY8626791 Influenza A virus (A / chicken / Korea / S4 / 03 (H9N2)) PA gene (PA), partial cds. gi | 58429722 IAY862680 | Influenza A virus (A / chicken / Korea / S5 / 03 (H9N2)) PA gene (PA), complete cds. gi I 58429724 IAY862681 | Influenza A virus (A / chicken / Korea / S12 / 03 (H9N2)) PA gene (PA), partial cds. gil 58429726IAY862682 | Influenza A virus (A / duck / Korea / S13 / 03 (H9N2)) PA gene (PA), partial cds. Gil 58429728 | AY862683 | Influenza A virus (A / pigeon / Korea / S14 / 03 (H9N2)) PA gene (PA), partial cds. gi | 58429730 IAY86268 | Influenza A virus (A / chicken / Korea / S15 / 03 (H9N2)) PA gene (PA), partial cds. gi | 58429732 | AY862685 | Influenza A virus (A / chicken / Korea / S16 / 03 (H9N2)) PA gene (PA), partial cds. gi 158429734 | AY862686 I Influenza A virus (A / chicken / Korea / S18 / 03 (H9N2)) PA gene (PA), partial cds. gil 5732356IAF156444 | Influenza A virus (A / Chicken / Hong Kong / G9 / 97 (H9N2)) polymerase gene segment 3 (PA), partial cds. gil 5732358 IAF156445 | Influenza A virus (A / Chicken / Hong Kong / G23 / 97 (H9N2)) polymerase gene segment 3 (PA), complete cds. gi | 5732360 IAF156446I Influenza A virus (A / Pigeon / Hong Ksng / Y233 / 97 (H9N2)) polymerase gene segment 3 (PA), partial cds. gi I 5732362 IAF156447 | Influenza A virus (A / Pato / Hong Kong / Y280 / 97 (H9N2)) polymerase gene segment 3 (PA), partial cds. gi 1573236 | AF156448 | Influenza A virus (A / Pato / Hong Kong / Y439 / 97 (H9N2)) polymerase gene segment 3 (PA), partial cds. gil 5732366 | AF156449 | Influenza A virus (A / Quail / Hong Kong / Gl / 97 (H9N2)) polymerase gene segment 3 (PA), partial cds. gi | 5732368 IAF156450 | Influenza A virus (A / Chicken / Hong Kong / 739/94 (H9N2)) polymerase gene of segment 3 (PA), partial cds. gi | 5732370 IAF156451 | Influenza A virus (A / Quail / Hong Kong / AF157 / 92 (H9N2)) polymerase gene of segment 3 (PA), partial cds. gi 15732372 | AF156452 | Influenza A virus (A / Chicken / Beij ing / 1/94 (H9N2)) polymerase gene of segment 3 (PA), partial cds. gi | 5732374 IAF156453 | Influenza A virus (A / Chicken / Korea / 38349-p96323 / 96 (H9N2)) polymerase gene segment 3 (PA), partial cds. gil 5732376IAF15645 | Influenza A virus (A / Chicken / Korea / 25232-96006 / 96 (H9N2)) polymerase gene segment 3 (PA), partial cds. gi I 5732378 IAF1564551 Influenza A virus (A / Beach bird / Delaware / 9/96 (H9N2)) polymerase gene segment 3 (PA), partial cds. gi | 5732380 | AF156456 | Influenza A virus (A / Quail / Arkansas / 29209-1 / 93 (H9N2)) polymerase gene segment 3 (PA), partial cds. gi | 5732382 | AF156457 | Influenza A virus (A / Pavo / California / 189/66 (H9N2)) polymerase gene segment 3 (PA), partial cds. gi I 12060671 IAF222642 | Influenza A virus (A / Quail / Hong Kong / A17 / 99 (H9N2)) PA gene from segment 3 (PA), partial cds. gi | 12060673 | AF222643 | Influenza A virus (A / Pigeon / Hong Kong / FY6 / 99 (H9N2)) PA gene from segment 3 (PA), partial cds. gi I 12060675 IAF222644 | Influenza A virus (A / Chicken / Hong Kong / NT16 / 99 (H9N2)) PA gene of segment 3 (PA), partial cds. gi I 12060677 | AF222645 | Influenza A virus (A / Quail / Hong Kong / SSP10 / 99 (H9N2)) PA gene from segment 3 (PA), partial cds. Gil 12060679 | AF222646 | Influenza A virus (A / Pheasant / Hong Kong / SSPll / 99 (H9N2)) PA gene from segment 3 (PA), partial cds. gi | 12060681 IAF222647 | Influenza A virus (A / Chicken / Hong Kong / FY20 / 99 (H9N2)) PA gene from segment 3 (PA), partial cds. gil 120606831 AF222648 | Influenza A virus (A / Chicken / Hong Kong / KC12 / 99 (H9N2)) PA gene of segment 3 (PA), partial cds. gil 120606851 AF2226491 Influenza A virus (A / Quail / Hong Kong / NT28 / 99 (H9N2)) PA gene from segment 3 (PA), partial cds. gi I 12060687 IAF222650 | Influenza A virus (A / Chicken / Hong Kong / SF2 / 99 (H9N2)) PA gene of segment 3 (PA), partial cds, gi | 12060689 | AF222651 | Influenza A virus (A / Chicken silky / Hong Kong / SF44 / 99 (H9N2)) PA gene from segment 3 (PA), partial cds. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (23)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. An RNAi agent, characterized in that it comprises a sense strand, wherein the sense strand comprises at least 15 continuous nucleotides that are different by no more than 1, 2, or 3 nucleotides of the sense strand sequence of any of the agents provided in Tables 1A-1H, agents numbered AL-DP-2241-AL-DP-8631, and an antisense strand, wherein the The antisense strand comprises at least 15 continuous nucleotides that are different by no more than 1, 2, or 3 nucleotides from the antisense sequences of any of the agents provided in Tables 1 A-IH, agents numbered AL-DP-2241- AL-DP-8631.
2. 2. An RNAi agent including a sense strand, characterized in that the sense strand comprises at least 15 continuous nucleotides that are different by no more than 1, 2, or 3 nucleotides from the sense strand sequences of any of the provided agents in Tables 1A-1H, agents numbered AL-DP-2241-AL-DP-8631, and an antisense strand wherein the antisense strand comprises at least 15 continuous nucleotides of the antisense sequences of any of the agents provided in the Tables 1A-1H, agents numbered AL-DP-2241-AL-DP-8631, and wherein the RNAi agent reduces the expression of its respective target gene in Cos-7 cells engineered to express the respective target gene by more than 20%, 30%, 40%, 50%, 60%, 70%, or 80% compared to cells that have not been incubated with the RNAi agent.
3. 3. An RNAi agent, characterized in that it comprises a sense strand and an antisense strand each comprising a sequence of at least 16, 17 or 18 nucleotides that are essentially identical to one of the sequences of any of the agents provided in the Tables 1A-1H, agents numbered AL-DP-2241-AL-DP-8631, except that no more than 1, 2 or 3 nucleotides per strand, respectively, have been replaced by other nucleotides (for example adenosine replaced by uracil), while essentially maintain the ability to reduce the amount of influenza A plaques formed in cells in a plaque forming assay.
4. 4. The RNAi agent according to any of claims 1 to 3, characterized in that the strand of antisense RNA is 30 or less nucleotides in length, and the double region of the RNAi agent is 15-30 nucleotide pairs in length.
5. 5. The RNAi agent of any of claims 1 to 3, characterized in that it comprises a modification that causes the RNAi agent to have increased stability in a biological sample.
6. 6. The RNAi agent according to any of claims 1 to 3, characterized in that it comprises a phosphorothioate or a 2'-modified nucleotide.
7. 7. The RNAi agent according to any of claims 1 to 3, characterized in that it comprises at least one 5'-uridine-adenine-3 '(5' -ua-3 ') dinucleotide wherein the uridine is a modified nucleotide. '; or at least one 5'-uridine-guanine-3 '(5'-ug-3') dinucleotide, wherein 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; or at least one 5'-uridine-uridine-3 '(5'-uu-3') dinucleotide, wherein the 5'-uridine is a 2 'modified nucleotide.
8. 8. The RNAi agent according to claim 6 or 7, characterized in that the 2 'modification is selected from the group consisting of: 2'-deoxy, 2'-deoxy-2'-fluoro, 2'-0-methyl, 2'-O-methoxyethyl (2'-0) -MOE), 2'-O-aminopropyl (2'-0-AP), 2'-0-dimethylaminoethyl (2'-0-DMAOE), 2'-0 dimethylaminopropyl (2'-0-DMAP), 2'-O-dimethylaminoethyloxyethyl (2'-0-DMAEOE), and 2 '-ON-methylacetamido (2'-0-NMA).
9. 9. The RNAi agent according to any of claims 1 to 3, characterized in that it comprises a hanging nucleotide having 1 to 4 disparate nucleotides.
10. 10. The RNAi agent according to claim 9, characterized in that the hanging nucleotide has 2 or 3 disparate nucleotides.
11. 11. The RNAi agent according to claim 9, characterized in that the hanging nucleotide is at the 3 'end of the antisense strand of the RNAi agent.
12. 12. The RNAi agent according to any of claims 1 to 3, characterized in that it comprises a portion of cholesterol.
13. The RNAi agent according to claim 12, characterized in that the cholesterol portion is conjugated to the 3 'end of the sense strand of the RNAi agent.
14. 14. The RNAi agent according to any of claims 1 to 3, characterized in that the RNAi agent is directed for uptake by lung cells.
15. 15. The RNAi agent according to any of claims 1 to 3, characterized in that the RNAi agent comprises at least one non-natural nucleobase.
16. 16. The RNAi agent according to claim 15, characterized in that the non-natural nucleobase is difluorotolyl, nitroindolyl, nitropyrrolyl, or nitroimidazolyl.
17. 17. The RNAi agent according to claim 15, characterized in that the non-natural nucleobase is difluorotolil.
18. 18. The RNAi agent according to claim 15, characterized in that only one of the two oligonucleotide strands comprising the double oligonucleotide strand contains an unnatural nucleus.
19. 19. The RNAi agent according to claim 15, characterized in that both of the oligonucleotide strands comprising the oligonucleotide double strand independently contain an unnatural nucleus base.
20. 20. A method for treating a human subject having a pathological process mediated in part by the replication of influenza A virus, characterized in that the RNAi agent comprises a sense strand wherein the sense strand comprises at least 15 continuous nucleotides that are different by no more than 1, 2, or 3 nucleotides of the sense strand sequences of any of the agents provided in Tables 1A-1H, agents numbered AL-DP-2241-AL-DP-8631, and an antisense strand, wherein the antisense strand comprises at least 15 continuous nucleotides that are different by no more than 1, 2, or 3 nucleotides from the antisense strand sequences of any of the agents provided in Tables 1A-1H, agents numbered AL-DP- 2241-AL-DP-8631.
21. 21. The method according to claim 20, characterized in that the RNAi agent is administered in an amount sufficient to reduce the replication of influenza virus in a cell or tissue of the subject.
22. 22. The method according to claim 20, characterized in that the subject is a human.
23. 23. A pharmaceutical composition, characterized in that it comprises: a.) An RNAi agent of any of claims 1 to 3; and b.) a pharmaceutically acceptable carrier.