Patent Publication Number: US-2020291405-A1

Title: HEPATITIS D VIRUS (HDV) iRNA COMPOSITIONS AND METHODS OF USE THEREOF

Description:
RELATED APPLICATIONS 
     This application is a continuation of U.S. patent application Ser. No. 15/591,558, filed on May 10, 2017, which is a 35 § U.S.C. 111(a) continuation application which claims the benefit of priority to PCT/US2015/059958, filed on Nov. 10, 2015, which claims priority to U.S. Provisional Application, 62/077,672, filed on Nov. 10, 2014. The entire contents of each of the foregoing patent applications are incorporated herein by reference. 
     This application also claims priority to U.S. Provisional Application, 62/077,799, filed on Nov. 10, 2014 and U.S. Provisional Application, 62/137,464, filed on Mar. 24, 2015. The entire contents of each of the foregoing patent applications are incorporated herein by reference. 
     This application is related to International Patent Application, PCT/US2015/059916, filed on Nov. 10, 2015 and U.S. patent application Ser. No. 15/591,532, filed on May 10, 2017. The entire contents of each of the foregoing patent applications are incorporated herein by reference. 
    
    
     SEQUENCE LISTING 
     The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Feb. 25, 2020, is named 121301_02803_SL.txt and is 774,863 bytes in size. 
     BACKGROUND OF THE INVENTION 
     Hepatitis D virus or hepatitis delta virus (HDV) is a human pathogen. Indeed HDV infection is highly endemic to several African countries, the Amazonian region, and the Middle East, while its prevalence is low in industrialized countries, except in the Mediterranean. However, the virus is defective and depends on obligatory helper functions provided by the hepatitis B virus (HBV) for transmission; indeed, HDV requires a simultaneous infection with HBV (co-infection) or superimposition on a pre-existing HBV infection (superinfection) to become infectious and thrive. In particular, HDV requires the HBV viral envelope containing the surface antigen of hepatitis B. 
     HDV is unique in human virology; it has a circular RNA genome of about 1,700 bases (see, e.g., Genbank Accession No. M21012.1 (GI:329989)) and is therefore the smallest infectious agent in man, and is similar to viroids and satellite RNAs of plants. HDV replicates by a rolling circle mechanism unknown to animal cells, possesses a self-cleaving ribozyme and is transcribed by host RNA polymerases that normally accept only DNA templates (Ciancio and Rizzetto,  Nat. Rev.  11:68-71, 2014). 
     HDV is a circular, single stranded RNA virus that ranges from 1,672 (strain dFr45, Genbank accession number AX741144) to 1,697 nucleotides (dFr47, GenBank accession number AX741149). A unique open reading frame encodes the small and large hepatitis delta (sHD and 1HD, respectively) antigens by way of an editing step in the hepatocyte nucleus. 
     The genetic diversity of HDV is related to the geographic origin of the isolates and there are at least eight genotypes that are referred to as HDV-1 through HDV-8. Apart from HDV-1, which is ubiquitous, HDV-2 (previously labeled HDV-IIa) is found in Japan, Taiwan, and Yakoutia, Russia; HDV-4 (previously labeled HDV-IIb) in Taiwan and Japan; HDV-3 which causes epidemics of severe and fulminant hepatitis in the Amazonian region (9); and HDV-5, HDV-6, HDV-7, and HDV-8 in Africa (LeGal et al.,  Emerg. Infect. Dis.  12:1447-1450, 2006). 
     Worldwide more than 400 million people are chronically infected with HBV. Furthermore, at the end of the 1980s, at least 5% of hepatitis B surface antigen (HBsAg) carriers throughout the globe (˜15 million individuals) were estimated to also be infected with HDV. Subjects infected with HBV are at increased risk of developing serious liver disease, such as chronic hepatitis, cirrhosis, liver failure and hepatocellular carcinoma (HCC) resulting in an estimated 600,000 deaths each year, HDV infection in such subjects (either co-infection or superinfection) can lead to severe acute and chronic forms of liver disease in association with HBV. In fact, both superinfection and coinfection with HDV results in more severe complications compared to infection with HBV alone. These complications include resistance to treatment with standard therapies and a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis, with an increased chance of developing liver cancer in chronic infections. In combination with hepatitis B virus, hepatitis D has the highest fatality rate of all the hepatitis infections, at 20%. 
     Accordingly, there is a need in the art for alternative therapies and combination therapies for subjects infected with HDV and/or having an HDV-associated disease. 
     SUMMARY OF THE INVENTION 
     The present invention provides iRNA compositions which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a Hepatitis D virus (HDV) gene. The HDV gene may be within a cell, e.g., a cell within a subject, such as a human. 
     The present invention also provides methods and therapies for treating a subject having a disorder that would benefit from inhibiting or reducing the expression of an HDV gene, e.g., an HDV infection and/or an HDV-associated disease, such as hepatitis B virus infection, chronic hepatitis B infection (CHB), chronic Hepatitis D infection (CHD), cirrhosis, liver failure, and hepatocellular carcinoma (HCC), using iRNA compositions which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of an HDV gene for inhibiting the expression of an HDV gene. As HDV depends on obligatory helper functions provided by HBV for transmission, the methods for treatment of HDV can comprise agents and therapies useful for treating an HBV infection and/or an HBV-associated disorder, such as hepatitis D virus infection, chronic hepatitis D infection (CHD), chronic Hepatitis B infection (CHB), cirrhosis, liver failure, and hepatocellular carcinoma (HCC). 
     In certain embodiments, the RNAi agents of the invention have been designed to target regions in the HDV genomes that are conserved across at least two, preferably 3, or more of the 8 serotypes of HDV (HDV-1, HDV-2, HDV-3, HDV-4, HDV-5, HDV-6, HDV-7, and HDV-8). 
     Accordingly, in one aspect, the present invention provides double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell. The double stranded RNAi agents include a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:29, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:30, wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In another aspect, the present invention provides double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell. The double stranded RNAi agents include a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:31, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:32, wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In one aspect, the present invention provides double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell. The double stranded RNAi agents include a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:33, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:34, wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In one aspect, the present invention provides double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell. The double stranded RNAi agents include a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:35, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:36, wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In another aspect, the present invention provides double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell. The double stranded RNAi agents include a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:37, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:38, wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In yet another aspect, the present invention provides double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell. The double stranded RNAi agents include a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:39, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:40, wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In one aspect, the present invention provides double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell. The double stranded RNAi agents include a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:41, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:42, wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In another aspect, the present invention provides double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell. The double stranded RNAi agents include a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:43, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:44, wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In one aspect, the present invention provides double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell. The double stranded RNAi agents include a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:2551, and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: 2552, wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. In certain embodiments, the sense strand of the double stranded RNAi agents comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from nucleotides 1451-1484, nucleotides 1455-1480, nucleotides 1455-1474, or nucleotides 1417-1443 of the nucleotide sequence of SEQ ID NO:2551. 
     In one embodiment, the one or more of the 3 nucleotide differences in the nucleotide sequence of the antisense strand is a nucleotide mismatch in the antisense strand. 
     In another embodiment, the one or more of the 3 nucleotide differences in the nucleotide sequence of the antisense strand is a nucleotide mismatch in the sense strand. 
     In one embodiment, all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides. 
     In one embodiment, the sense strand and the antisense strand comprise a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the sequences listed in any one of Tables 11, 12, 31, and 32. 
     In some embodiments, the sense strand and the antisense strand comprise a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequences of the sense strand and the antisense strand sequences of any one of duplexes AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, and AD-70275.1. In other embodiments, the sense strand and the antisense strand comprise a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequences of the sense strand and the antisense strand sequences of any one of duplexes AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, and AD-70295.1. 
     In one embodiment, the at least one of the modified nucleotides is selected from the group consisting of a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, 2′-hydroxyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, and a nucleotide comprising a 5′-phosphate mimic. 
     In one embodiment, the at least one strand comprises a 3′ overhang of at least 1 nucleotide. In another embodiment, the at least one strand comprises a 3′ overhang of at least 2 nucleotides. 
     In one embodiment, the double-stranded region is 15-30 nucleotide pairs in length. In another embodiment, the double-stranded region is 17-23 nucleotide pairs in length. In yet another embodiment, the double-stranded region is 17-25 nucleotide pairs in length. In one embodiment, the e double-stranded region is 23-27 nucleotide pairs in length. In another embodiment, the double-stranded region is 19-21 nucleotide pairs in length. In yet another embodiment, the double-stranded region is 21-23 nucleotide pairs in length. 
     In one embodiment, each strand has 15-30 nucleotides. In another embodiment, each strand has 19-30 nucleotides. 
     In one embodiment, the ligand is 
     
       
         
         
             
             
         
       
     
     In one embodiment, the RNAi agent is conjugated to the ligand as shown in the following schematic 
     
       
         
         
             
             
         
       
     
     wherein X is O or S. 
     In one embodiment, the RNAi agent is selected from the group of RNAi agents listed in any one of Tables 11, 12, 31, and 32. 
     In one embodiment the agent is selected from the group consisting of AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, and AD-70275.1. 
     In one aspect, the present invention provides double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell. The double stranded RNAi agents include a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises any one of the sense sequences from Tables 11, 12, 31, and 32, and the antisense strand comprises any one of the antisense sequences from Tables 11, 12, 31, and 32, wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In one embodiment, the sense strand is selected from the group consisting of the sense strand sequences of AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1. 
     In another embodiment, the antisense strand is selected from the group consisting of the antisense strand sequences of AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1. 
     The present invention also provides RNAi agents comprising sense and antisense nucleotide sequences which are at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over their entire length to the foregoing sense and antisense nucleotide sequences 
     In one embodiment, all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a modification. 
     In one embodiment, at least one of the modified nucleotides is selected from the group consisting of a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, 2′-hydroxyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, and a nucleotide comprising a 5′-phosphate mimic. 
     In one embodiment, the 5′-phosphate mimic is a 5′-vinyl phosphate (5′-VP). 
     In one embodiment, the ligand is 
     
       
         
         
             
             
         
       
     
     In one embodiment, the RNAi agent is conjugated to the ligand as shown in the following schematic 
     
       
         
         
             
             
         
       
     
     wherein X is O or S. 
     In one aspect, the present invention provides compositions comprising two or more double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell, wherein each double stranded RNAi agent independently comprises a sense strand and an antisense strand forming a double-stranded region, wherein each of the sense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:29, and each of the antisense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:30, wherein substantially all of the nucleotides of each of the sense strands and substantially all of the nucleotides of each of the antisense strands are independently modified nucleotides, wherein each of the sense strands are independently conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In another aspect, the present invention provides compositions comprising two or more double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell, wherein each double stranded RNAi agent independently comprises a sense strand and an antisense strand forming a double-stranded region, wherein each of the sense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:31, and each of the antisense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:32, wherein substantially all of the nucleotides of each of the sense strands and substantially all of the nucleotides of each of the antisense strands are independently modified nucleotides, wherein each of the sense strands are independently conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In another aspect, the present invention provides compositions comprising two or more double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell, wherein each double stranded RNAi agent independently comprises a sense strand and an antisense strand forming a double-stranded region, wherein each of the sense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:33, and each of the antisense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:34, wherein substantially all of the nucleotides of each of the sense strands and substantially all of the nucleotides of each of the antisense strands are independently modified nucleotides, wherein each of the sense strands are independently conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In yet another aspect, the present invention provides compositions comprising two or more double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell, wherein each double stranded RNAi agent independently comprises a sense strand and an antisense strand forming a double-stranded region, wherein each of the sense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:35, and each of the antisense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:36, wherein substantially all of the nucleotides of each of the sense strands and substantially all of the nucleotides of each of the antisense strands are independently modified nucleotides, wherein each of the sense strands are independently conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In one aspect, the present invention provides compositions comprising two or more double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell, wherein each double stranded RNAi agent independently comprises a sense strand and an antisense strand forming a double-stranded region, wherein each of the sense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:37, and each of the antisense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:38, wherein substantially all of the nucleotides of each of the sense strands and substantially all of the nucleotides of each of the antisense strands are independently modified nucleotides, wherein each of the sense strands are independently conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In another aspect, the present invention provides compositions comprising two or more double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell, wherein each double stranded RNAi agent independently comprises a sense strand and an antisense strand forming a double-stranded region, wherein each of the sense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:39, and each of the antisense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:40, wherein substantially all of the nucleotides of each of the sense strands and substantially all of the nucleotides of each of the antisense strands are independently modified nucleotides, wherein each of the sense strands are independently conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In another aspect, the present invention provides compositions comprising two or more double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell, wherein each double stranded RNAi agent independently comprises a sense strand and an antisense strand forming a double-stranded region, wherein each of the sense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:41, and each of the antisense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:42, wherein substantially all of the nucleotides of each of the sense strands and substantially all of the nucleotides of each of the antisense strands are independently modified nucleotides, wherein each of the sense strands are independently conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In one aspect, the present invention provides compositions comprising two or more double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell, wherein each double stranded RNAi agent independently comprises a sense strand and an antisense strand forming a double-stranded region, wherein each of the sense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:43, and each of the antisense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:44, wherein substantially all of the nucleotides of each of the sense strands and substantially all of the nucleotides of each of the antisense strands are independently modified nucleotides, wherein each of the sense strands are independently conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In another aspect, the present invention provides compositions comprising two or more double stranded RNAi agents for inhibiting expression of hepatitis D virus (HDV) in a cell, wherein each double stranded RNAi agent independently comprises a sense strand and an antisense strand forming a double-stranded region, wherein each of the sense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:2551, and each of the antisense strands independently comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:2552, wherein substantially all of the nucleotides of each of the sense strands and substantially all of the nucleotides of each of the antisense strands are independently modified nucleotides, wherein each of the sense strands are independently conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In certain embodiments, the sense strand of one or both of the first and second double stranded RNAi agents comprises at least 15 contiguous nucleotides from nucleotides 1451-1484, nucleotides 1455-1480, nucleotides 1455-1474, or nucleotides 1417-1443 of the nucleotide sequence of SEQ ID NO:2551. 
     In one embodiment, the one or more of the 3 nucleotide differences in the nucleotide sequence of the antisense strand is a nucleotide mismatch in the antisense strand. In another embodiment, the one or more of the 3 nucleotide differences in the nucleotide sequence of the antisense strand is a nucleotide mismatch in the sense strand. 
     In one embodiment, all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides. 
     In one embodiment, the sense strand and the antisense strand comprise a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the sequences listed in any one of Tables 11, 12, 31, and 32. 
     In some embodiments, the sense strand and the antisense strand comprise a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequences of the sense strand and the antisense strand sequences of any one of duplexes AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1. 
     In other embodiments, the sense strand and the antisense strand comprise a region of complementarity which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequences of the sense strand and antisense strand sequences of any one of duplexes AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, or AD-70295.1. 
     In one embodiment, the at least one of the modified nucleotides is selected from the group consisting of a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, 2′-hydroxyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, and a nucleotide comprising a 5′-phosphate mimic. 
     In another aspect, the present invention provides compositions for inhibiting expression of hepatitis D virus (HDV) in a cell, the composition comprising (a) a first double-stranded RNAi agent comprising a first sense strand and a first antisense strand forming a double-stranded region, wherein substantially all of the nucleotides of the first sense strand and substantially all of the nucleotides of the first antisense strand are modified nucleotides, wherein the first sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker; and (b) a second double-stranded RNAi agent comprising a second sense strand and a second antisense strand forming a double-stranded region, wherein substantially all of the nucleotides of the second sense strand and substantially all of the nucleotides of the second antisense strand are modified nucleotides, wherein the second sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker; wherein the first and second sense strands each independently comprise a sequence selected from the group consisting of any one of the sense sequences from Tables 11, 12, 31, and 32 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequences), and wherein the first and second antisense strands each independently comprise a sequence selected from the group consisting of any one of the antisense sequences from Tables 11, 12, 31, and 32 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequences). 
     In one embodiment, the first and second sense strands each independently comprise a sequence selected from the group consisting of any one of the sense sequences from AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequences). 
     In another embodiment, the first and second antisense strands each independently comprise a sequence selected from the group consisting of any one of the antisense sequences from AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequences). 
     In one embodiment, the first and second sense strand and/or all of the nucleotides of the first and second antisense strand comprise a modification. 
     In one embodiment, the at least one of the modified nucleotides is selected from the group consisting of a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, 2′-hydroxyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, and a nucleotide comprising a 5′-phosphate mimic. 
     In one embodiment, the first and second RNAi agent are selected from the group consisting of any one of the the sequences provided in Tables 11, 12, 31, and 32. 
     In one embodiment, the first and second RNAi agent are selected from the group consisting of any one of AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1. 
     In one embodiment, the first and second RNAi agent are selected from the group consisting of any one of AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, or AD-70295.1. 
     In one aspect, the present invention provides a double stranded RNAi agent comprising any one of the RNAi agents listed in any one of Tables 11, 12, 31, 32, 
     In one embodiment the agent is selected from the group consisting of AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1. In another embodiment, the agent is selected from the group consisting of AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, or AD-70295.1. 
     The present invention also provides vectors and cells comprising the double stranded RNAi agent of the invention. 
     In another aspect, the present invention provides pharmaceutical compositions comprising the double stranded RNAi agents of the invention, or the compositions of the invention, or the vectors of the invention. 
     In one embodiment, the double stranded RNAi agent is administered in an unbuffered solution. In one embodiment, the unbuffered solution is saline or water. 
     In another embodiment, the double stranded RNAi agent is administered with a buffer solution. In one embodiment, the buffer solution comprises acetate, citrate, prolamine, carbonate, or phosphate or any combination thereof. In another embodiment, the buffer solution is phosphate buffered saline (PBS). 
     In one aspect, the present invention provides methods of inhibiting Hepatitis D virus (HDV) gene expression in a cell. The methods include contacting the cell with the double stranded RNAi agent of the invention, or the composition of the invention, or the vector of the invention, or the pharmaceutical composition of the invention; and maintaining the cell produced for a time sufficient to obtain degradation of the mRNA transcript of an HDV gene, thereby inhibiting expression of the HDV gene in the cell. 
     In one aspect, the present invention provides methods of inhibiting replication of a Hepatitis D virus (HDV) in a cell. The methods include contacting the cell with the double stranded RNAi agent of the invention, or the composition of the invention, or the vector of the invention, or the pharmaceutical composition of the invention; and maintaining the cell produced for a time sufficient to obtain degradation of the mRNA transcript of an HDV gene, thereby inhibiting replication of the HDV in the cell. 
     In one embodiment, the cell is within a subject. In one embodiment, the subject is a human. 
     In one embodiment, the subject suffers from an HDV-associated disease. 
     In one embodiment, HDV gene expression is inhibited by at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98% or about 100%. 
     In one embodiment, replication of HDV in the cell is inhibited by at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98% or about 100%. 
     In one aspect, the present invention provides methods of reducing the level of Hepatitis D virus (HDV) DNA in a subject infected with HDV. The methods include administering to the subject a therapeutically effective amount of the double stranded RNAi agent of the invention, or the composition of the invention, or the vector of the invention, or the pharmaceutical composition of the invention, thereby reducing the level of HDV DNA in the subject. 
     In another aspect, the present invention provides methods of reducing the level of a Hepatitis D virus (HDV) antigen in a subject infected with HDV. The methods include administering to the subject a therapeutically effective amount of the double stranded RNAi agent of the invention, or the composition of the invention, or the vector of the invention, or the pharmaceutical composition of the invention, thereby reducing the level of the HDV antigen in the subject. The level of the large HDV antigen may be reduced, the level of the small HDV antigen may be reduced, or the level of both the large and the small HDV antigens may be reduced. 
     In another aspect, the present invention provides methods of reducing the viral load of Hepatitis D virus (HDV) in a subject infected with HDV. The methods include administering to the subject a therapeutically effective amount of the double stranded RNAi agent of the invention, or the composition of the invention, or the vector of the invention, or the pharmaceutical composition of the invention, thereby reducing the viral load of HDV in the subject. 
     In one aspect, the present invention provides methods of treating a subject having a Hepatitis D virus (HDV) infection. The methods include administering to the subject a therapeutically effective amount of the double stranded RNAi agent of the invention, or the composition of the invention, or the vector of the invention, or the pharmaceutical composition of the invention, thereby treating the subject. 
     In another aspect, the present invention provides methods of treating a subject having a Hepatitis D virus (HDV)-associated disorder. The methods include administering to the subject a therapeutically effective amount of the double stranded RNAi agent of the invention, or the composition of the invention, or the vector of the invention, or the pharmaceutical composition of the invention, thereby treating the subject. 
     In one embodiment, the HDV-associated disorder is selected from the group consisting of hepatitis B virus infection, acute hepatitis B, acute hepatitis D; acute fulminant hepatitis D; chronic hepatitis D; liver fibrosis; end-stage liver disease; hepatocellular carcinoma. 
     In one aspect, the present invention provides methods of treating a subject having a Hepatitis D virus (HDV) infection. The methods include administering to the subject a therapeutically effective amount of a double stranded RNAi agent, wherein the double stranded RNAi agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises any one sense sequences from any one of Tables 11, 12, 31, and 32 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequence), and the antisense strand comprises any one of the antisense sequences from any one of Tables 11, 12, 31, and 32 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequence), wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker, thereby treating the subject. 
     In one embodiment, the sense strand comprises a sequence selected from the group consisting of any one of the sense sequences from AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequences). 
     In another embodiment, the antisense strand comprises a sequence selected from the group consisting of any one of the antisense sequences from AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequences). 
     In one embodiment, all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a modification. 
     In one embodiment, the at least one of the modified nucleotides is selected from the group consisting of a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, 2′-hydroxyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, and a nucleotide comprising a 5′-phosphate mimic. 
     In one embodiment, the 5′-phosphate mimic is a 5′-vinyl phosphate (5′-VP). 
     In one embodiment, the ligand is 
     
       
         
         
             
             
         
       
     
     In one embodiment, the RNAi agent is conjugated to the ligand as shown in the following schematic 
     
       
         
         
             
             
         
       
     
     wherein X is O or S. 
     In one embodiment, the HDV-associated disorder is selected from the group consisting of hepatitis B virus infection, acute hepatitis B, acute hepatitis D; acute fulminant hepatitis D; chronic hepatitis D; liver fibrosis; end-stage liver disease; hepatocellular carcinoma. 
     In one aspect, the present invention provides methods of treating a subject having a Hepatitis D virus (HDV) infection. The methods include administering to the subject a therapeutically effective amount of a composition for inhibiting expression of hepatitis D virus (HDV) in a cell. The composition includes: (a) a first double-stranded RNAi agent comprising a first sense strand and a first antisense strand forming a double-stranded region, wherein substantially all of the nucleotides of the first sense strand and substantially all of the nucleotides of the first antisense strand are modified nucleotides, wherein the first sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker; and (b) a second double-stranded RNAi agent comprising a second sense strand and a second antisense strand forming a double-stranded region, wherein substantially all of the nucleotides of the second sense strand and substantially all of the nucleotides of the second antisense strand are modified nucleotides, wherein the second sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker; wherein the first and second sense strands each independently comprise a sequence selected from the group consisting of any one of the sense sequences in any one of Tables 11, 12, 31, and 32 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to any of the foregoing nucleotide sequences), and wherein the first and second antisense strands each independently comprise a sequence selected from the group consisting of any one of the antisense sequences from any one of Tables 11, 12, 31, and 32 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to any of the foregoing nucleotide sequences), thereby treating the subject. 
     In one embodiment, the first and second sense strands each independently comprise a sequence selected from the group consisting of any one of the sense sequences from AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequences). 
     In another embodiment, the first and second antisense strands each independently comprise a sequence selected from the group consisting of any one of the antisense sequences from AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequences). 
     In another aspect, the present invention provides methods of treating a subject having a Hepatitis D virus (HDV)-associated disorder. The methods include administering to the subject a therapeutically effective amount of a composition for inhibiting expression of hepatitis D virus (HDV) in a cell. The composition includes: (a) a first double-stranded RNAi agent comprising a first sense strand and a first antisense strand forming a double-stranded region, wherein substantially all of the nucleotides of the first sense strand and substantially all of the nucleotides of the first antisense strand are modified nucleotides, wherein the first sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker; and (b) a second double-stranded RNAi agent comprising a second sense strand and a second antisense strand forming a double-stranded region, wherein substantially all of the nucleotides of the second sense strand and substantially all of the nucleotides of the second antisense strand are modified nucleotides, wherein the second sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker; wherein the first and second sense strands each independently comprise a sequence selected from the group consisting of any one of the sense sequences from any one of Tables 11, 12, 31, and 32 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to any of the foregoing nucleotide sequences), and wherein the first and second antisense strands each independently comprise a sequence selected from the group consisting of any one of the antisense sequences from any one of Tables 11, 12, 31, and 32 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to any of the foregoing nucleotide sequences), thereby treating the subject. 
     In one embodiment, the first and second sense strands each independently comprise a sequence selected from the group consisting of any one of the sense sequences from AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequences). 
     In another embodiment, the first and second antisense strands each independently comprise a sequence selected from the group consisting of any one of the antisense sequences from AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequences). 
     In one embodiment, all of the nucleotides of the first and second sense strand and all of the nucleotides of the first and second antisense strand comprise a modification. 
     In one embodiment, the at least one of the modified nucleotides is selected from the group consisting of a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, 2′-hydroxyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, and a nucleotide comprising a 5′-phosphate mimic. 
     In one embodiment, the ligand is 
     
       
         
         
             
             
         
       
     
     In one embodiment, the RNAi agent is conjugated to the ligand as shown in the following schematic 
     
       
         
         
             
             
         
       
     
     wherein X is O or S. 
     In one embodiment, the subject is a human. 
     In one embodiment, the HDV-associated disorder is selected from the group consisting of hepatitis B virus infection, acute hepatitis B, acute hepatitis D; acute fulminant hepatitis D; chronic hepatitis D; liver fibrosis; end-stage liver disease; hepatocellular carcinoma. 
     In some embodiments, the methods of the invention further comprise treatment of hepatitis B virus (HBV) in the subject. Methods of treatment can include any methods of treatment known in the art. In certain embodiments, HBV is treated in the subject using one of more if the iRNA agents provided herein. 
     In some embodiments, the methods of the invention further include methods to modulate, preferably decrease the expression of PD-L1. Compositions and methods to reduce the expression of PD-L1 are provided, for example, in PCT publication no. WO2011/127180, which is hereby incorporated by reference. 
     In one embodiment, the double stranded RNAi agent is administered at a dose of about 0.01 mg/kg to about 10 mg/kg or about 0.5 mg/kg to about 50 mg/kg. 
     In one embodiment, the double stranded RNAi agent is administered at a dose of about 10 mg/kg to about 30 mg/kg. In another embodiment, the double stranded RNAi agent is administered at a dose of about 3 mg/kg. In one embodiment, the double stranded RNAi agent is administered at a dose of about 10 mg/kg. 
     In one embodiment, the double stranded RNAi agent is administered at a dose of about 0.5 mg/kg twice per week. 
     In one embodiment, the double stranded RNAi agent is administered at a fixed dose of about 50 mg to 200 mg. 
     In one embodiment, the double stranded RNAi agent is administered subcutaneously. In another embodiment, the double stranded RNAi agent is administered intravenously. In another embodiment, the agent is administered intramuscularly. 
     In one embodiment, the RNAi agent is administered in two or more doses. 
     In one embodiment, the RNAi agent is administered at intervals selected from the group consisting of once every about 12 hours, once every about 24 hours, once every about 48 hours, once every about 72 hours, and once every about 96 hours. 
     In one embodiment, the RNAi agent is administered twice per week. In another embodiment, the RNAi agent is administered every other week. 
     In one embodiment, the methods of the invention further include administering to the subject an additional therapeutic agent. 
     In one embodiment, the additional therapeutic agent is selected from the group consisting of an antiviral agent, a reverse transcriptase inhibitor, an immune stimulator, a therapeutic vaccine, a viral entry inhibitor, an oligonucleotide that inhibits the secretion or release of HbsAg, a capsid inhibitor, a cccDNA inhibitor, a double-stranded iRNA agent targeting HBV, and a combination of any of the foregoing. 
     In another embodiment, the methods of the invention further include administering administering to the subject a reverse transcriptase inhibitor. In yet another embodiment, the methods of the invention further include administering to the subject a reverse transcriptase inhibitor and an immune stimulator. 
     In one embodiment, the reverse transcriptase inhibitor is selected from the group consisting of Tenofovir disoproxil fumarate (TDF), Tenofovir alafenamide, Lamivudine, Adefovir dipivoxil, Entecavir (ETV), Telbivudine, and AGX-1009. 
     In one embodiment, the immune stimulator is selected from the group consisting of pegylated interferon alfa 2a (PEG-IFN-α2a), Interferon alfa-2b, a recombinant human interleukin-7, and aToll-like receptor 7 (TLR7) agonist. 
     In one embodiment, the double-stranded iRNA agent targeting HBV is any one of the agents provided in any one of Tables 3, 4, 6, 14, 15, 24, 25, 27, and 28. In another embodiment, the agent is AD-65403, AD-66810, or a combination thereof. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention provides iRNA compositions, which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a Hepatitis D virus (HDV) gene. The gene may be within a cell, e.g., a cell within a subject, such as a human. The use of these iRNAs enables the targeted degradation of mRNAs of the corresponding gene (HDV gene) in mammals. 
     The RNAi agents of the invention have been designed to target regions in the HDV across various clades of HDV. 
     Also provided herein are HBV targeted RNAi agents of that have been designed to inhibit all steps of the HBV life cycle, e.g., replication, assembly, secretion of virus, and secretion of sub-viral antigens, by inhibiting expression of more than one HBV gene. In particular, since transcription of the HBV genome results in polycistronic, overlapping RNAs, an RNAi agent of the invention targeting a single HBV gene results in significant inhibition of expression of most or all HBV transcripts. For example, because the HBV genome is transcribed into a single mRNA, an RNAi agent of the invention targeting the S gene will result in inhibition of not only S gene expression but also the expression of the “downstream” reverse transcriptase gene. Furthermore, the RNAi agents of the invention have been designed to inhibit HBV viral replication by targeting HBV structural genes, and the HBV X gene thereby permitting a subject&#39;s immune system to detect and respond to the presence of HBsAg to produce anti-HBV antibodies to clear an HBV infection. 
     HDV infection requires the presence of an HBV infection. Using in vitro assays, the present inventors have demonstrated that iRNA targeting HDV can potently mediate RNAi, resulting in significant inhibition of expression of the HDV gene. Moreover, using in vitro and in vivo assays, it is demonstrated herein that iRNAs targeting an HBV gene can potently mediate RNAi, resulting in significant inhibition of expression of more than one HBV gene, is effective in treating HDV infection as well. Thus, methods and compositions including these iRNAs are useful for treating a subject having an HDV infection and/or an HDV-associated disease, by administration of a iRNA targeted to one or both of HBV and HDV. Further, the compositions provided herein can be used in a subject with an HBV infection to prevent the development of an HDV infection. 
     Accordingly, the present invention also provides methods for treating a subject having a disorder that would benefit from inhibiting or reducing the expression of an HBV gene, e.g., HDV infection, using iRNA compositions which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of an HBV gene. 
     Very low dosages of the iRNAs of the invention, in particular, can specifically and efficiently mediate RNA interference (RNAi), resulting in significant inhibition of expression of the corresponding gene (HDV gene). 
     The iRNAs of the invention include an RNA strand (the antisense strand) having a region which is about 30 nucleotides or less in length, e.g., 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides in length, which region is substantially complementary to at least part of an mRNA transcript of an HBV gene. 
     The following detailed description discloses how to make and use compositions containing iRNAs to inhibit the expression of an angiotensinogen gene as well as compositions, uses, and methods for treating subjects having diseases and disorders that would benefit from inhibition and/or reduction of the expression of an HDV gene. 
     I. Definitions 
     In order that the present invention may be more readily understood, certain terms are first defined. In addition, it should be noted that whenever a value or range of values of a parameter are recited, it is intended that values and ranges intermediate to the recited values are also intended to be part of this invention. 
     The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element, e.g., a plurality of elements. 
     The term “including” is used herein to mean, and is used interchangeably with, the phrase “including but not limited to”. 
     The term “or” is used herein to mean, and is used interchangeably with, the term “and/or,” unless context clearly indicates otherwise. 
     As used herein, “Hepatitis D virus,” used interchangeably with the term “HDV” refers to the well-known noncytopathic, liver-tropic DNA virus belonging to the Hepadnaviridae family. See, e.g., Ciancio and Rizzetto, Nat. Rev. 11:68-71, 2014; Le Gal et al., Emerg. Infect. Dis. 12:1447-1450, 2006; and Abbas and afzal, World J. Hep., 5:666-675, 2013, all of which are incorporated by reference. Unless otherwise indicate, HDV refers to all clades and variants of HDV. 
     HDV produces one protein, namely HDAg. It comes in two forms; a 27 kDa large-HDAg (also referred to herein as 1HD and large HDV antigen), and a small-HDAg of 24 kDa (also referred to herein as sHD and small HDV antigen). The N-terminals of the two forms are identical, they differ by 19 more amino acids in the C-terminal of the large HDAg. Both isoforms are produced from the same reading frame which contains an UAG stop codon at codon 196, which normally produces only the small-HDAg. However, editing by cellular enzyme adenosine deaminase-1 changes the stop codon to UCG, allowing the large-HDAg to be produced. Despite having 90% identical sequences, these two proteins play diverging roles during the course of an infection. HDAg-S is produced in the early stages of an infection and enters the nucleus and supports viral replication. HDAg-L, in contrast, is produced during the later stages of an infection, acts as an inhibitor of viral replication, and is required for assembly of viral particles. 
     Additional examples of HDV mRNA sequences are readily available using publicly available databases, e.g., GenBank, UniProt, and OMIM. 
     The term “HDV,” as used herein, also refers to naturally occurring DNA sequence variations of the HDV genome. 
     As used herein, “Hepatitis B virus,” used interchangeably with the term “HBV” refers to the well-known noncytopathic, liver-tropic DNA virus belonging to the Hepadnaviridae family. 
     The HBV genome is partially double-stranded, circular DNA with overlapping reading frames. 
     There are four known genes encoded by the HBC genome, called C, X, P, and S. The core protein is coded for by gene C (HBcAg). Hepatitis B antigen (HBeAg) is produced by proteolytic processing of the pre-core (pre-C) protein. The DNA polymerase is encoded by gene P. Gene S is the gene that codes for the surface antigen (HBsAg). The HBsAg gene is one long open reading frame but contains three in frame “start” (ATG) codons that divide the gene into three sections, pre-S1, pre-S2, and S. Because of the multiple start codons, polypeptides of three different sizes called large, middle, and small (pre-S1+pre-S2+S, pre-S2+S, or S) are produced. The function of the non-structural protein coded for by gene X is not fully understood but it is associated with the development of liver cancer and encodes a decoy protein which permits HBsAg in the blood to sequester anti-HBsAg antibodies and allow infectious viral particles to escape immune detection. 
     The proteins encoded by the HBV genome include: envelope proteins—i) small, Hepatitis B surface antigen (HBsAg); ii) middle—preS2 plus HBsAg; iii) large—preS1 plus preS2 plus HBsAg; nucleocapsid protein, hepatitis B core antigen (HBcAg). Hepatitis B e antigen (HBeAg) is a non-structural protein produced during the HBV replication which shares 90% amino acids with the nucleocapsid HBcAg; and the X protein is a nonstructural protein (HBx) which functions in the cytoplasm to activate various signaling pathways, many of which are controlled by modulation of cytosolic calcium and in the nucleus to regulate transcription through a direct interaction with different transcription factors and, in some cases, enhance their binding to specific transcription elements. 
     HBV is one of the few DNA viruses that utilize reverse transcriptase in the replication process which involves multiple stages including entry, uncoating and transport of the virus genome to the nucleus. Initially, replication of the HBV genome involves the generation of an RNA intermediate that is then reverse transcribed to produce the DNA viral genome. 
     Upon infection of a cell with HBV, the viral genomic relaxed circular DNA (rcDNA) is transported into the cell nucleus and converted into episomal covalently closed circular DNA (cccDNA), which serves as the transcription template for the viral mRNAs. After transcription and nuclear export, cytoplasmic viral pregenomic RNA (pgRNA) is assembled with HBV polymerase and capsid proteins to form the nucleocapsid, inside which polymerase-catalyzed reverse transcription yields minus-strand DNA, which is subsequently copied into plus-strand DNA to form the progeny rcDNA genome. The mature nucleocapsids are then either packaged with viral envelope proteins to egress as virion particles or shuttled to the nucleus to amplify the cccDNA reservoir through the intracellular cccDNA amplification pathway. cccDNA is an essential component of the HBV replication cycle and is responsible for the establishment of infection and viral persistence. 
     HBV infection results in the production of two different particles: 1) the HBV virus itself (or Dane particle) which includes a viral capsid assembled from the HBcAg and is covered by the HBsAg and is capable of reinfecting cells and 2) subviral particles (or SVPs) which are high density lipoprotein-like particles comprised of lipids, cholesterol, cholesterol esters and the small and medium forms of the hepatitis B surface antigen HBsAg which are non-infectious. For each viral particle produced, 1,000-10,000 SVPs are released into the blood. As such SVPs (and the HBsAg protein they carry) represent the overwhelming majority of viral protein in the blood. HBV infected cells also secrete a soluble proteolytic product of the pre-core protein called the HBV e-antigen (HBeAg). 
     Eight genotypes of HBV, designated A to H, have been determined, each having a distinct geographical distribution. The virus is non-cytopathic, with virus-specific cellular immunity being the main determinant for the outcome of exposure to HBV-acute infection with resolution of liver diseases with 6 months, or chronic HBV infection that is frequently associated with progressive liver injury. 
     The term “HBV” includes any of the eight genotypes of HBV (A to H). The amino acid and complete coding sequence of the reference sequence of the HBV genome may be found in for example, GenBank Accession Nos. GI:21326584 (SEQ ID NO:1) and GI:3582357 (SEQ ID NO:3). 
     Additional examples of HBV mRNA sequences are readily available using publicly available databases, e.g., GenBank, UniProt, and OMIM. 
     The term “HBV,” as used herein, also refers to naturally occurring DNA sequence variations of the HBV genome. 
     As used herein, “target sequence” refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of an HDV gene, including mRNA that is a product of RNA processing of a primary transcription product. In one embodiment, the target portion of the sequence will be at least long enough to serve as a substrate for iRNA-directed cleavage at or near that portion of the nucleotide sequence of an mRNA molecule formed during the transcription of an HDV gene. 
     The target sequence may be from about 9-36 nucleotides in length, e.g., about 15-30 nucleotides in length. For example, the target sequence can be from about 15-30 nucleotides, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the invention. 
     As used herein, the term “strand comprising a sequence” refers to an oligonucleotide comprising a chain of nucleotides that is described by the sequence referred to using the standard nucleotide nomenclature. 
     “G,” “C,” “A,” “T” and “U” each generally stand for a nucleotide that contains guanine, cytosine, adenine, thymidine and uracil as a base, respectively. However, it will be understood that the term “ribonucleotide” or “nucleotide” can also refer to a modified nucleotide, as further detailed below, or a surrogate replacement moiety (see, e.g., Table 2). The skilled person is well aware that guanine, cytosine, adenine, and uracil can be replaced by other moieties without substantially altering the base pairing properties of an oligonucleotide comprising a nucleotide bearing such replacement moiety. For example, without limitation, a nucleotide comprising inosine as its base can base pair with nucleotides containing adenine, cytosine, or uracil. Hence, nucleotides containing uracil, guanine, or adenine can be replaced in the nucleotide sequences of dsRNA featured in the invention by a nucleotide containing, for example, inosine. In another example, adenine and cytosine anywhere in the oligonucleotide can be replaced with guanine and uracil, respectively to form G-U Wobble base pairing with the target mRNA. Sequences containing such replacement moieties are suitable for the compositions and methods featured in the invention. 
     The terms “iRNA”, “RNAi agent,” “iRNA agent,”, “RNA interference agent” as used interchangeably herein, refer to an agent that contains RNA as that term is defined herein, and which mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC) pathway. iRNA directs the sequence-specific degradation of mRNA through a process known as RNA interference (RNAi). The iRNA modulates, e.g., inhibits, the expression of an HDV gene (e.g., one or more HDV genes) in a cell, e.g., a cell within a subject, such as a mammalian subject. 
     In one embodiment, an RNAi agent of the invention includes a single stranded RNA that interacts with a target RNA sequence, e.g., an HDV target mRNA sequence, to direct the cleavage of the target RNA. Without wishing to be bound by theory it is believed that long double stranded RNA introduced into cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et al. (2001)  Genes Dev.  15:485). Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pair short interfering RNAs with characteristic two base 3′ overhangs (Bernstein, et al., (2001)  Nature  409:363). The siRNAs are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001)  Cell  107:309). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001)  Genes Dev.  15:188). Thus, in one aspect the invention relates to a single stranded RNA (siRNA) generated within a cell and which promotes the formation of a RISC complex to effect silencing of the target gene, i.e., an HDV gene. Accordingly, the term “siRNA” is also used herein to refer to an RNAi as described above. 
     In another embodiment, the RNAi agent may be a single-stranded siRNA that is introduced into a cell or organism to inhibit a target mRNA. Single-stranded RNAi agents bind to the RISC endonuclease, Argonaute 2, which then cleaves the target mRNA. The single-stranded siRNAs are generally 15-30 nucleotides and are chemically modified. The design and testing of single-stranded siRNAs are described in U.S. Pat. No. 8,101,348 and in Lima et al., (2012)  Cell  150:883-894, the entire contents of each of which are hereby incorporated herein by reference. Any of the antisense nucleotide sequences described herein may be used as a single-stranded siRNA as described herein or as chemically modified by the methods described in Lima et al., (2012)  Cell  150:883-894. 
     In another embodiment, an “iRNA” for use in the compositions, uses, and methods of the invention is a double-stranded RNA and is referred to herein as a “double stranded RNAi agent,” “double-stranded RNA (dsRNA) molecule,” “dsRNA agent,” or “dsRNA”. The term “dsRNA”, refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary nucleic acid strands, referred to as having “sense” and “antisense” orientations with respect to a target RNA, i.e., an HDV gene. In some embodiments of the invention, a double-stranded RNA (dsRNA) triggers the degradation of a target RNA, e.g., an mRNA, through a post-transcriptional gene-silencing mechanism referred to herein as RNA interference or RNAi. 
     In general, the majority of nucleotides of each strand of a dsRNA molecule are ribonucleotides, but as described in detail herein, each or both strands can also include one or more non-ribonucleotides, e.g., a deoxyribonucleotide and/or a modified nucleotide. In addition, as used in this specification, an “RNAi agent” may include ribonucleotides with chemical modifications; an RNAi agent may include substantial modifications at multiple nucleotides. As used herein, the term “modified nucleotide” refers to a nucleotide having, independently, a modified sugar moiety, a modified internucleotide linkage, and/or modified nucleobase. Thus, the term modified nucleotide encompasses substitutions, additions or removal of, e.g., a functional group or atom, to internucleoside linkages, sugar moieties, or nucleobases. The modifications suitable for use in the agents of the invention include all types of modifications disclosed herein or known in the art. Any such modifications, as used in a siRNA type molecule, are encompassed by “RNAi agent” for the purposes of this specification and claims. 
     The duplex region may be of any length that permits specific degradation of a desired target RNA through a RISC pathway, and may range from about 9 to 36 base pairs in length, e.g., about 15-30 base pairs in length, for example, about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 base pairs in length, such as about 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the invention. 
     The two strands forming the duplex structure may be different portions of one larger RNA molecule, or they may be separate RNA molecules. Where the two strands are part of one larger molecule, and therefore are connected by an uninterrupted chain of nucleotides between the 3′-end of one strand and the 5′-end of the respective other strand forming the duplex structure, the connecting RNA chain is referred to as a “hairpin loop.” A hairpin loop can comprise at least one unpaired nucleotide. In some embodiments, the hairpin loop can comprise at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 23 or more unpaired nucleotides. 
     Where the two substantially complementary strands of a dsRNA are comprised by separate RNA molecules, those molecules need not, but can be covalently connected. Where the two strands are connected covalently by means other than an uninterrupted chain of nucleotides between the 3′-end of one strand and the 5′-end of the respective other strand forming the duplex structure, the connecting structure is referred to as a “linker.” The RNA strands may have the same or a different number of nucleotides. The maximum number of base pairs is the number of nucleotides in the shortest strand of the dsRNA minus any overhangs that are present in the duplex. In addition to the duplex structure, an RNAi may comprise one or more nucleotide overhangs. 
     In one embodiment, an RNAi agent of the invention is a dsRNA of 24-30 nucleotides that interacts with a target RNA sequence, e.g., an HDV target mRNA sequence, to direct the cleavage of the target RNA. Without wishing to be bound by theory, long double stranded RNA introduced into cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et al. (2001)  Genes Dev.  15:485). Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pair short interfering RNAs with characteristic two base 3′ overhangs (Bernstein, et al., (2001)  Nature  409:363). The siRNAs are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001)  Cell  107:309). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001)  Genes Dev.  15:188). 
     As used herein, the term “nucleotide overhang” refers to at least one unpaired nucleotide that protrudes from the duplex structure of an iRNA, e.g., a dsRNA. For example, when a 3′-end of one strand of a dsRNA extends beyond the 5′-end of the other strand, or vice versa, there is a nucleotide overhang. A dsRNA can comprise an overhang of at least one nucleotide; alternatively the overhang can comprise at least two nucleotides, at least three nucleotides, at least four nucleotides, at least five nucleotides or more. A nucleotide overhang can comprise or consist of a nucleotide/nucleoside analog, including a deoxynucleotide/nucleoside. The overhang(s) can be on the sense strand, the antisense strand or any combination thereof. Furthermore, the nucleotide(s) of an overhang can be present on the 5′-end, 3′-end or both ends of either an antisense or sense strand of a dsRNA. 
     In one embodiment, the antisense strand of a dsRNA has a 1-10 nucleotide, e.g., a 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotide, overhang at the 3′-end and/or the 5′-end. In one embodiment, the sense strand of a dsRNA has a 1-10 nucleotide, e.g., a 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotide, overhang at the 3′-end and/or the 5′-end. In another embodiment, one or more of the nucleotides in the overhang is replaced with a nucleoside thiophosphate. 
     “Blunt” or “blunt end” means that there are no unpaired nucleotides at that end of the double stranded RNAi agent, i.e., no nucleotide overhang. A “blunt ended” RNAi agent is a dsRNA that is double-stranded over its entire length, i.e., no nucleotide overhang at either end of the molecule. The RNAi agents of the invention include RNAi agents with nucleotide overhangs at one end (i.e., agents with one overhang and one blunt end) or with nucleotide overhangs at both ends. 
     The term “antisense strand” or “guide strand” refers to the strand of an iRNA, e.g., a dsRNA, which includes a region that is substantially complementary to a target sequence, e.g., a HDV mRNA. As used herein, the term “region of complementarity” refers to the region on the antisense strand that is substantially complementary to a sequence, for example a target sequence, e.g., an HDV nucleotide sequence, as defined herein. Where the region of complementarity is not fully complementary to the target sequence, the mismatches can be in the internal or terminal regions of the molecule. Generally, the most tolerated mismatches are in the terminal regions, e.g., within 5, 4, 3, 2, or 1 nucleotides of the 5′- and/or 3′-terminus of the iRNA. In one embodiment, a double-stranded RNAi agent of the invention include a a nucleotide mismatch in the antisense strand. In another embodiment, a double-stranded RNAi agent of the invention include a a nucleotide mismatch in the sense strand. In one embodiment, the nucleotide mismatch is, for example, within 5, 4, 3, 2, or 1 nucleotides from the 3′-terminus of the iRNA. In another embodiment, the nucleotide mismatch is, for example, in the 3′-terminal nucleotide of the iRNA. 
     The term “sense strand,” or “passenger strand” as used herein, refers to the strand of an iRNA that includes a region that is substantially complementary to a region of the antisense strand as that term is defined herein. 
     As used herein, the term “cleavage region” refers to a region that is located immediately adjacent to the cleavage site. The cleavage site is the site on the target at which cleavage occurs. In some embodiments, the cleavage region comprises three bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage region comprises two bases on either end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage site specifically occurs at the site bound by nucleotides 10 and 11 of the antisense strand, and the cleavage region comprises nucleotides 11, 12 and 13. 
     As used herein, and unless otherwise indicated, the term “complementary,” when used to describe a first nucleotide sequence in relation to a second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize and form a duplex structure under certain conditions with an oligonucleotide or polynucleotide comprising the second nucleotide sequence, as will be understood by the skilled person. Such conditions can, for example, be stringent conditions, where stringent conditions can include: 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50° C. or 70° C. for 12-16 hours followed by washing (see, e.g., “Molecular Cloning: A Laboratory Manual, Sambrook, et al. (1989) Cold Spring Harbor Laboratory Press). Other conditions, such as physiologically relevant conditions as can be encountered inside an organism, can apply. The skilled person will be able to determine the set of conditions most appropriate for a test of complementarity of two sequences in accordance with the ultimate application of the hybridized nucleotides. 
     Complementary sequences within an iRNA, e.g., within a dsRNA as described herein, include base-pairing of the oligonucleotide or polynucleotide comprising a first nucleotide sequence to an oligonucleotide or polynucleotide comprising a second nucleotide sequence over the entire length of one or both nucleotide sequences. Such sequences can be referred to as “fully complementary” with respect to each other herein. However, where a first sequence is referred to as “substantially complementary” with respect to a second sequence herein, the two sequences can be fully complementary, or they can form one or more, but generally not more than 5, 4, 3 or 2 mismatched base pairs upon hybridization for a duplex up to 30 base pairs, while retaining the ability to hybridize under the conditions most relevant to their ultimate application, e.g., inhibition of gene expression via a RISC pathway. However, where two oligonucleotides are designed to form, upon hybridization, one or more single stranded overhangs, such overhangs shall not be regarded as mismatches with regard to the determination of complementarity. For example, a dsRNA comprising one oligonucleotide 21 nucleotides in length and another oligonucleotide 23 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 21 nucleotides that is fully complementary to the shorter oligonucleotide, can yet be referred to as “fully complementary” for the purposes described herein. 
     “Complementary” sequences, as used herein, can also include, or be formed entirely from, non-Watson-Crick base pairs and/or base pairs formed from non-natural and modified nucleotides, in so far as the above requirements with respect to their ability to hybridize are fulfilled. Such non-Watson-Crick base pairs include, but are not limited to, G:U Wobble or Hoogstein base pairing. 
     The terms “complementary,” “fully complementary” and “substantially complementary” herein can be used with respect to the base matching between the sense strand and the antisense strand of a dsRNA, or between the antisense strand of an iRNA agent and a target sequence, as will be understood from the context of their use. 
     As used herein, a polynucleotide that is “substantially complementary to at least part of” a messenger RNA (mRNA) refers to a polynucleotide that is substantially complementary to a contiguous portion of the mRNA of interest (e.g., an mRNA encoding an HDV gene). For example, a polynucleotide is complementary to at least a part of an HDV mRNA if the sequence is substantially complementary to a non-interrupted portion of an mRNA encoding an HDV gene. 
     Accordingly, in some embodiments, the sense strand polynucleotides and the antisense polynucleotides disclosed herein are fully complementary to the target HDV sequence. In other embodiments, the sense strand polynucleotides and/or the antisense polynucleotides disclosed herein are substantially complementary to the target HDV sequence and comprise a contiguous nucleotide sequence which is at least about 80% complementary over its entire length to the equivalent region of the nucleotide sequence of any one of the sequences in Tables 11, 12, 31, and 32, or a fragment of any one of the sequences in Tables 11, 12, 31, and 32, such as about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about % 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% complementary. 
     In one embodiment, an RNAi agent of the invention includes a sense strand that is substantially complementary to the target HDV sequence and comprise a contiguous nucleotide sequence which is at least about 80% complementary over its entire length to the equivalent region of the nucleotide sequence of any one of the sequences in Tables 11, 12, 31, and 32, or a fragment of any one of the sequences in Tables 11, 12, 31, and 32, such as about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about % 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% complementary. 
     In another embodiment, an RNAi agent of the invention includes an antisense strand that is substantially complementary to the target HDV sequence and comprise a contiguous nucleotide sequence which is at least about 80% complementary over its entire length to the equivalent region of the nucleotide sequence of any one of the sequences in Tables 11, 12, 31, and 32, or a fragment of any one of the sequences in Tables 11, 12, 31, and 32, such as about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about % 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% complementary. 
     In some embodiments, the RNAi agents for use in the invention target HBV. In some embodiment, such agents are fully complementary to the target HBV sequence. In other embodiments, the sense strand polynucleotides and/or the antisense polynucleotides disclosed herein are substantially complementary to the target HBV sequence and comprise a contiguous nucleotide sequence which is at least about 80% complementary over its entire length to the equivalent region of the nucleotide sequence of any one of the nucleotide sequences of the agents targeting HBV provided herein, such as about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about % 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% complementary. 
     In one embodiment, an RNAi agent targeting HBV for use in the present invention includes a sense strand that is substantially complementary to the target HBV sequence and comprise a contiguous nucleotide sequence which is at least about 80% complementary over its entire length to the equivalent region of the nucleotide sequence of any one of the nucleotide sequences of the agents targeting HBV provided herein, such as about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about % 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% complementary. 
     In another embodiment, an RNAi agent targeting HBV for use in the present invention includes an antisense strand that is substantially complementary to the target HBV sequence and comprise a contiguous nucleotide sequence which is at least about 80% complementary over its entire length to the equivalent region of the nucleotide sequence of any one of the nucleotide sequences of the agents targeting HBV provided herein, or a fragment of any one of the nucleotide sequences of the agents targeting HBV provided herein, such as about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about % 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% complementary. 
     In general, the majority of nucleotides of each strand are ribonucleotides, but as described in detail herein, each or both strands can also include one or more non-ribonucleotides, e.g., a deoxyribonucleotide and/or a modified nucleotide. In addition, an “iRNA” may include ribonucleotides with chemical modifications. Such modifications may include all types of modifications disclosed herein or known in the art. Any such modifications, as used in an iRNA molecule, are encompassed by “iRNA” for the purposes of this specification and claims. 
     In one aspect of the invention, an agent for use in the methods and compositions of the invention is a single-stranded antisense RNA molecule that inhibits a target mRNA via an antisense inhibition mechanism. The single-stranded antisense RNA molecule is complementary to a sequence within the target mRNA. The single-stranded antisense oligonucleotides can inhibit translation in a stoichiometric manner by base pairing to the mRNA and physically obstructing the translation machinery, see Dias, N. et al., (2002)  Mol Cancer Ther  1:347-355. The single-stranded antisense RNA molecule may be about 15 to about 30 nucleotides in length and have a sequence that is complementary to a target sequence. For example, the single-stranded antisense RNA molecule may comprise a sequence that is at least about 15, 16, 17, 18, 19, 20, or more contiguous nucleotides from any one of the antisense sequences described herein. 
     As used herein, a “subject” is an animal, such as a mammal, including a primate (such as a human, a non-human primate, e.g., a monkey, and a chimpanzee), a non-primate (such as a cow, a pig, a camel, a llama, a horse, a goat, a rabbit, a sheep, a hamster, a guinea pig, a cat, a dog, a rat, a mouse, a horse, and a whale), or a bird (e.g., a duck or a goose). In an embodiment, the subject is a human, such as a human being treated or assessed for a disease, disorder or condition that would benefit from reduction in HDV gene expression and/or replication; a human at risk for a disease, disorder or condition that would benefit from reduction in HDV gene expression and/or replication; a human having a disease, disorder or condition that would benefit from reduction in HDV gene expression and/or replication; and/or human being treated for a disease, disorder or condition that would benefit from reduction in HDV gene expression and/or replication, as described herein. 
     As used herein, the terms “treating” or “treatment” refer to a beneficial or desired result including, but not limited to, alleviation or amelioration of one or more symptoms associated with unwanted HDV gene expression and/or HDV replication. “Treatment” can also mean prolonging survival as compared to expected survival in the absence of treatment. 
     The term “lower” in the context of the level of HDV gene expression and/or HDV replication in a subject or a disease marker or symptom refers to a statistically significant decrease in such level. The decrease can be, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more and is preferably down to a level accepted as within the range of normal for an individual without such disorder. In certain embodiments, the expression of the target is normalized, i.e., decreased to a level accepted as within the range of normal for an individual without such disorder, e.g., the level of a disease marker, such as, ALT or AST, is decreased to a level accepted as within the range of normal for an individual without such disorder. 
     As used herein, “prevention” or “preventing,” when used in reference to a disease, disorder or condition thereof, that would benefit from a reduction in expression of an HDV gene and/or replication, refers to a reduction in the likelihood that a subject will develop a symptom associated with such a disease, disorder, or condition, e.g., a symptom of unwanted HDV infection, such as the presence of serum and/or liver HDV ccc DNA, the presence of serum HDV DNA, the presence of serum and/or liver HDV antigen. 
     As used herein, the term “Hepatitis D virus-associated disease” or “HDV-associated disease,” is a disease or disorder that is caused by, or associated with HDV infection and/or replication. The term “HDV-associated disease” includes a disease, disorder or condition that would benefit from reduction in HDV gene expression and/or replication. Non-limiting examples of HDV-associated diseases include, for example, hepatitis B virus infection, acute hepatitis B, acute hepatitis D; acute fulminant hepatitis D; chronic hepatitis D; liver fibrosis; end-stage liver disease; hepatocellular carcinoma. 
     “Therapeutically effective amount,” as used herein, is intended to include the amount of an RNAi agent that, when administered to a patient for treating a subject having an HDV infection and/or HDV-associated disease, is sufficient to effect treatment of the disease (e.g., by diminishing, ameliorating or maintaining the existing disease or one or more symptoms of disease). The “therapeutically effective amount” may vary depending on the RNAi agent, how the agent is administered, the disease and its severity and the history, age, weight, family history, genetic makeup, stage of pathological processes mediated by HDV gene expression, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated. 
     “Prophylactically effective amount,” as used herein, is intended to include the amount of an RNAi agent that, when administered to a subject who does not yet experience or display symptoms of an HDV infection and/or HDV-associated disease, but who may be predisposed, is sufficient to prevent or ameliorate the disease or one or more symptoms of the disease. Ameliorating the disease includes slowing the course of the disease or reducing the severity of later-developing disease. The “prophylactically effective amount” may vary depending on the RNAi agent, how the agent is administered, the degree of risk of disease, and the history, age, weight, family history, genetic makeup, the types of preceding or concomitant treatments, if any, and other individual characteristics of the patient to be treated. 
     A “therapeutically-effective amount” or “prophylactically effective amount” also includes an amount of an RNAi agent that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. RNAi agents employed in the methods of the present invention may be administered in a sufficient amount to produce a reasonable benefit/risk ratio applicable to such treatment. 
     The term “sample,” as used herein, includes a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Examples of biological fluids include blood, serum and serosal fluids, plasma, cerebrospinal fluid, ocular fluids, lymph, urine, saliva, and the like. Tissue samples may include samples from tissues, organs or localized regions. For example, samples may be derived from particular organs, parts of organs, or fluids or cells within those organs. In certain embodiments, samples may be derived from the liver (e.g., whole liver or certain segments of liver or certain types of cells in the liver, such as, e.g., hepatocytes), the retina or parts of the retina (e.g., retinal pigment epithelium), the central nervous system or parts of the central nervous system (e.g., ventricles or choroid plexus), or the pancreas or certain cells or parts of the pancreas. In some embodiments, a “sample derived from a subject” refers tocerebrospinal fluid obtained from the subject. In preferred embodiments, a “sample derived from a subject” refers to blood or plasma drawn from the subject. In further embodiments, a “sample derived from a subject” refers to liver tissue (or subcomponents thereof) or retinal tissue (or subcomponents thereof) derived from the subject. 
     II. iRNAs of the Invention 
     The present invention provides iRNAs which inhibit the expression of one or more HDV genes. In one embodiment, the iRNA agent includes double-stranded ribonucleic acid (dsRNA) molecules for inhibiting the expression of an HDV gene in a cell, such as a cell within a subject, e.g., a mammal, such as a human having an HDV-associated disease, e.g., chronic hepatitis D. The dsRNA includes an antisense strand having a region of complementarity which is complementary to at least a part of an mRNA formed in the expression of an HDV gene. The region of complementarity is about 30 nucleotides or less in length (e.g., about 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, or 18 nucleotides or less in length). Upon contact with a cell expressing the HDV gene, the iRNA inhibits the expression of the HDV gene (e.g., a human, a primate, a non-primate, or a bird HDV gene) by at least about 10% as assayed by, for example, a PCR or branched DNA (bDNA)-based method, or by a protein-based method, such as by immunofluorescence analysis, using, for example, western Blotting or flowcytometric techniques. 
     A dsRNA includes two RNA strands that are complementary and hybridize to form a duplex structure under conditions in which the dsRNA will be used. One strand of a dsRNA (the antisense strand) includes a region of complementarity that is substantially complementary, and generally fully complementary, to a target sequence. The target sequence can be derived from the sequence of an mRNA formed during the expression of an HDV gene. The other strand (the sense strand) includes a region that is complementary to the antisense strand, such that the two strands hybridize and form a duplex structure when combined under suitable conditions. As described elsewhere herein and as known in the art, the complementary sequences of a dsRNA can also be contained as self-complementary regions of a single nucleic acid molecule, as opposed to being on separate oligonucleotides. 
     Generally, the duplex structure is between 15 and 30 base pairs in length, e.g., between, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the invention. 
     Similarly, the region of complementarity to the target sequence is between 15 and 30 nucleotides in length, e.g., between 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the invention. 
     In some embodiments, the dsRNA is between about 15 and about 20 nucleotides in length, or between about 25 and about 30 nucleotides in length. In general, the dsRNA is long enough to serve as a substrate for the Dicer enzyme. For example, it is well-known in the art that dsRNAs longer than about 21-23 nucleotides in length may serve as substrates for Dicer. As the ordinarily skilled person will also recognize, the region of an RNA targeted for cleavage will most often be part of a larger RNA molecule, often an mRNA molecule. Where relevant, a “part” of an mRNA target is a contiguous sequence of an mRNA target of sufficient length to allow it to be a substrate for RNAi-directed cleavage (i.e., cleavage through a RISC pathway). 
     One of skill in the art will also recognize that the duplex region is a primary functional portion of a dsRNA, e.g., a duplex region of about 9 to 36 base pairs, e.g., about 10-36, 11-36, 12-36, 13-36, 14-36, 15-36, 9-35, 10-35, 11-35, 12-35, 13-35, 14-35, 15-35, 9-34, 10-34, 11-34, 12-34, 13-34, 14-34, 15-34, 9-33, 10-33, 11-33, 12-33, 13-33, 14-33, 15-33, 9-32, 10-32, 11-32, 12-32, 13-32, 14-32, 15-32, 9-31, 10-31, 11-31, 12-31, 13-32, 14-31, 15-31, 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs. Thus, in one embodiment, to the extent that it becomes processed to a functional duplex, of e.g., 15-30 base pairs, that targets a desired RNA for cleavage, an RNA molecule or complex of RNA molecules having a duplex region greater than 30 base pairs is a dsRNA. Thus, an ordinarily skilled artisan will recognize that in one embodiment, a miRNA is a dsRNA. In another embodiment, a dsRNA is not a naturally occurring miRNA. In another embodiment, an iRNA agent useful to target HDV gene expression is not generated in the target cell by cleavage of a larger dsRNA. 
     A dsRNA as described herein can further include one or more single-stranded nucleotide overhangs e.g., 1, 2, 3, or 4 nucleotides. dsRNAs having at least one nucleotide overhang can have unexpectedly superior inhibitory properties relative to their blunt-ended counterparts. A nucleotide overhang can comprise or consist of a nucleotide/nucleoside analog, including a deoxynucleotide/nucleoside. The overhang(s) can be on the sense strand, the antisense strand or any combination thereof. Furthermore, the nucleotide(s) of an overhang can be present on the 5′-end, 3′-end or both ends of either an antisense or sense strand of a dsRNA. 
     A dsRNA can be synthesized by standard methods known in the art as further discussed below, e.g., by use of an automated DNA synthesizer, such as are commercially available from, for example, Biosearch, Applied Biosystems, Inc. 
     iRNA compounds of the invention may be prepared using a two-step procedure. First, the individual strands of the double-stranded RNA molecule are prepared separately. Then, the component strands are annealed. The individual strands of the siRNA compound can be prepared using solution-phase or solid-phase organic synthesis or both. Organic synthesis offers the advantage that the oligonucleotide strands comprising unnatural or modified nucleotides can be easily prepared. Single-stranded oligonucleotides of the invention can be prepared using solution-phase or solid-phase organic synthesis or both. 
     In one aspect, a dsRNA of the invention includes at least two nucleotide sequences, a sense sequence and an anti-sense sequence. The sense strand is selected from the group of sequences provided in any one of Tables 11, 12, 31, and 32 and the corresponding antisense strand of the sense strand is selected from the group of sequences of any one of Tables 11, 12, 31, and 32. In this aspect, one of the two sequences is complementary to the other of the two sequences, with one of the sequences being substantially complementary to a sequence of an mRNA generated in the expression of an HDV gene. As such, in this aspect, a dsRNA will include two oligonucleotides, where one oligonucleotide is described as the sense strand in any one of Tables 11, 12, 31, and 32 and the second oligonucleotide is described as the corresponding antisense strand of the sense strand in any one of Tables 11, 12, 31, and 32. In one embodiment, the substantially complementary sequences of the dsRNA are contained on separate oligonucleotides. In another embodiment, the substantially complementary sequences of the dsRNA are contained on a single oligonucleotide. 
     It will be understood that, although some of the sequences in Tables 12 and 32 are described as modified and/or conjugated sequences, the RNA of the iRNA of the invention e.g., a dsRNA of the invention, may comprise any one of the sequences set forth in any one of Tables 11, 12, 31, and 32 that is un-modified, un-conjugated, and/or modified and/or conjugated differently than described therein. 
     The skilled person is well aware that dsRNAs having a duplex structure of between about 20 and 23 base pairs, e.g., 21, base pairs have been hailed as particularly effective in inducing RNA interference (Elbashir et al.,  EMBO  2001, 20:6877-6888). However, others have found that shorter or longer RNA duplex structures can also be effective (Chu and Rana (2007)  RNA  14:1714-1719; Kim et al. (2005)  Nat Biotech  23:222-226). In the embodiments described above, by virtue of the nature of the oligonucleotide sequences provided in any one of Tables 11, 12, 31, and 32, dsRNAs described herein can include at least one strand of a length of minimally 21 nucleotides. It can be reasonably expected that shorter duplexes having one of the sequences of any one of Tables 11, 12, 31, and 32 minus only a few nucleotides on one or both ends can be similarly effective as compared to the dsRNAs described above. Hence, dsRNAs having a sequence of at least 15, 16, 17, 18, 19, 20, or more contiguous nucleotides derived from one of the sequences of any one of Tables 11, 12, 31, and 32, and differing in their ability to inhibit the expression of a HDV gene by not more than about 5, 10, 15, 20, 25, or 30% inhibition from a dsRNA comprising the full sequence, are contemplated to be within the scope of the present invention. 
     In addition, the RNAs provided in any one of Tables 11, 12, 31, and 32 identify a site(s) in a HDV transcript that is susceptible to RISC-mediated cleavage. As such, the present invention further features iRNAs that target within one of these sites. As used herein, an iRNA is said to target within a particular site of an RNA transcript if the iRNA promotes cleavage of the transcript anywhere within that particular site. Such an iRNA will generally include at least about 15 contiguous nucleotides from one of the sequences provided inany one of Tables 11, 12, 31, and 32 coupled to additional nucleotide sequences taken from the region contiguous to the selected sequence in a HDV gene. 
     While a target sequence is generally about 15-30 nucleotides in length, there is wide variation in the suitability of particular sequences in this range for directing cleavage of any given target RNA. Various software packages and the guidelines set out herein provide guidance for the identification of optimal target sequences for any given gene target, but an empirical approach can also be taken in which a “window” or “mask” of a given size (as a non-limiting example, 21 nucleotides) is literally or figuratively (including, e.g., in silico) placed on the target RNA sequence to identify sequences in the size range that can serve as target sequences. By moving the sequence “window” progressively one nucleotide upstream or downstream of an initial target sequence location, the next potential target sequence can be identified, until the complete set of possible sequences is identified for any given target size selected. This process, coupled with systematic synthesis and testing of the identified sequences (using assays as described herein or as known in the art) to identify those sequences that perform optimally can identify those RNA sequences that, when targeted with an iRNA agent, mediate the best inhibition of target gene expression. Thus, while the sequences identified, for example, in any one of Tables 11, 12, 31, and 32 represent effective target sequences, it is contemplated that further optimization of inhibition efficiency can be achieved by progressively “walking the window” one nucleotide upstream or downstream of the given sequences to identify sequences with equal or better inhibition characteristics. 
     Further, it is contemplated that for any sequence identified, e.g., in any one of Tables 11, 12, 31, and 32, further optimization could be achieved by systematically either adding or removing nucleotides to generate longer or shorter sequences and testing those sequences generated by walking a window of the longer or shorter size up or down the target RNA from that point. Again, coupling this approach to generating new candidate targets with testing for effectiveness of iRNAs based on those target sequences in an inhibition assay as known in the art and/or as described herein can lead to further improvements in the efficiency of inhibition. Further still, such optimized sequences can be adjusted by, e.g., the introduction of modified nucleotides as described herein or as known in the art, addition or changes in overhang, or other modifications as known in the art and/or discussed herein to further optimize the molecule (e.g., increasing serum stability or circulating half-life, increasing thermal stability, enhancing transmembrane delivery, targeting to a particular location or cell type, increasing interaction with silencing pathway enzymes, increasing release from endosomes) as an expression inhibitor. 
     An iRNA as described herein can contain one or more mismatches to the target sequence. In one embodiment, an iRNA as described herein contains no more than 3 mismatches. If the antisense strand of the iRNA contains mismatches to a target sequence, it is preferable that the area of mismatch is not located in the center of the region of complementarity. If the antisense strand of the iRNA contains mismatches to the target sequence, it is preferable that the mismatch be restricted to be within the last 5 nucleotides from either the 5′- or 3′-end of the region of complementarity. For example, for a 23 nucleotide iRNA agent the strand which is complementary to a region of an HDV gene, generally does not contain any mismatch within the central 13 nucleotides. The methods described herein or methods known in the art can be used to determine whether an iRNA containing a mismatch to a target sequence is effective in inhibiting the expression of an HDV gene. Consideration of the efficacy of iRNAs with mismatches in inhibiting expression of an HDV gene is important, especially if the particular region of complementarity in an HDV gene is known to have polymorphic sequence variation within the population. 
     III. Modified iRNAs of the Invention 
     In one embodiment, the RNA of the iRNA of the invention e.g., a dsRNA, is un-modified, and does not comprise, e.g., chemical modifications and/or conjugations known in the art and described herein. In another embodiment, the RNA of an iRNA of the invention, e.g., a dsRNA, is chemically modified to enhance stability or other beneficial characteristics. In certain embodiments of the invention, substantially all of the nucleotides of an iRNA of the invention are modified. In other embodiments of the invention, all of the nucleotides of an iRNA of the invention are modified iRNAs of the invention in which “substantially all of the nucleotides are modified” are largely but not wholly modified and can include not more than 5, 4, 3, 2, or 1 unmodified nucleotides. 
     The nucleic acids featured in the invention can be synthesized and/or modified by methods well established in the art, such as those described in “Current protocols in nucleic acid chemistry,” Beaucage, S. L. et al. (Edrs.), John Wiley &amp; Sons, Inc., New York, N.Y., USA, which is hereby incorporated herein by reference. Modifications include, for example, end modifications, e.g., 5′-end modifications (phosphorylation, conjugation, inverted linkages) or 3′-end modifications (conjugation, DNA nucleotides, inverted linkages, etc.); base modifications, e.g., replacement with stabilizing bases, destabilizing bases, or bases that base pair with an expanded repertoire of partners, removal of bases (abasic nucleotides), or conjugated bases; sugar modifications (e.g., at the 2′-position or 4′-position) or replacement of the sugar; and/or backbone modifications, including modification or replacement of the phosphodiester linkages. Specific examples of iRNA compounds useful in the embodiments described herein include, but are not limited to RNAs containing modified backbones or no natural internucleoside linkages. RNAs having modified backbones include, among others, those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified RNAs that do not have a phosphorus atom in their internucleoside backbone can also be considered to be oligonucleosides. In some embodiments, a modified iRNA will have a phosphorus atom in its internucleoside backbone. 
     Modified RNA backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3′-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3′-5′ linkages, 2′-5′-linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3′-5′ to 5′-3′ or 2′-5′ to 5′-2′. Various salts, mixed salts and free acid forms are also included. 
     Representative U.S. patents that teach the preparation of the above phosphorus-containing linkages include, but are not limited to, U.S. Pat. Nos. 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,195; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,316; 5,550,111; 5,563,253; 5,571,799; 5,587,361; 5,625,050; 6,028,188; 6,124,445; 6,160,109; 6,169,170; 6,172,209; 6,239,265; 6,277,603; 6,326,199; 6,346,614; 6,444,423; 6,531,590; 6,534,639; 6,608,035; 6,683,167; 6,858,715; 6,867,294; 6,878,805; 7,015,315; 7,041,816; 7,273,933; 7,321,029; and U.S. Pat. RE39464, the entire contents of each of which are hereby incorporated herein by reference. 
     Modified RNA backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatoms and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH 2  component parts. 
     Representative U.S. patents that teach the preparation of the above oligonucleosides include, but are not limited to, U.S. Pat. Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,64,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; and, 5,677,439, the entire contents of each of which are hereby incorporated herein by reference. 
     In other embodiments, suitable RNA mimetics are contemplated for use in iRNAs, in which both the sugar and the internucleoside linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an RNA mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar backbone of an RNA is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative U.S. patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262, the entire contents of each of which are hereby incorporated herein by reference. Additional PNA compounds suitable for use in the iRNAs of the invention are described in, for example, in Nielsen et al.,  Science,  1991, 254, 1497-1500. 
     Some embodiments featured in the invention include RNAs with phosphorothioate backbones and oligonucleosides with heteroatom backbones, and in particular —CH 2 —NH—CH 2 —, —CH 2 —N(CH 3 )—O—CH 2 —[known as a methylene (methylimino) or MMI backbone], —CH 2 —O—N(CH 3 )—CH 2 —, —CH 2 —N(CH 3 )—N(CH 3 )—CH 2 — and —N(CH 3 )—CH 2 —CH 2 —[wherein the native phosphodiester backbone is represented as —O—P—O—CH 2 —] of the above-referenced U.S. Pat. No. 5,489,677, and the amide backbones of the above-referenced U.S. Pat. No. 5,602,240. In some embodiments, the RNAs featured herein have morpholino backbone structures of the above-referenced U.S. Pat. No. 5,034,506. 
     Modified RNAs can also contain one or more substituted sugar moieties. The iRNAs, e.g., dsRNAs, featured herein can include one of the following at the 2′-position: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted C 1  to C 10  alkyl or C 2  to C 10  alkenyl and alkynyl. Exemplary suitable modifications include O[(CH 2 ) n O] m CH 3 , O(CH 2 ). n OCH 3 , O(CH 2 ) n NH 2 , O(CH 2 ) n CH 3 , O(CH 2 ) n ONH 2 , and O(CH 2 ) n ON[(CH 2 ) n CH 3 )] 2 , where n and m are from 1 to about 10. In other embodiments, dsRNAs include one of the following at the 2′ position: C 1  to C 10  lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH 3 , OCN, Cl, Br, CN, CF 3 , OCF 3 , SOCH 3 , SO 2 CH 3 , ONO 2 , NO 2 , N 3 , NH 2 , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an iRNA, or a group for improving the pharmacodynamic properties of an iRNA, and other substituents having similar properties. In some embodiments, the modification includes a 2′-methoxyethoxy (2′-O—CH 2 CH 2 OCH 3 , also known as 2′-O-(2-methoxyethyl) or 2′-MOE) (Martin et al.,  Helv. Chim. Acta,  1995, 78:486-504) i.e., an alkoxy-alkoxy group. Another exemplary modification is 2′-dimethylaminooxyethoxy, i.e., a O(CH 2 ) 2 ON(CH 3 ) 2  group, also known as 2′-DMAOE, as described in examples herein below, and 2′-dimethylaminoethoxyethoxy (also known in the art as 2′-O-dimethylaminoethoxyethyl or 2′-DMAEOE), i.e., 2′-O—CH 2 —O—CH 2 —N(CH 2 ) 2 . 
     Other modifications include 2′-methoxy (2′-OCH 3 ), 2′-aminopropoxy (2′-OCH 2 CH 2 CH 2 NH 2 ) and 2′-fluoro (2′-F). Similar modifications can also be made at other positions on the RNA of an iRNA, particularly the 3′ position of the sugar on the 3′ terminal nucleotide or in 2′-5′ linked dsRNAs and the 5′ position of 5′ terminal nucleotide. iRNAs can also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; and 5,700,920, certain of which are commonly owned with the instant application. The entire contents of each of the foregoing are hereby incorporated herein by reference. 
     An iRNA can also include nucleobase (often referred to in the art simply as “base”) modifications or substitutions. As used herein, “unmodified” or “natural” nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified nucleobases include other synthetic and natural nucleobases such as deoxy-thymine (dT), 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl anal other 8-substituted adenines and guanines, 5-halo, particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-daazaadenine and 3-deazaguanine and 3-deazaadenine. Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed. Wiley-VCH, 2008; those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, J. L, ed. John Wiley &amp; Sons, 1990, these disclosed by Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613, and those disclosed by Sanghvi, Y S., Chapter 15, dsRNA Research and Applications, pages 289-302, Crooke, S. T. and Lebleu, B., Ed., CRC Press, 1993. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds featured in the invention. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2° C. (Sanghvi, Y. S., Crooke, S. T. and Lebleu, B., Eds., dsRNA Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278) and are exemplary base substitutions, even more particularly when combined with 2′-O-methoxyethyl sugar modifications. 
     Representative U.S. patents that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include, but are not limited to, the above noted U.S. Pat. Nos. 3,687,808, 4,845,205; 5,130,30; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121, 5,596,091; 5,614,617; 5,681,941; 5,750,692; 6,015,886; 6,147,200; 6,166,197; 6,222,025; 6,235,887; 6,380,368; 6,528,640; 6,639,062; 6,617,438; 7,045,610; 7,427,672; and 7,495,088, the entire contents of each of which are hereby incorporated herein by reference. 
     The RNA of an iRNA can also be modified to include one or more bicyclic sugar moities. A “bicyclic sugar” is a furanosyl ring modified by the bridging of two atoms. A“bicyclic nucleoside” (“BNA”) is a nucleoside having a sugar moiety comprising a bridge connecting two carbon atoms of the sugar ring, thereby forming a bicyclic ring system. In certain embodiments, the bridge connects the 4′-carbon and the 2′-carbon of the sugar ring. Thus, in some embodiments an agent of the invention may include one or more locked nucleic acids (LNA). A locked nucleic acid is a nucleotide having a modified ribose moiety in which the ribose moiety comprises an extra bridge connecting the 2′ and 4′ carbons. In other words, an LNA is a nucleotide comprising a bicyclic sugar moiety comprising a 4′-CH2-O-2′ bridge. This structure effectively “locks” the ribose in the 3′-endo structural conformation. The addition of locked nucleic acids to siRNAs has been shown to increase siRNA stability in serum, and to reduce off-target effects (Elmen, J. et al., (2005)  Nucleic Acids Research  33(1):439-447; Mook, O R. et al., (2007)  Mol Canc Ther  6(3):833-843; Grunweller, A. et al., (2003)  Nucleic Acids Research  31(12):3185-3193). Examples of bicyclic nucleosides for use in the polynucleotides of the invention include without limitation nucleosides comprising a bridge between the 4′ and the 2′ ribosyl ring atoms. In certain embodiments, the antisense polynucleotide agents of the invention include one or more bicyclic nucleosides comprising a 4′ to 2′ bridge. Examples of such 4′ to 2′ bridged bicyclic nucleosides, include but are not limited to 4′-(CH2)-O-2′ (LNA); 4′-(CH2)-S-2′; 4′-(CH2)2-O-2′ (ENA); 4′-CH(CH3)-O-2′ (also referred to as “constrained ethyl” or “cEt”) and 4′-CH(CH2OCH3)-O-2′ (and analogs thereof; see, e.g., U.S. Pat. No. 7,399,845); 4′-C(CH3)(CH3)-O-2′ (and analogs thereof; see e.g., U.S. Pat. No. 8,278,283); 4′-CH2-N(OCH3)-2′ (and analogs thereof; see e.g., U.S. Pat. No. 8,278,425); 4′-CH2-O—N(CH3)-2′ (see, e.g., U.S. Patent Publication No. 2004/0171570); 4′-CH2-N(R)—O-2′, wherein R is H, C1-C12 alkyl, or a protecting group (see, e.g., U.S. Pat. No. 7,427,672); 4′-CH2-C(H)(CH3)-2′ (see, e.g., Chattopadhyaya et al.,  J. Org. Chem.,  2009, 74, 118-134); and 4′-CH2-C(═CH2)-2′ (and analogs thereof; see, e.g., U.S. Pat. No. 8,278,426). The entire contents of each of the foregoing are hereby incorporated herein by reference. 
     Additional representative U.S. patents and US Patent Publications that teach the preparation of locked nucleic acid nucleotides include, but are not limited to, the following: U.S. Pat. Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7,034,133; 7,084,125; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US 2008/0039618; and US 2009/0012281, the entire contents of each of which are hereby incorporated herein by reference. 
     Any of the foregoing bicyclic nucleosides can be prepared having one or more stereochemical sugar configurations including for example α-L-ribofuranose and β-D-ribofuranose (see WO 99/14226). 
     The RNA of an iRNA can also be modified to include one or more constrained ethyl nucleotides. As used herein, a “constrained ethyl nucleotide” or “cEt” is a locked nucleic acid comprising a bicyclic sugar moiety comprising a 4′-CH(CH3)-0-2′ bridge. In one embodiment, a constrained ethyl nucleotide is in the S conformation referred to herein as “S-cEt.” 
     An iRNA of the invention may also include one or more “conformationally restricted nucleotides” (“CRN”). CRN are nucleotide analogs with a linker connecting the C2′ and C4′ carbons of ribose or the C3 and —C5′ carbons of ribose. CRN lock the ribose ring into a stable conformation and increase the hybridization affinity to mRNA. The linker is of sufficient length to place the oxygen in an optimal position for stability and affinity resulting in less ribose ring puckering. 
     Representative publications that teach the preparation of certain of the above noted CRN include, but are not limited to, US Patent Publication No. 2013/0190383; and PCT publication WO 2013/036868, the entire contents of each of which are hereby incorporated herein by reference. 
     One or more of the nucleotides of an iRNA of the invention may also include a hydroxymethyl substituted nucleotide. A “hydroxymethyl substituted nucleotide” is an acyclic 2′-3′-seco-nucleotide, also referred to as an “unlocked nucleic acid” (“UNA”) modification 
     Representative U.S. publications that teach the preparation of UNA include, but are not limited to, U.S. Pat. No. 8,314,227; and US Patent Publication Nos. 2013/0096289; 2013/0011922; and 2011/0313020, the entire contents of each of which are hereby incorporated herein by reference. 
     Potentially stabilizing modifications to the ends of RNA molecules can include N-(acetylaminocaproyl)-4-hydroxyprolinol (Hyp-C6-NHAc), N-(caproyl-4-hydroxyprolinol (Hyp-C6), N-(acetyl-4-hydroxyprolinol (Hyp-NHAc), thymidine-2′-0-deoxythymidine (ether), N-(aminocaproyl)-4-hydroxyprolinol (Hyp-C6-amino), 2-docosanoyl-uridine-3″-phosphate, inverted base dT(idT) and others. Disclosure of this modification can be found in PCT Publication No. WO 2011/005861. 
     Other modifications of the nucleotides of an iRNA of the invention include a 5′ phosphate or 5′ phosphate mimic, e.g., a 5′-terminal phosphate or phosphate mimic on the antisense strand of an RNAi agent. Suitable phosphate mimics are disclosed in, for example US Patent Publication No. 2012/0157511, the entire contents of which are incorporated herein by reference. 
     A. Modified iRNAs Comprising Motifs of the Invention 
     In certain aspects of the invention, the double-stranded RNAi agents of the invention include agents with chemical modifications as disclosed, for example, in WO 2013/075035, filed on Nov. 16, 2012, the entire contents of which are incorporated herein by reference. As shown herein and in PCT Publication No. WO 2013/075035, a superior result may be obtained by introducing one or more motifs of three identical modifications on three consecutive nucleotides into a sense strand and/or antisense strand of an RNAi agent, particularly at or near the cleavage site. In some embodiments, the sense strand and antisense strand of the RNAi agent may otherwise be completely modified. The introduction of these motifs interrupts the modification pattern, if present, of the sense and/or antisense strand. The RNAi agent may be optionally conjugated with a GalNAc derivative ligand, for instance on the sense strand. The resulting RNAi agents present superior gene silencing activity. 
     More specifically, it has been surprisingly discovered that when the sense strand and antisense strand of the double-stranded RNAi agent are completely modified to have one or more motifs of three identical modifications on three consecutive nucleotides at or near the cleavage site of at least one strand of an RNAi agent, the gene silencing activity of the RNAi agent was superiorly enhanced. 
     Accordingly, the invention provides double-stranded RNAi agents capable of inhibiting the expression of a target gene (i.e., HDV gene) in vivo. The RNAi agent comprises a sense strand and an antisense strand. Each strand of the RNAi agent may range from 12-30 nucleotides in length. For example, each strand may be between 14-30 nucleotides in length, 17-30 nucleotides in length, 25-30 nucleotides in length, 27-30 nucleotides in length, 17-23 nucleotides in length, 17-21 nucleotides in length, 17-19 nucleotides in length, 19-25 nucleotides in length, 19-23 nucleotides in length, 19-21 nucleotides in length, 21-25 nucleotides in length, or 21-23 nucleotides in length. 
     The sense strand and antisense strand typically form a duplex double stranded RNA (“dsRNA”), also referred to herein as an “RNAi agent.” The duplex region of an RNAi agent may be 12-30 nucleotide pairs in length. For example, the duplex region can be between 14-30 nucleotide pairs in length, 17-30 nucleotide pairs in length, 27-30 nucleotide pairs in length, 17-23 nucleotide pairs in length, 17-21 nucleotide pairs in length, 17-19 nucleotide pairs in length, 19-25 nucleotide pairs in length, 19-23 nucleotide pairs in length, 19-21 nucleotide pairs in length, 21-25 nucleotide pairs in length, or 21-23 nucleotide pairs in length. In another example, the duplex region is selected from 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27 nucleotides in length. 
     In one embodiment, the RNAi agent may contain one or more overhang regions and/or capping groups at the 3′-end, 5′-end, or both ends of one or both strands. The overhang can be 1-6 nucleotides in length, for instance 2-6 nucleotides in length, 1-5 nucleotides in length, 2-5 nucleotides in length, 1-4 nucleotides in length, 2-4 nucleotides in length, 1-3 nucleotides in length, 2-3 nucleotides in length, or 1-2 nucleotides in length. The overhangs can be the result of one strand being longer than the other, or the result of two strands of the same length being staggered. The overhang can form a mismatch with the target mRNA or it can be complementary to the gene sequences being targeted or can be another sequence. The first and second strands can also be joined, e.g., by additional bases to form a hairpin, or by other non-base linkers. 
     In one embodiment, the nucleotides in the overhang region of the RNAi agent can each independently be a modified or unmodified nucleotide including, but no limited to 2′-sugar modified, such as, 2-F, 2′-Omethyl, thymidine (T), 2′-O-methoxyethyl-5-methyluridine (Teo), 2′-O-methoxyethyladenosine (Aeo), 2′-O-methoxyethyl-5-methylcytidine (m5Ceo), and any combinations thereof. For example, TT can be an overhang sequence for either end on either strand. The overhang can form a mismatch with the target mRNA or it can be complementary to the gene sequences being targeted or can be another sequence. 
     The 5′- or 3′-overhangs at the sense strand, antisense strand or both strands of the RNAi agent may be phosphorylated. In some embodiments, the overhang region(s) contains two nucleotides having a phosphorothioate between the two nucleotides, where the two nucleotides can be the same or different. In one embodiment, the overhang is present at the 3′-end of the sense strand, antisense strand, or both strands. In one embodiment, this 3′-overhang is present in the antisense strand. In one embodiment, this 3′-overhang is present in the sense strand. 
     The RNAi agent may contain only a single overhang, which can strengthen the interference activity of the RNAi, without affecting its overall stability. For example, the single-stranded overhang may be located at the 3′-terminal end of the sense strand or, alternatively, at the 3′-terminal end of the antisense strand. The RNAi may also have a blunt end, located at the 5′-end of the antisense strand (or the 3′-end of the sense strand) or vice versa. Generally, the antisense strand of the RNAi has a nucleotide overhang at the 3′-end, and the 5′-end is blunt. While not wishing to be bound by theory, the asymmetric blunt end at the 5′-end of the antisense strand and 3′-end overhang of the antisense strand favor the guide strand loading into RISC process. 
     In one embodiment, the RNAi agent is a double ended bluntmer of 19 nucleotides in length, wherein the sense strand contains at least one motif of three 2′-F modifications on three consecutive nucleotides at positions 7, 8, 9 from the 5′end. The antisense strand contains at least one motif of three 2′-O-methyl modifications on three consecutive nucleotides at positions 11, 12, 13 from the 5′end. 
     In another embodiment, the RNAi agent is a double ended bluntmer of 20 nucleotides in length, wherein the sense strand contains at least one motif of three 2′-F modifications on three consecutive nucleotides at positions 8, 9, 10 from the 5′end. The antisense strand contains at least one motif of three 2′-O-methyl modifications on three consecutive nucleotides at positions 11, 12, 13 from the 5′end. 
     In yet another embodiment, the RNAi agent is a double ended bluntmer of 21 nucleotides in length, wherein the sense strand contains at least one motif of three 2′-F modifications on three consecutive nucleotides at positions 9, 10, 11 from the 5′end. The antisense strand contains at least one motif of three 2′-O-methyl modifications on three consecutive nucleotides at positions 11, 12, 13 from the 5′end. 
     In one embodiment, the RNAi agent comprises a 21 nucleotide sense strand and a 23 nucleotide antisense strand, wherein the sense strand contains at least one motif of three 2′-F modifications on three consecutive nucleotides at positions 9, 10, 11 from the 5′end; the antisense strand contains at least one motif of three 2′-O-methyl modifications on three consecutive nucleotides at positions 11, 12, 13 from the 5′end, wherein one end of the RNAi agent is blunt, while the other end comprises a 2 nucleotide overhang. Preferably, the 2 nucleotide overhang is at the 3′-end of the antisense strand. 
     When the 2 nucleotide overhang is at the 3′-end of the antisense strand, there may be two phosphorothioate internucleotide linkages between the terminal three nucleotides, wherein two of the three nucleotides are the overhang nucleotides, and the third nucleotide is a paired nucleotide next to the overhang nucleotide. In one embodiment, the RNAi agent additionally has two phosphorothioate internucleotide linkages between the terminal three nucleotides at both the 5′-end of the sense strand and at the 5′-end of the antisense strand. In one embodiment, every nucleotide in the sense strand and the antisense strand of the RNAi agent, including the nucleotides that are part of the motifs are modified nucleotides. In one embodiment each residue is independently modified with a 2′-O-methyl or 3′-fluoro, e.g., in an alternating motif. Optionally, the RNAi agent further comprises a ligand (preferably GalNAc 3 ). 
     In one embodiment, the RNAi agent comprises a sense and an antisense strand, wherein the sense strand is 25-30 nucleotide residues in length, wherein starting from the 5′ terminal nucleotide (position 1) positions 1 to 23 of the first strand comprise at least 8 ribonucleotides; the antisense strand is 36-66 nucleotide residues in length and, starting from the 3′ terminal nucleotide, comprises at least 8 ribonucleotides in the positions paired with positions 1-23 of sense strand to form a duplex; wherein at least the 3′ terminal nucleotide of antisense strand is unpaired with sense strand, and up to 6 consecutive 3′ terminal nucleotides are unpaired with sense strand, thereby forming a 3′ single stranded overhang of 1-6 nucleotides; wherein the 5′ terminus of antisense strand comprises from 10-30 consecutive nucleotides which are unpaired with sense strand, thereby forming a 10-30 nucleotide single stranded 5′ overhang; wherein at least the sense strand 5′ terminal and 3′ terminal nucleotides are base paired with nucleotides of antisense strand when sense and antisense strands are aligned for maximum complementarity, thereby forming a substantially duplexed region between sense and antisense strands; and antisense strand is sufficiently complementary to a target RNA along at least 19 ribonucleotides of antisense strand length to reduce target gene expression when the double stranded nucleic acid is introduced into a mammalian cell; and wherein the sense strand contains at least one motif of three 2′-F modifications on three consecutive nucleotides, where at least one of the motifs occurs at or near the cleavage site. The antisense strand contains at least one motif of three 2′-O-methyl modifications on three consecutive nucleotides at or near the cleavage site. 
     In one embodiment, the RNAi agent comprises sense and antisense strands, wherein the RNAi agent comprises a first strand having a length which is at least 25 and at most 29 nucleotides and a second strand having a length which is at most 30 nucleotides with at least one motif of three 2′-O-methyl modifications on three consecutive nucleotides at position 11, 12, 13 from the 5′ end; wherein the 3′ end of the first strand and the 5′ end of the second strand form a blunt end and the second strand is 1-4 nucleotides longer at its 3′ end than the first strand, wherein the duplex region region which is at least 25 nucleotides in length, and the second strand is sufficiently complementary to a target mRNA along at least 19 nucleotide of the second strand length to reduce target gene expression when the RNAi agent is introduced into a mammalian cell, and wherein dicer cleavage of the RNAi agent preferentially results in an siRNA comprising the 3′ end of the second strand, thereby reducing expression of the target gene in the mammal. Optionally, the RNAi agent further comprises a ligand. 
     In one embodiment, the sense strand of the RNAi agent contains at least one motif of three identical modifications on three consecutive nucleotides, where one of the motifs occurs at the cleavage site in the sense strand. 
     In one embodiment, the antisense strand of the RNAi agent can also contain at least one motif of three identical modifications on three consecutive nucleotides, where one of the motifs occurs at or near the cleavage site in the antisense strand 
     For an RNAi agent having a duplex region of 17-23 nucleotide in length, the cleavage site of the antisense strand is typically around the 10, 11 and 12 positions from the 5′-end. Thus the motifs of three identical modifications may occur at the 9, 10, 11 positions; 10, 11, 12 positions; 11, 12, 13 positions; 12, 13, 14 positions; or 13, 14, 15 positions of the antisense strand, the count starting from the 1 st  nucleotide from the 5′-end of the antisense strand, or, the count starting from the 1 st  paired nucleotide within the duplex region from the 5′-end of the antisense strand. The cleavage site in the antisense strand may also change according to the length of the duplex region of the RNAi from the 5′-end. 
     The sense strand of the RNAi agent may contain at least one motif of three identical modifications on three consecutive nucleotides at the cleavage site of the strand; and the antisense strand may have at least one motif of three identical modifications on three consecutive nucleotides at or near the cleavage site of the strand. When the sense strand and the antisense strand form a dsRNA duplex, the sense strand and the antisense strand can be so aligned that one motif of the three nucleotides on the sense strand and one motif of the three nucleotides on the antisense strand have at least one nucleotide overlap, i.e., at least one of the three nucleotides of the motif in the sense strand forms a base pair with at least one of the three nucleotides of the motif in the antisense strand. Alternatively, at least two nucleotides may overlap, or all three nucleotides may overlap. 
     In one embodiment, the sense strand of the RNAi agent may contain more than one motif of three identical modifications on three consecutive nucleotides. The first motif may occur at or near the cleavage site of the strand and the other motifs may be a wing modification. The term “wing modification” herein refers to a motif occurring at another portion of the strand that is separated from the motif at or near the cleavage site of the same strand. The wing modification is either adjacent to the first motif or is separated by at least one or more nucleotides. When the motifs are immediately adjacent to each other then the chemistry of the motifs are distinct from each other and when the motifs are separated by one or more nucleotide than the chemistries can be the same or different. Two or more wing modifications may be present. For instance, when two wing modifications are present, each wing modification may occur at one end relative to the first motif which is at or near cleavage site or on either side of the lead motif. 
     Like the sense strand, the antisense strand of the RNAi agent may contain more than one motifs of three identical modifications on three consecutive nucleotides, with at least one of the motifs occurring at or near the cleavage site of the strand. This antisense strand may also contain one or more wing modifications in an alignment similar to the wing modifications that may be present on the sense strand. 
     In one embodiment, the wing modification on the sense strand or antisense strand of the RNAi agent typically does not include the first one or two terminal nucleotides at the 3′-end, 5′-end or both ends of the strand. 
     In another embodiment, the wing modification on the sense strand or antisense strand of the RNAi agent typically does not include the first one or two paired nucleotides within the duplex region at the 3′-end, 5′-end or both ends of the strand. 
     When the sense strand and the antisense strand of the RNAi agent each contain at least one wing modification, the wing modifications may fall on the same end of the duplex region, and have an overlap of one, two or three nucleotides. 
     When the sense strand and the antisense strand of the RNAi agent each contain at least two wing modifications, the sense strand and the antisense strand can be so aligned that two modifications each from one strand fall on one end of the duplex region, having an overlap of one, two or three nucleotides; two modifications each from one strand fall on the other end of the duplex region, having an overlap of one, two or three nucleotides; two modifications one strand fall on each side of the lead motif, having an overlap of one, two or three nucleotides in the duplex region. 
     In one embodiment, every nucleotide in the sense strand and antisense strand of the RNAi agent, including the nucleotides that are part of the motifs, may be modified. Each nucleotide may be modified with the same or different modification which can include one or more alteration of one or both of the non-linking phosphate oxygens and/or of one or more of the linking phosphate oxygens; alteration of a constituent of the ribose sugar, e.g., of the 2′ hydroxyl on the ribose sugar; wholesale replacement of the phosphate moiety with “dephospho” linkers; modification or replacement of a naturally occurring base; and replacement or modification of the ribose-phosphate backbone. 
     As nucleic acids are polymers of subunits, many of the modifications occur at a position which is repeated within a nucleic acid, e.g., a modification of a base, or a phosphate moiety, or a non-linking O of a phosphate moiety. In some cases the modification will occur at all of the subject positions in the nucleic acid but in many cases it will not. By way of example, a modification may only occur at a 3′ or 5′ terminal position, may only occur in a terminal region, e.g., at a position on a terminal nucleotide or in the last 2, 3, 4, 5, or 10 nucleotides of a strand. A modification may occur in a double strand region, a single strand region, or in both. A modification may occur only in the double strand region of a RNA or may only occur in a single strand region of a RNA. For example, a phosphorothioate modification at a non-linking O position may only occur at one or both termini, may only occur in a terminal region, e.g., at a position on a terminal nucleotide or in the last 2, 3, 4, 5, or 10 nucleotides of a strand, or may occur in double strand and single strand regions, particularly at termini. The 5′ end or ends can be phosphorylated. 
     It may be possible, e.g., to enhance stability, to include particular bases in overhangs, or to include modified nucleotides or nucleotide surrogates, in single strand overhangs, e.g., in a 5′ or 3′ overhang, or in both. For example, it can be desirable to include purine nucleotides in overhangs. In some embodiments all or some of the bases in a 3′ or 5′ overhang may be modified, e.g., with a modification described herein. Modifications can include, e.g., the use of modifications at the 2′ position of the ribose sugar with modifications that are known in the art, e.g., the use of deoxyribonucleotides, 2′-deoxy-2′-fluoro (2′-F) or 2′-O-methyl modified instead of the ribosugar of the nucleobase, and modifications in the phosphate group, e.g., phosphorothioate modifications. Overhangs need not be homologous with the target sequence. 
     In one embodiment, each residue of the sense strand and antisense strand is independently modified with LNA, CRN, cET, UNA, HNA, CeNA, 2′-methoxyethyl, 2′-O-methyl, 2′-O-allyl, 2′-C-allyl, 2′-deoxy, 2′-hydroxyl, or 2′-fluoro. The strands can contain more than one modification. In one embodiment, each residue of the sense strand and antisense strand is independently modified with 2′-O-methyl or 2′-fluoro. 
     At least two different modifications are typically present on the sense strand and antisense strand. Those two modifications may be the 2′-O-methyl or 2′-fluoro modifications, or others. 
     In one embodiment, the N a  and/or N b  comprise modifications of an alternating pattern. The term “alternating motif” as used herein refers to a motif having one or more modifications, each modification occurring on alternating nucleotides of one strand. The alternating nucleotide may refer to one per every other nucleotide or one per every three nucleotides, or a similar pattern. For example, if A, B and C each represent one type of modification to the nucleotide, the alternating motif can be “ABABABABABAB . . . ,” “AABBAABBAABB . . . ,” “AABAABAABAAB . . . ,” “AAABAAABAAAB . . . ,” “AAABBBAAABBB . . . ,” or “ABCABCABCABC . . . ,” etc. 
     The type of modifications contained in the alternating motif may be the same or different. For example, if A, B, C, D each represent one type of modification on the nucleotide, the alternating pattern, i.e., modifications on every other nucleotide, may be the same, but each of the sense strand or antisense strand can be selected from several possibilities of modifications within the alternating motif such as “ABABAB . . . ”, “ACACAC . . . ” “BDBDBD . . . ” or “CDCDCD . . . ,” etc. 
     In one embodiment, the RNAi agent of the invention comprises the modification pattern for the alternating motif on the sense strand relative to the modification pattern for the alternating motif on the antisense strand is shifted. The shift may be such that the modified group of nucleotides of the sense strand corresponds to a differently modified group of nucleotides of the antisense strand and vice versa. For example, the sense strand when paired with the antisense strand in the dsRNA duplex, the alternating motif in the sense strand may start with “ABABAB” from 5′-3′ of the strand and the alternating motif in the antisense strand may start with “BABABA” from 5′-3′ of the strand within the duplex region. As another example, the alternating motif in the sense strand may start with “AABBAABB” from 5′-3′ of the strand and the alternating motif in the antisense strand may start with “BBAABBAA” from 5′-3′ of the strand within the duplex region, so that there is a complete or partial shift of the modification patterns between the sense strand and the antisense strand. 
     In one embodiment, the RNAi agent comprises the pattern of the alternating motif of 2′-O-methyl modification and 2′-F modification on the sense strand initially has a shift relative to the pattern of the alternating motif of 2′-O-methyl modification and 2′-F modification on the antisense strand initially, i.e., the 2′-O-methyl modified nucleotide on the sense strand base pairs with a 2′-F modified nucleotide on the antisense strand and vice versa. The 1 position of the sense strand may start with the 2′-F modification, and the 1 position of the antisense strand may start with the 2′-O-methyl modification. 
     The introduction of one or more motifs of three identical modifications on three consecutive nucleotides to the sense strand and/or antisense strand interrupts the initial modification pattern present in the sense strand and/or antisense strand. This interruption of the modification pattern of the sense and/or antisense strand by introducing one or more motifs of three identical modifications on three consecutive nucleotides to the sense and/or antisense strand surprisingly enhances the gene silencing activity to the target gene. 
     In one embodiment, when the motif of three identical modifications on three consecutive nucleotides is introduced to any of the strands, the modification of the nucleotide next to the motif is a different modification than the modification of the motif. For example, the portion of the sequence containing the motif is “ . . . N a YYYN b  . . . ,” where “Y” represents the modification of the motif of three identical modifications on three consecutive nucleotide, and “N a ” and “N b ” represent a modification to the nucleotide next to the motif “YYY” that is different than the modification of Y, and where N a  and N b  can be the same or different modifications. Alternatively, N a  and/or N b  may be present or absent when there is a wing modification present. 
     The RNAi agent may further comprise at least one phosphorothioate or methylphosphonate internucleotide linkage. The phosphorothioate or methylphosphonate internucleotide linkage modification may occur on any nucleotide of the sense strand or antisense strand or both strands in any position of the strand. For instance, the internucleotide linkage modification may occur on every nucleotide on the sense strand and/or antisense strand; each internucleotide linkage modification may occur in an alternating pattern on the sense strand and/or antisense strand; or the sense strand or antisense strand may contain both internucleotide linkage modifications in an alternating pattern. The alternating pattern of the internucleotide linkage modification on the sense strand may be the same or different from the antisense strand, and the alternating pattern of the internucleotide linkage modification on the sense strand may have a shift relative to the alternating pattern of the internucleotide linkage modification on the antisense strand. In one embodiment, a double-stranded RNAi agent comprises 6-8phosphorothioate internucleotide linkages. In one embodiment, the antisense strand comprises two phosphorothioate internucleotide linkages at the 5′-terminus and two phosphorothioate internucleotide linkages at the 3′-terminus, and the sense strand comprises at least two phosphorothioate internucleotide linkages at either the 5′-terminus or the 3′-terminus. 
     In one embodiment, the RNAi comprises a phosphorothioate or methylphosphonate internucleotide linkage modification in the overhang region. For example, the overhang region may contain two nucleotides having a phosphorothioate or methylphosphonate internucleotide linkage between the two nucleotides. Internucleotide linkage modifications also may be made to link the overhang nucleotides with the terminal paired nucleotides within the duplex region. For example, at least 2, 3, 4, or all the overhang nucleotides may be linked through phosphorothioate or methylphosphonate internucleotide linkage, and optionally, there may be additional phosphorothioate or methylphosphonate internucleotide linkages linking the overhang nucleotide with a paired nucleotide that is next to the overhang nucleotide. For instance, there may be at least two phosphorothioate internucleotide linkages between the terminal three nucleotides, in which two of the three nucleotides are overhang nucleotides, and the third is a paired nucleotide next to the overhang nucleotide. These terminal three nucleotides may be at the 3′-end of the antisense strand, the 3′-end of the sense strand, the 5′-end of the antisense strand, and/or the 5′end of the antisense strand. 
     In one embodiment, the 2 nucleotide overhang is at the 3′-end of the antisense strand, and there are two phosphorothioate internucleotide linkages between the terminal three nucleotides, wherein two of the three nucleotides are the overhang nucleotides, and the third nucleotide is a paired nucleotide next to the overhang nucleotide. Optionally, the RNAi agent may additionally have two phosphorothioate internucleotide linkages between the terminal three nucleotides at both the 5′-end of the sense strand and at the 5′-end of the antisense strand. 
     In one embodiment, the RNAi agent comprises mismatch(es) with the target, within the duplex, or combinations thereof. The mismatch may occur in the overhang region or the duplex region. The base pair may be ranked on the basis of their propensity to promote dissociation or melting (e.g., on the free energy of association or dissociation of a particular pairing, the simplest approach is to examine the pairs on an individual pair basis, though next neighbor or similar analysis can also be used). In terms of promoting dissociation: A:U is preferred over G:C; G:U is preferred over G:C; and I:C is preferred over G:C (I=inosine). Mismatches, e.g., non-canonical or other than canonical pairings (as described elsewhere herein) are preferred over canonical (A:T, A:U, G:C) pairings; and pairings which include a universal base are preferred over canonical pairings. 
     In one embodiment, the RNAi agent comprises at least one of the first 1, 2, 3, 4, or 5 base pairs within the duplex regions from the 5′-end of the antisense strand independently selected from the group of: A:U, G:U, I:C, and mismatched pairs, e.g., non-canonical or other than canonical pairings or pairings which include a universal base, to promote the dissociation of the antisense strand at the 5′-end of the duplex. 
     In one embodiment, the nucleotide at the 1 position within the duplex region from the 5′-end in the antisense strand is selected from the group consisting of A, dA, dU, U, and dT. Alternatively, at least one of the first 1, 2 or 3 base pair within the duplex region from the 5′-end of the antisense strand is an AU base pair. For example, the first base pair within the duplex region from the 5′-end of the antisense strand is an AU base pair. 
     In another embodiment, the nucleotide at the 3′-end of the sense strand is deoxy-thymine (dT). In another embodiment, the nucleotide at the 3′-end of the antisense strand is deoxy-thymine (dT). In one embodiment, there is a short sequence of deoxy-thymine nucleotides, for example, two dT nucleotides on the 3′-end of the sense and/or antisense strand. 
     In one embodiment, the sense strand sequence may be represented by formula (I): 
     
       
         
           
               
               
            
               
                   
                 (I) 
               
               
                   
                 5′ n p -N a -(XXX) i -N b -YYY-N b -(ZZZ) j -N a -n q  3′ 
               
            
           
         
       
     
     wherein: 
     i and j are each independently 0 or 1; 
     p and q are each independently 0-6; 
     each N a  independently represents an oligonucleotide sequence comprising 0-25 modified nucleotides, each sequence comprising at least two differently modified nucleotides; 
     each N b  independently represents an oligonucleotide sequence comprising 0-10 modified nucleotides; 
     each n p  and n q  independently represent an overhang nucleotide; 
     wherein Nb and Y do not have the same modification; and 
     XXX, YYY and ZZZ each independently represent one motif of three identical modifications on three consecutive nucleotides. Preferably YYY is all 2′-F modified nucleotides. 
     In one embodiment, the N a  and/or N b  comprise modifications of alternating pattern. 
     In one embodiment, the YYY motif occurs at or near the cleavage site of the sense strand. For example, when the RNAi agent has a duplex region of 17-23 nucleotides in length, the YYY motif can occur at or the vicinity of the cleavage site (e.g.: can occur at positions 6, 7, 8, 7, 8, 9, 8, 9, 10, 9, 10, 11, 10, 11, 12 or 11, 12, 13) of—the sense strand, the count starting from the 1 st  nucleotide, from the 5′-end; or optionally, the count starting at the 1 st  paired nucleotide within the duplex region, from the 5′-end. 
     In one embodiment, i is 1 and j is 0, or i is 0 and j is 1, or both i and j are 1. The sense strand can therefore be represented by the following formulas: 
     
       
         
           
               
               
            
               
                   
                 (Ib) 
               
               
                   
                 5′ n p -N a -YYY-N b -ZZZ-N a -n q  3′; 
               
               
                   
                   
               
               
                   
                 (Ic) 
               
               
                   
                 5′ n p -N a -XXX-N b -YYY-N a -n q  3′; 
               
               
                   
                 or 
               
               
                   
                   
               
               
                   
                 (Id) 
               
               
                   
                 5′ n p -N a -XXX-N b -YYY-N b -ZZZ-N a -n q  3′. 
               
            
           
         
       
     
     When the sense strand is represented by formula (Ib), N b  represents an oligonucleotide sequence comprising 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each N a  independently can represent an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     When the sense strand is represented as formula (Ic), N b  represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each N a  can independently represent an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     When the sense strand is represented as formula (Id), each N b  independently represents an oligonucleotide sequence comprising 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Preferably, N b  is 0, 1, 2, 3, 4, 5 or 6 Each N a  can independently represent an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     Each of X, Y and Z may be the same or different from each other. 
     In other embodiments, i is 0 and j is 0, and the sense strand may be represented by the formula: 
     
       
         
           
               
               
            
               
                   
                 (Ia) 
               
               
                   
                 5′ n p -N a -YYY-N a -n q  3′. 
               
            
           
         
       
     
     When the sense strand is represented by formula (Ia), each N a  independently can represent an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     In one embodiment, the antisense strand sequence of the RNAi may be represented by formula (II): 
     
       
         
           
               
            
               
                 (II) 
               
               
                 5′ n q′ -N a ′-(Z′Z′Z′) k -N b ′-Y′Y′Y′-N b ′-(X′X′X′) 1 -N′ a - 
               
               
                   
               
               
                 n p ′ 3&#39; 
               
            
           
         
       
     
     wherein: 
     k and l are each independently 0 or 1; 
     p′ and q′ are each independently 0-6; 
     each N a ′ independently represents an oligonucleotide sequence comprising 0-25 modified nucleotides, each sequence comprising at least two differently modified nucleotides; 
     each N b ′ independently represents an oligonucleotide sequence comprising 0-10 modified nucleotides; 
     each n p ′ and n q ′ independently represent an overhang nucleotide; 
     wherein N b ′ and Y′ do not have the same modification; and 
     X′X′X′, Y′Y′Y′ and Z′Z′Z′ each independently represent one motif of three identical modifications on three consecutive nucleotides. 
     In one embodiment, the N a ′ and/or N b ′ comprise modifications of alternating pattern. 
     The Y′Y′Y′ motif occurs at or near the cleavage site of the antisense strand. For example, when the RNAi agent has a duplex region of 17-23 nucleotide in length, the Y′Y′Y′ motif can occur at positions 9, 10, 11; 10, 11, 12; 11, 12, 13; 12, 13, 14; or 13, 14, 15 of the antisense strand, with the count starting from the 1 st  nucleotide, from the 5′-end; or optionally, the count starting at the 1 st  paired nucleotide within the duplex region, from the 5′-end. Preferably, the Y′Y′Y′ motif occurs at positions 11, 12, 13. 
     In one embodiment, Y′Y′Y′ motif is all 2′-OMe modified nucleotides. 
     In one embodiment, k is 1 and l is 0, or k is 0 and l is 1, or both k and l are 1. 
     The antisense strand can therefore be represented by the following formulas: 
     
       
         
           
               
            
               
                 (IIb) 
               
               
                 5′ n q′ -N a ′-Z′Z′Z′-N b ′-Y′Y′Y′-N a ′-n p′  3′; 
               
               
                   
               
               
                 (IIc) 
               
               
                 5′ n q′ -N a ′-Y′Y′Y′-N b ′-X′X′X′-n p′ 3′; 
               
               
                 or 
               
               
                   
               
               
                 (IId) 
               
               
                 5′ n q′ -N a ′-Z′Z′Z′-N b ′-Y′Y′Y′-N b ′-X′X′X′-N a ′-n p′  3′. 
               
            
           
         
       
     
     When the antisense strand is represented by formula (IIb), N b ′ represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each N a ′ independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     When the antisense strand is represented as formula (IIc), N b ′ represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each N a ′ independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     When the antisense strand is represented as formula (IId), each N b ′ independently represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each N a ′ independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. Preferably, N b  is 0, 1, 2, 3, 4, 5 or 6. 
     In other embodiments, k is 0 and l is 0 and the antisense strand may be represented by the formula: 
     
       
         
           
               
               
            
               
                   
                 (Ia) 
               
               
                   
                 5′ n p′ -N a′ -Y′Y′Y′-N a′ -n q′  3′. 
               
            
           
         
       
     
     When the antisense strand is represented as formula (IIa), each N a ′ independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     Each of X′, Y′ and Z′ may be the same or different from each other.
 
Each nucleotide of the sense strand and antisense strand may be independently modified with LNA, CRN, UNA, cEt, HNA, CeNA, 2′-methoxyethyl, 2′-O-methyl, 2′-O-allyl, 2′-C-allyl, 2′-hydroxyl, or 2′-fluoro. For example, each nucleotide of the sense strand and antisense strand is independently modified with 2′-O-methyl or 2′-fluoro. Each X, Y, Z, X′, Y′ and Z′, in particular, may represent a 2′-O-methyl modification or a 2′-fluoro modification.
 
     In one embodiment, the sense strand of the RNAi agent may contain YYY motif occurring at 9, 10 and 11 positions of the strand when the duplex region is 21 nt, the count starting from the 1 st  nucleotide from the 5′-end, or optionally, the count starting at the 1 st  paired nucleotide within the duplex region, from the 5′-end; and Y represents 2′-F modification. The sense strand may additionally contain XXX motif or ZZZ motifs as wing modifications at the opposite end of the duplex region; and XXX and ZZZ each independently represents a 2′-OMe modification or 2′-F modification. 
     In one embodiment the antisense strand may contain Y′Y′Y′ motif occurring at positions 11, 12, 13 of the strand, the count starting from the 1 st  nucleotide from the 5′-end, or optionally, the count starting at the 1 st  paired nucleotide within the duplex region, from the 5′-end; and Y′ represents 2′-O-methyl modification. The antisense strand may additionally contain X′X′X′ motif or Z′Z′Z′ motifs as wing modifications at the opposite end of the duplex region; and X′X′X′ and Z′Z′Z′ each independently represents a 2′-OMe modification or 2′-F modification. 
     The sense strand represented by any one of the above formulas (Ia), (Ib), (Ic), and (Id) forms a duplex with a antisense strand being represented by any one of formulas (IIa), (IIb), (IIc), and (IId), respectively. 
     Accordingly, the RNAi agents for use in the methods of the invention may comprise a sense strand and an antisense strand, each strand having 14 to 30 nucleotides, the RNAi duplex represented by formula (III): 
     
       
         
           
               
            
               
                 (III) 
               
               
                 sense: 
               
               
                 5′ n p -N a -(XXX) i -N b -YYY-N b -(ZZZ) j -N a -n q  3&#39; 
               
               
                   
               
               
                 antisense: 
               
               
                 3′ n p ′-N a ′-(X′X′X′) k -N b ′-Y′Y′Y′-N b ′-(Z′Z′Z′) 1 -N a ′- 
               
               
                   
               
               
                 n q ′ 5′ 
               
            
           
         
       
     
     wherein: 
     i, j, k, and l are each independently 0 or 1; 
     p, p′, q, and q′ are each independently 0-6; 
     each N a  and N a ′ independently represents an oligonucleotide sequence comprising 0-25 modified nucleotides, each sequence comprising at least two differently modified nucleotides; 
     each N b  and N b ′ independently represents an oligonucleotide sequence comprising 0-10 modified nucleotides; 
     wherein each n p ′, n p , n q ′, and n q , each of which may or may not be present, independently represents an overhang nucleotide; and 
     XXX, YYY, ZZZ, X′X′X′, Y′Y′Y′, and Z′Z′Z′ each independently represent one motif of three identical modifications on three consecutive nucleotides. 
     In one embodiment, i is 0 and j is 0; or i is 1 and j is 0; or i is 0 and j is 1; or both i and j are 0; or both i and j are 1. In another embodiment, k is 0 and l is 0; or k is 1 and l is 0; k is 0 and l is 1; or both k and l are 0; or both k and l are 1. 
     Exemplary combinations of the sense strand and antisense strand forming a RNAi duplex include the formulas below: 
     
       
         
           
               
            
               
                 (IIIa) 
               
               
                 5′ n p -N a -YYY-N a -n q  3′ 
               
               
                   
               
               
                 3′ n p ′-N a ′-Y′Y′Y′-N a ′n q ′ 5′ 
               
               
                   
               
               
                 (IIIb) 
               
               
                 5′ n p -N a -YYY-N b -ZZZ-N a -n q  3′ 
               
               
                   
               
               
                 3′ n p ′-N a ′-Y′Y′Y′-N b &#39;-Z′Z′Z′-N a ′n q ′ 5′ 
               
               
                   
               
               
                 (IIIc) 
               
               
                 5′ n p -N a -XXX-N b -YYY-N a -n q  3′ 
               
               
                   
               
               
                 3′ n p ′-N a ′-X′X′X′-N b ′-Y′Y′Y′-N a ′-n q ′ 5′ 
               
               
                   
               
               
                 (IIId) 
               
               
                 5′ n p -N a -XXX-N b -YYY-N b -ZZZ-N a -n q  3&#39; 
               
               
                   
               
               
                 3′ n p ′-N a ′-X′X′X′-N b ′-Y′Y′Y′-N b ′-Z′Z′Z′-N a -n q ′ 5′ 
               
            
           
         
       
     
     When the RNAi agent is represented by formula (IIIa), each N a  independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     When the RNAi agent is represented by formula (IIIb), each N b  independently represents an oligonucleotide sequence comprising 1-10, 1-7, 1-5 or 1-4 modified nucleotides. Each N a  independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     When the RNAi agent is represented as formula (IIIc), each N b , N b ′ independently represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each N a  independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. 
     When the RNAi agent is represented as formula (IIId), each N b , N b ′ independently represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each N a , N a ′ independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. Each of N a , N a ′, N b  and N b ′ independently comprises modifications of alternating pattern. 
     Each of X, Y and Z in formulas (III), (IIIa), (IIIb), (IIIc), and (IIId) may be the same or different from each other. 
     When the RNAi agent is represented by formula (III), (IIIa), (IIIb), (IIIc), and (IIId), at least one of the Y nucleotides may form a base pair with one of the Y′ nucleotides. Alternatively, at least two of the Y nucleotides form base pairs with the corresponding Y′ nucleotides; or all three of the Y nucleotides all form base pairs with the corresponding Y′ nucleotides. 
     When the RNAi agent is represented by formula (IIIb) or (IIId), at least one of the Z nucleotides may form a base pair with one of the Z′ nucleotides. Alternatively, at least two of the Z nucleotides form base pairs with the corresponding Z′ nucleotides; or all three of the Z nucleotides all form base pairs with the corresponding Z′ nucleotides. 
     When the RNAi agent is represented as formula (IIIc) or (IIId), at least one of the X nucleotides may form a base pair with one of the X′ nucleotides. Alternatively, at least two of the X nucleotides form base pairs with the corresponding X′ nucleotides; or all three of the X nucleotides all form base pairs with the corresponding X′ nucleotides. 
     In one embodiment, the modification on the Y nucleotide is different than the modification on the Y′ nucleotide, the modification on the Z nucleotide is different than the modification on the Z′ nucleotide, and/or the modification on the X nucleotide is different than the modification on the X′ nucleotide. 
     In one embodiment, when the RNAi agent is represented by formula (IIId), the N a  modifications are 2′-O-methyl or 2′-fluoro modifications. In another embodiment, when the RNAi agent is represented by formula (IIId), the N a  modifications are 2′-O-methyl or 2′-fluoro modifications and n p ′&gt;0 and at least one n p ′ is linked to a neighboring nucleotide a via phosphorothioate linkage. In yet another embodiment, when the RNAi agent is represented by formula (IIId), the N a  modifications are 2′-O-methyl or 2′-fluoro modifications, n p ′&gt;0 and at least one n p ′ is linked to a neighboring nucleotide via phosphorothioate linkage, and the sense strand is conjugated to one or more GalNAc derivatives attached through a bivalent or trivalent branched linker (described below). In another embodiment, when the RNAi agent is represented by formula (IIId), the N a  modifications are 2′-O-methyl or 2′-fluoro modifications, n p ′&gt;0 and at least one n p ′ is linked to a neighboring nucleotide via phosphorothioate linkage, the sense strand comprises at least one phosphorothioate linkage, and the sense strand is conjugated to one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In one embodiment, when the RNAi agent is represented by formula (IIIa), the N a  modifications are 2′-O-methyl or 2′-fluoro modifications, n p ′&gt;0 and at least one n p ′ is linked to a neighboring nucleotide via phosphorothioate linkage, the sense strand comprises at least one phosphorothioate linkage, and the sense strand is conjugated to one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. 
     In one embodiment, the RNAi agent is a multimer containing at least two duplexes represented by formula (III), (IIIa), (IIIb), (IIIc), and (IIId), wherein the duplexes are connected by a linker. The linker can be cleavable or non-cleavable. Optionally, the multimer further comprises a ligand. Each of the duplexes can target the same gene or two different genes; or each of the duplexes can target same gene at two different target sites. 
     In one embodiment, the RNAi agent is a multimer containing three, four, five, six or more duplexes represented by formula (III), (IIIa), (IIIb), (IIIc), and (IIId), wherein the duplexes are connected by a linker. The linker can be cleavable or non-cleavable. Optionally, the multimer further comprises a ligand. Each of the duplexes can target the same gene or two different genes; or each of the duplexes can target same gene at two different target sites. 
     In one embodiment, two RNAi agents represented by formula (III), (IIIa), (IIIb), (IIIc), and (IIId) are linked to each other at the 5′ end, and one or both of the 3′ ends and are optionally conjugated to to a ligand. Each of the agents can target the same gene or two different genes; or each of the agents can target same gene at two different target sites. 
     Various publications describe multimeric RNAi agents that can be used in the methods of the invention. Such publications include WO2007/091269, U.S. Pat. No. 7,858,769, WO2010/141511, WO2007/117686, WO2009/014887 and WO2011/031520 the entire contents of each of which are hereby incorporated herein by reference. 
     As described in more detail below, the RNAi agent that contains conjugations of one or more carbohydrate moieties to a RNAi agent can optimize one or more properties of the RNAi agent. In many cases, the carbohydrate moiety will be attached to a modified subunit of the RNAi agent. For example, the ribose sugar of one or more ribonucleotide subunits of a dsRNA agent can be replaced with another moiety, e.g., a non-carbohydrate (preferably cyclic) carrier to which is attached a carbohydrate ligand. A ribonucleotide subunit in which the ribose sugar of the subunit has been so replaced is referred to herein as a ribose replacement modification subunit (RRMS). A cyclic carrier may be a carbocyclic ring system, i.e., all ring atoms are carbon atoms, or a heterocyclic ring system, i.e., one or more ring atoms may be a heteroatom, e.g., nitrogen, oxygen, sulfur. The cyclic carrier may be a monocyclic ring system, or may contain two or more rings, e.g. fused rings. The cyclic carrier may be a fully saturated ring system, or it may contain one or more double bonds. 
     The ligand may be attached to the polynucleotide via a carrier. The carriers include (i) at least one “backbone attachment point,” preferably two “backbone attachment points” and (ii) at least one “tethering attachment point.” A “backbone attachment point” as used herein refers to a functional group, e.g. a hydroxyl group, or generally, a bond available for, and that is suitable for incorporation of the carrier into the backbone, e.g., the phosphate, or modified phosphate, e.g., sulfur containing, backbone, of a ribonucleic acid. A “tethering attachment point” (TAP) in some embodiments refers to a constituent ring atom of the cyclic carrier, e.g., a carbon atom or a heteroatom (distinct from an atom which provides a backbone attachment point), that connects a selected moiety. The moiety can be, e.g., a carbohydrate, e.g. monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide and polysaccharide. Optionally, the selected moiety is connected by an intervening tether to the cyclic carrier. Thus, the cyclic carrier will often include a functional group, e.g., an amino group, or generally, provide a bond, that is suitable for incorporation or tethering of another chemical entity, e.g., a ligand to the constituent ring. 
     The RNAi agents may be conjugated to a ligand via a carrier, wherein the carrier can be cyclic group or acyclic group; preferably, the cyclic group is selected from pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3]dioxolane, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuryl and and decalin; preferably, the acyclic group is selected from serinol backbone or diethanolamine backbone. 
     In certain specific embodiments, the RNAi agent for use in the methods of the invention is an agent selected from the group of agents listed in any one of Tables 11, 12, 31, and 32. These agents may further comprise a ligand. In one embodiment, the agent is selected from the group consisting of AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1. In another embodiment, the agent is selected from the group consisting of AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, or AD-70295.1. 
     IV. iRNAs Conjugated to Ligands 
     Another modification of the RNA of an iRNA of the invention involves chemically linking to the RNA one or more ligands, moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the iRNA. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al.,  Proc. Natl. Acid. Sci. USA,  1989, 86: 6553-6556), cholic acid (Manoharan et al.,  Biorg. Med. Chem. Let.,  1994, 4:1053-1060), a thioether, e.g., beryl-S-tritylthiol (Manoharan et al.,  Ann. N.Y. Acad. Sci.,  1992, 660:306-309; Manoharan et al.,  Biorg. Med. Chem. Let.,  1993, 3:2765-2770), a thiocholesterol (Oberhauser et al.,  Nucl. Acids Res.,  1992, 20:533-538), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al.,  EMBO J,  1991, 10:1111-1118; Kabanov et al.,  FEBS Lett.,  1990, 259:327-330; Svinarchuk et al.,  Biochimie,  1993, 75:49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium 1,2-di-O-hexadecyl-rac-glycero-3-phosphonate (Manoharan et al.,  Tetrahedron Lett.,  1995, 36:3651-3654; Shea et al.,  Nucl. Acids Res.,  1990, 18:3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al.,  Nucleosides  &amp;  Nucleotides,  1995, 14:969-973), or adamantane acetic acid (Manoharan et al.,  Tetrahedron Lett.,  1995, 36:3651-3654), a palmityl moiety (Mishra et al.,  Biochim. Biophys. Acta,  1995, 1264:229-237), or an octadecylamine or hexylamino-carbonyloxycholesterol moiety (Crooke et al.,  J. Pharmacol. Exp. Ther.,  1996, 277:923-937). 
     In one embodiment, a ligand alters the distribution, targeting or lifetime of an iRNA agent into which it is incorporated. In preferred embodiments a ligand provides an enhanced affinity for a selected target, e.g., molecule, cell or cell type, compartment, e.g., a cellular or organ compartment, tissue, organ or region of the body, as, e.g., compared to a species absent such a ligand. Preferred ligands will not take part in duplex pairing in a duplexed nucleic acid. 
     Ligands can include a naturally occurring substance, such as a protein (e.g., human serum albumin (HSA), low-density lipoprotein (LDL), or globulin); carbohydrate (e.g., a dextran, pullulan, chitin, chitosan, inulin, cyclodextrin, N-acetylgalactosamine, or hyaluronic acid); or a lipid. The ligand can also be a recombinant or synthetic molecule, such as a synthetic polymer, e.g., a synthetic polyamino acid. Examples of polyamino acids include polyamino acid is a polylysine (PLL), poly L-aspartic acid, poly L-glutamic acid, styrene-maleic acid anhydride copolymer, poly(L-lactide-co-glycolide) copolymer, divinyl ether-maleic anhydride copolymer, N-(2-hydroxypropyl)methacrylamide copolymer (HMPA), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyurethane, poly(2-ethylacryllic acid), N-isopropylacrylamide polymers, or polyphosphazine. Example of polyamines include: polyethylenimine, polylysine (PLL), spermine, spermidine, polyamine, pseudopeptide-polyamine, peptidomimetic polyamine, dendrimer polyamine, arginine, amidine, protamine, cationic lipid, cationic porphyrin, quaternary salt of a polyamine, or an alpha helical peptide. 
     Ligands can also include targeting groups, e.g., a cell or tissue targeting agent, e.g., a lectin, glycoprotein, lipid or protein, e.g., an antibody, that binds to a specified cell type such as a kidney cell. A targeting group can be a thyrotropin, melanotropin, lectin, glycoprotein, surfactant protein A, Mucin carbohydrate, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-gulucoseamine multivalent mannose, multivalent fucose, glycosylated polyaminoacids, multivalent galactose, transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, vitamin A, biotin, or an RGD peptide or RGD peptide mimetic. 
     Other examples of ligands include dyes, intercalating agents (e.g. acridines), cross-linkers (e.g. psoralene, mitomycin C), porphyrins (TPPC4, texaphyrin, Sapphyrin), polycyclic aromatic hydrocarbons (e.g., phenazine, dihydrophenazine), artificial endonucleases (e.g. EDTA), lipophilic molecules, e.g., cholesterol, cholic acid, adamantane acetic acid, 1-pyrene butyric acid, dihydrotestosterone, 1,3-Bis-O(hexadecyl)glycerol, geranyloxyhexyl group, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid,O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethoxytrityl, or phenoxazine) and peptide conjugates (e.g., antennapedia peptide, Tat peptide), alkylating agents, phosphate, amino, mercapto, PEG (e.g., PEG-40K), MPEG, [MPEG] 2 , polyamino, alkyl, substituted alkyl, radiolabeled markers, enzymes, haptens (e.g. biotin), transport/absorption facilitators (e.g., aspirin, vitamin E, folic acid), synthetic ribonucleases (e.g., imidazole, bisimidazole, histamine, imidazole clusters, acridine-imidazole conjugates, Eu3+ complexes of tetraazamacrocycles), dinitrophenyl, HRP, or AP. 
     Ligands can be proteins, e.g., glycoproteins, or peptides, e.g., molecules having a specific affinity for a co-ligand, or antibodies e.g., an antibody, that binds to a specified cell type such as a hepatic cell. Ligands can also include hormones and hormone receptors. They can also include non-peptidic species, such as lipids, lectins, carbohydrates, vitamins, cofactors, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-gulucosamine multivalent mannose, or multivalent fucose. The ligand can be, for example, a lipopolysaccharide, an activator of p38 MAP kinase, or an activator of NF-κB. 
     The ligand can be a substance, e.g., a drug, which can increase the uptake of the iRNA agent into the cell, for example, by disrupting the cell&#39;s cytoskeleton, e.g., by disrupting the cell&#39;s microtubules, microfilaments, and/or intermediate filaments. The drug can be, for example, taxon, vincristine, vinblastine, cytochalasin, nocodazole, japlakinolide, latrunculin A, phalloidin, swinholide A, indanocine, or myoservin. 
     In some embodiments, a ligand attached to an iRNA as described herein acts as a pharmacokinetic modulator (PK modulator). PK modulators include lipophiles, bile acids, steroids, phospholipid analogues, peptides, protein binding agents, PEG, vitamins etc. Exemplary PK modulators include, but are not limited to, cholesterol, fatty acids, cholic acid, lithocholic acid, dialkylglycerides, diacylglyceride, phospholipids, sphingolipids, naproxen, ibuprofen, vitamin E, biotin etc. Oligonucleotides that comprise a number of phosphorothioate linkages are also known to bind to serum protein, thus short oligonucleotides, e.g., oligonucleotides of about 5 bases, 10 bases, 15 bases or 20 bases, comprising multiple of phosphorothioate linkages in the backbone are also amenable to the present invention as ligands (e.g. as PK modulating ligands). In addition, aptamers that bind serum components (e.g. serum proteins) are also suitable for use as PK modulating ligands in the embodiments described herein. 
     Ligand-conjugated oligonucleotides of the invention may be synthesized by the use of an oligonucleotide that bears a pendant reactive functionality, such as that derived from the attachment of a linking molecule onto the oligonucleotide (described below). This reactive oligonucleotide may be reacted directly with commercially-available ligands, ligands that are synthesized bearing any of a variety of protecting groups, or ligands that have a linking moiety attached thereto. 
     The oligonucleotides used in the conjugates of the present invention may be conveniently and routinely made through the well-known technique of solid-phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is also known to use similar techniques to prepare other oligonucleotides, such as the phosphorothioates and alkylated derivatives. 
     In the ligand-conjugated oligonucleotides and ligand-molecule bearing sequence-specific linked nucleosides of the present invention, the oligonucleotides and oligonucleosides may be assembled on a suitable DNA synthesizer utilizing standard nucleotide or nucleoside precursors, or nucleotide or nucleoside conjugate precursors that already bear the linking moiety, ligand-nucleotide or nucleoside-conjugate precursors that already bear the ligand molecule, or non-nucleoside ligand-bearing building blocks. 
     When using nucleotide-conjugate precursors that already bear a linking moiety, the synthesis of the sequence-specific linked nucleosides is typically completed, and the ligand molecule is then reacted with the linking moiety to form the ligand-conjugated oligonucleotide. In some embodiments, the oligonucleotides or linked nucleosides of the present invention are synthesized by an automated synthesizer using phosphoramidites derived from ligand-nucleoside conjugates in addition to the standard phosphoramidites and non-standard phosphoramidites that are commercially available and routinely used in oligonucleotide synthesis. 
     A. Lipid Conjugates 
     In one embodiment, the ligand or conjugate is a lipid or lipid-based molecule. Such a lipid or lipid-based molecule preferably binds a serum protein, e.g., human serum albumin (HSA). An HSA binding ligand allows for distribution of the conjugate to a target tissue, e.g., a non-kidney target tissue of the body. For example, the target tissue can be the liver, including parenchymal cells of the liver. Other molecules that can bind HSA can also be used as ligands. For example, naproxen or aspirin can be used. A lipid or lipid-based ligand can (a) increase resistance to degradation of the conjugate, (b) increase targeting or transport into a target cell or cell membrane, and/or (c) can be used to adjust binding to a serum protein, e.g., HSA. 
     A lipid based ligand can be used to inhibit, e.g., control the binding of the conjugate to a target tissue. For example, a lipid or lipid-based ligand that binds to HSA more strongly will be less likely to be targeted to the kidney and therefore less likely to be cleared from the body. A lipid or lipid-based ligand that binds to HSA less strongly can be used to target the conjugate to the kidney. 
     In a preferred embodiment, the lipid based ligand binds HSA. Preferably, it binds HSA with a sufficient affinity such that the conjugate will be preferably distributed to a non-kidney tissue. However, it is preferred that the affinity not be so strong that the HSA-ligand binding cannot be reversed. 
     In another preferred embodiment, the lipid based ligand binds HSA weakly or not at all, such that the conjugate will be preferably distributed to the kidney. Other moieties that target to kidney cells can also be used in place of or in addition to the lipid based ligand. 
     In another aspect, the ligand is a moiety, e.g., a vitamin, which is taken up by a target cell, e.g., a proliferating cell. These are particularly useful for treating disorders characterized by unwanted cell proliferation, e.g., of the malignant or non-malignant type, e.g., cancer cells. Exemplary vitamins include vitamin A, E, and K. Other exemplary vitamins include are B vitamin, e.g., folic acid, B12, riboflavin, biotin, pyridoxal or other vitamins or nutrients taken up by target cells such as liver cells. Also included are HSA and low density lipoprotein (LDL). 
     B. Cell Permeation Agents 
     In another aspect, the ligand is a cell-permeation agent, preferably a helical cell-permeation agent. Preferably, the agent is amphipathic. An exemplary agent is a peptide such as tat or antennopedia. If the agent is a peptide, it can be modified, including a peptidylmimetic, invertomers, non-peptide or pseudo-peptide linkages, and use of D-amino acids. The helical agent is preferably an alpha-helical agent, which preferably has a lipophilic and a lipophobic phase. 
     The ligand can be a peptide or peptidomimetic. A peptidomimetic (also referred to herein as an oligopeptidomimetic) is a molecule capable of folding into a defined three-dimensional structure similar to a natural peptide. The attachment of peptide and peptidomimetics to iRNA agents can affect pharmacokinetic distribution of the iRNA, such as by enhancing cellular recognition and absorption. The peptide or peptidomimetic moiety can be about 5-50 amino acids long, e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids long. 
     A peptide or peptidomimetic can be, for example, a cell permeation peptide, cationic peptide, amphipathic peptide, or hydrophobic peptide (e.g., consisting primarily of Tyr, Trp or Phe). The peptide moiety can be a dendrimer peptide, constrained peptide or crosslinked peptide. In another alternative, the peptide moiety can include a hydrophobic membrane translocation sequence (MTS). An exemplary hydrophobic MTS-containing peptide is RFGF having the amino acid sequence AAVALLPAVLLALLAP (SEQ ID NO: 1831). An RFGF analogue (e.g., amino acid sequence AALLPVLLAAP (SEQ ID NO: 1832) containing a hydrophobic MTS can also be a targeting moiety. The peptide moiety can be a “delivery” peptide, which can carry large polar molecules including peptides, oligonucleotides, and protein across cell membranes. For example, sequences from the HIV Tat protein (GRKKRRQRRRPPQ (SEQ ID NO: 1833) and the Drosophila Antennapedia protein (RQIKIWFQNRRMKWKK (SEQ ID NO: 1834) have been found to be capable of functioning as delivery peptides. A peptide or peptidomimetic can be encoded by a random sequence of DNA, such as a peptide identified from a phage-display library, or one-bead-one-compound (OBOC) combinatorial library (Lam et al., Nature, 354:82-84, 1991). Examples of a peptide or peptidomimetic tethered to a dsRNA agent via an incorporated monomer unit for cell targeting purposes is an arginine-glycine-aspartic acid (RGD)-peptide, or RGD mimic. A peptide moiety can range in length from about 5 amino acids to about 40 amino acids. The peptide moieties can have a structural modification, such as to increase stability or direct conformational properties. Any of the structural modifications described below can be utilized. 
     An RGD peptide for use in the compositions and methods of the invention may be linear or cyclic, and may be modified, e.g., glycosylated or methylated, to facilitate targeting to a specific tissue(s). RGD-containing peptides and peptidiomimemtics may include D-amino acids, as well as synthetic RGD mimics. In addition to RGD, one can use other moieties that target the integrin ligand. Preferred conjugates of this ligand target PECAM-1 or VEGF. 
     A “cell permeation peptide” is capable of permeating a cell, e.g., a microbial cell, such as a bacterial or fungal cell, or a mammalian cell, such as a human cell. A microbial cell-permeating peptide can be, for example, an α-helical linear peptide (e.g., LL-37 or Ceropin P1), a disulfide bond-containing peptide (e.g., α-defensin, β-defensin or bactenecin), or a peptide containing only one or two dominating amino acids (e.g., PR-39 or indolicidin). A cell permeation peptide can also include a nuclear localization signal (NLS). For example, a cell permeation peptide can be a bipartite amphipathic peptide, such as MPG, which is derived from the fusion peptide domain of HIV-1 gp41 and the NLS of SV40 large T antigen (Simeoni et al., Nucl. Acids Res. 31:2717-2724, 2003). 
     C. Carbohydrate Conjugates 
     In some embodiments of the compositions and methods of the invention, an iRNA oligonucleotide further comprises a carbohydrate. The carbohydrate conjugated iRNA are advantageous for the in vivo delivery of nucleic acids, as well as compositions suitable for in vivo therapeutic use, as described herein. As used herein, “carbohydrate” refers to a compound which is either a carbohydrate per se made up of one or more monosaccharide units having at least 6 carbon atoms (which can be linear, branched or cyclic) with an oxygen, nitrogen or sulfur atom bonded to each carbon atom; or a compound having as a part thereof a carbohydrate moiety made up of one or more monosaccharide units each having at least six carbon atoms (which can be linear, branched or cyclic), with an oxygen, nitrogen or sulfur atom bonded to each carbon atom. Representative carbohydrates include the sugars (mono-, di-, tri- and oligosaccharides containing from about 4, 5, 6, 7, 8, or 9 monosaccharide units), and polysaccharides such as starches, glycogen, cellulose and polysaccharide gums. Specific monosaccharides include HDV and above (e.g., C6, C7, or C8) sugars; di- and trisaccharides include sugars having two or three monosaccharide units (e.g., C6, C7, or C8). 
     In one embodiment, a carbohydrate conjugate for use in the compositions and methods of the invention is a monosaccharide. In one embodiment, the monosaccharide is an N-acetylgalactosamine, such as 
     
       
         
         
             
             
         
       
     
     In another embodiment, a carbohydrate conjugate for use in the compositions and methods of the invention is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Another representative carbohydrate conjugate for use in the embodiments described herein includes, but is not limited to, 
     
       
         
         
             
             
         
       
         
         
           
             (Formula XXIII), when one of X or Y is an oligonucleotide, the other is a hydrogen. 
           
         
       
    
     In some embodiments, the carbohydrate conjugate further comprises one or more additional ligands as described above, such as, but not limited to, a PK modulator and/or a cell permeation peptide. 
     D. Linkers 
     In some embodiments, the conjugate or ligand described herein can be attached to an iRNA oligonucleotide with various linkers that can be cleavable or non-cleavable. 
     The term “linker” or “linking group” means an organic moiety that connects two parts of a compound, e.g., covalently attaches two parts of a compound. Linkers typically comprise a direct bond or an atom such as oxygen or sulfur, a unit such as NR8, C(O), C(O)NH, SO, SO 2 , SO 2 NH or a chain of atoms, such as, but not limited to, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, alkynylhereroaryl, which one or more methylenes can be interrupted or terminated by O, S, S(O), SO 2 , N(R8), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; where R8 is hydrogen, acyl, aliphatic or substituted aliphatic. In one embodiment, the linker is between about 1-24 atoms, 2-24, 3-24, 4-24, 5-24, 6-24, 6-18, 7-18, 8-18 atoms, 7-17, 8-17, 6-16, 7-16, or 8-16 atoms. 
     A cleavable linking group is one which is sufficiently stable outside the cell, but which upon entry into a target cell is cleaved to release the two parts the linker is holding together. In a preferred embodiment, the cleavable linking group is cleaved at least about 10 times, 20, times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times or more, or at least about 100 times faster in a target cell or under a first reference condition (which can, e.g., be selected to mimic or represent intracellular conditions) than in the blood of a subject, or under a second reference condition (which can, e.g., be selected to mimic or represent conditions found in the blood or serum). 
     Cleavable linking groups are susceptible to cleavage agents, e.g., pH, redox potential or the presence of degradative molecules. Generally, cleavage agents are more prevalent or found at higher levels or activities inside cells than in serum or blood. Examples of such degradative agents include: redox agents which are selected for particular substrates or which have no substrate specificity, including, e.g., oxidative or reductive enzymes or reductive agents such as mercaptans, present in cells, that can degrade a redox cleavable linking group by reduction; esterases; endosomes or agents that can create an acidic environment, e.g., those that result in a pH of five or lower; enzymes that can hydrolyze or degrade an acid cleavable linking group by acting as a general acid, peptidases (which can be substrate specific), and phosphatases. 
     A cleavable linkage group, such as a disulfide bond can be susceptible to pH. The pH of human serum is 7.4, while the average intracellular pH is slightly lower, ranging from about 7.1-7.3. Endosomes have a more acidic pH, in the range of 5.5-6.0, and lysosomes have an even more acidic pH at around 5.0. Some linkers will have a cleavable linking group that is cleaved at a preferred pH, thereby releasing a cationic lipid from the ligand inside the cell, or into the desired compartment of the cell. 
     A linker can include a cleavable linking group that is cleavable by a particular enzyme. The type of cleavable linking group incorporated into a linker can depend on the cell to be targeted. For example, a liver-targeting ligand can be linked to a cationic lipid through a linker that includes an ester group. Liver cells are rich in esterases, and therefore the linker will be cleaved more efficiently in liver cells than in cell types that are not esterase-rich. Other cell-types rich in esterases include cells of the lung, renal cortex, and testis. 
     Linkers that contain peptide bonds can be used when targeting cell types rich in peptidases, such as liver cells and synoviocytes. 
     In general, the suitability of a candidate cleavable linking group can be evaluated by testing the ability of a degradative agent (or condition) to cleave the candidate linking group. It will also be desirable to also test the candidate cleavable linking group for the ability to resist cleavage in the blood or when in contact with other non-target tissue. Thus, one can determine the relative susceptibility to cleavage between a first and a second condition, where the first is selected to be indicative of cleavage in a target cell and the second is selected to be indicative of cleavage in other tissues or biological fluids, e.g., blood or serum. The evaluations can be carried out in cell free systems, in cells, in cell culture, in organ or tissue culture, or in whole animals. It can be useful to make initial evaluations in cell-free or culture conditions and to confirm by further evaluations in whole animals. In preferred embodiments, useful candidate compounds are cleaved at least about 2, 4, 10, 20, 30, 40, 50, 60, 70, 80, 90, or about 100 times faster in the cell (or under in vitro conditions selected to mimic intracellular conditions) as compared to blood or serum (or under in vitro conditions selected to mimic extracellular conditions). 
     i. Redox Cleavable Linking Groups 
     In one embodiment, a cleavable linking group is a redox cleavable linking group that is cleaved upon reduction or oxidation. An example of reductively cleavable linking group is a disulphide linking group (—S—S—). To determine if a candidate cleavable linking group is a suitable “reductively cleavable linking group,” or for example is suitable for use with a particular iRNA moiety and particular targeting agent one can look to methods described herein. For example, a candidate can be evaluated by incubation with dithiothreitol (DTT), or other reducing agent using reagents know in the art, which mimic the rate of cleavage which would be observed in a cell, e.g., a target cell. The candidates can also be evaluated under conditions which are selected to mimic blood or serum conditions. In one, candidate compounds are cleaved by at most about 10% in the blood. In other embodiments, useful candidate compounds are degraded at least about 2, 4, 10, 20, 30, 40, 50, 60, 70, 80, 90, or about 100 times faster in the cell (or under in vitro conditions selected to mimic intracellular conditions) as compared to blood (or under in vitro conditions selected to mimic extracellular conditions). The rate of cleavage of candidate compounds can be determined using standard enzyme kinetics assays under conditions chosen to mimic intracellular media and compared to conditions chosen to mimic extracellular media. 
     ii. Phosphate-Based Cleavable Linking Groups 
     In another embodiment, a cleavable linker comprises a phosphate-based cleavable linking group. A phosphate-based cleavable linking group is cleaved by agents that degrade or hydrolyze the phosphate group. An example of an agent that cleaves phosphate groups in cells are enzymes such as phosphatases in cells. Examples of phosphate-based linking groups are —O—P(O)(ORk)-O—, —O—P(S)(ORk)-O—, —O—P(S)(SRk)-O—, —S—P(O)(ORk)-O—, —O—P(O)(ORk)-S—, —S—P(O)(ORk)-S—, —O—P(S)(ORk)-S—, —S—P(S)(ORk)-O—, —O—P(O)(Rk)-O—, —O—P(S)(Rk)-O—, —S—P(O)(Rk)-O—, —S—P(S)(Rk)-O—, —S—P(O)(Rk)-S—, —O—P(S)(Rk)-S—. Preferred embodiments are —O—P(O)(OH)—O—, —O—P(S)(OH)—O—, —O—P(S)(SH)—O—, —S—P(O)(OH)—O—, —O—P(O)(OH)—S—, —S—P(O)(OH)—S—, —O—P(S)(OH)—S—, —S—P(S)(OH)—O—, —O—P(O)(H)—O—, —O—P(S)(H)—O—, —S—P(O)(H)—O, —S—P(S)(H)—O—, —S—P(O)(H)—S—, —O—P(S)(H)—S—. A preferred embodiment is —O—P(O)(OH)—O—. These candidates can be evaluated using methods analogous to those described above. 
     iii. Acid Cleavable Linking Groups 
     In another embodiment, a cleavable linker comprises an acid cleavable linking group. An acid cleavable linking group is a linking group that is cleaved under acidic conditions. In preferred embodiments acid cleavable linking groups are cleaved in an acidic environment with a pH of about 6.5 or lower (e.g., about 6.0, 5.75, 5.5, 5.25, 5.0, or lower), or by agents such as enzymes that can act as a general acid. In a cell, specific low pH organelles, such as endosomes and lysosomes can provide a cleaving environment for acid cleavable linking groups. Examples of acid cleavable linking groups include but are not limited to hydrazones, esters, and esters of amino acids. Acid cleavable groups can have the general formula —C═NN—, C(O)O, or —OC(O). A preferred embodiment is when the carbon attached to the oxygen of the ester (the alkoxy group) is an aryl group, substituted alkyl group, or tertiary alkyl group such as dimethyl pentyl or t-butyl. These candidates can be evaluated using methods analogous to those described above. 
     iv. Ester-Based Linking Groups 
     In another embodiment, a cleavable linker comprises an ester-based cleavable linking group. An ester-based cleavable linking group is cleaved by enzymes such as esterases and amidases in cells. Examples of ester-based cleavable linking groups include but are not limited to esters of alkylene, alkenylene and alkynylene groups. Ester cleavable linking groups have the general formula —C(O)O—, or —OC(O)—. These candidates can be evaluated using methods analogous to those described above. 
     v. Peptide-Based Cleaving Groups 
     In yet another embodiment, a cleavable linker comprises a peptide-based cleavable linking group. A peptide-based cleavable linking group is cleaved by enzymes such as peptidases and proteases in cells. Peptide-based cleavable linking groups are peptide bonds formed between amino acids to yield oligopeptides (e.g., dipeptides, tripeptides etc.) and polypeptides. Peptide-based cleavable groups do not include the amide group (—C(O)NH—). The amide group can be formed between any alkylene, alkenylene or alkynelene. A peptide bond is a special type of amide bond formed between amino acids to yield peptides and proteins. The peptide based cleavage group is generally limited to the peptide bond (i.e., the amide bond) formed between amino acids yielding peptides and proteins and does not include the entire amide functional group. Peptide-based cleavable linking groups have the general formula —NHCHRAC(O)NHCHRBC(O)—, where RA and RB are the R groups of the two adjacent amino acids. These candidates can be evaluated using methods analogous to those described above. 
     In one embodiment, an iRNA of the invention is conjugated to a carbohydrate through a linker. Non-limiting examples of iRNA carbohydrate conjugates with linkers of the compositions and methods of the invention include, but are not limited to, 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     when one of X or Y is an oligonucleotide, the other is a hydrogen. 
     In certain embodiments of the compositions and methods of the invention, a ligand is one or more “GalNAc” (N-acetylgalactosamine) derivatives attached through a bivalent or trivalent branched linker. 
     In one embodiment, a dsRNA of the invention is conjugated to a bivalent or trivalent branched linker selected from the group of structures shown in any of formula (XXXII)-(XXXV): 
     
       
         
         
             
             
         
       
     
     wherein:
 
q2A, q2B, q3A, q3B, q4A, q4B, q5A, q5B and q5C represent independently for each occurrence 0-20 and wherein the repeating unit can be the same or different;
 
P 2A , P 2B , P 3A , P 3B , P 4A , P 4B , P 5A , P 5B , P 5C , T 2A , T 2B , T 3A , T 3B , T 4A , T 4B , T 4A , T 5B , T 5C  are each independently for each occurrence absent, CO, NH, O, S, OC(O), NHC(O), CH 2 , CH 2 NH or CH 2 O;
 
Q 2A , Q 2B , Q 3A , Q 3B , Q 4A , Q 4B , Q 5A , Q 5B , Q 5C  are independently for each occurrence absent, alkylene, substituted alkylene wherein one or more methylenes can be interrupted or terminated by one or more of O, S, S(O), SO 2 , N(R N ), C(R′)═C(R″), C≡C or C(O);
 
R 2A , R 2B , R 3A , R 3B , R 4A , R 4B , R 5A , R 5B , R 5C  are each independently for each occurrence absent, NH, O, S, CH 2 , C(O)O, C(O)NH, NHCH(R a )C(O), —C(O)—CH(R a )—NH—, CO, CH═N—O,
 
     
       
         
         
             
             
         
       
     
     or heterocyclyl; 
     L 2A , L 2B , L 3A , L 3B , L 4A , L 4B , L 5A , L 5B  and L 5C  represent the ligand; i.e. each independently for each occurrence a monosaccharide (such as GalNAc), disaccharide, trisaccharide, tetrasaccharide, oligosaccharide, or polysaccharide; and R a  is H or amino acid side chain. Trivalent conjugating GalNAc derivatives are particularly useful for use with RNAi agents for inhibiting the expression of a target gene, such as those of formula (XXXV): 
     
       
         
         
             
             
         
       
         
         
           
             wherein L 5A , L 5B  and L 5C  represent a monosaccharide, such as GalNAc derivative. 
           
         
       
    
     Examples of suitable bivalent and trivalent branched linker groups conjugating GalNAc derivatives include, but are not limited to, the structures recited above as formulas II, VII, XI, X, and XIII. 
     Representative U.S. patents that teach the preparation of RNA conjugates include, but are not limited to, U.S. Pat. Nos. 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830; 5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022; 5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241, 5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and 5,688,941; 6,294,664; 6,320,017; 6,576,752; 6,783,931; 6,900,297; 7,037,646; 8,106,022, the entire contents of each of which are hereby incorporated herein by reference. 
     It is not necessary for all positions in a given compound to be uniformly modified, and in fact more than one of the aforementioned modifications can be incorporated in a single compound or even at a single nucleoside within an iRNA. The present invention also includes iRNA compounds that are chimeric compounds. 
     “Chimeric” iRNA compounds or “chimeras,” in the context of this invention, are iRNA compounds, preferably dsRNAs, which contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of a dsRNA compound. These iRNAs typically contain at least one region wherein the RNA is modified so as to confer upon the iRNA increased resistance to nuclease degradation, increased cellular uptake, and/or increased binding affinity for the target nucleic acid. An additional region of the iRNA can serve as a substrate for enzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. By way of example, RNase H is a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of iRNA inhibition of gene expression. Consequently, comparable results can often be obtained with shorter iRNAs when chimeric dsRNAs are used, compared to phosphorothioate deoxy dsRNAs hybridizing to the same target region. Cleavage of the RNA target can be routinely detected by gel electrophoresis and, if necessary, associated nucleic acid hybridization techniques known in the art. 
     In certain instances, the RNA of an iRNA can be modified by a non-ligand group. A number of non-ligand molecules have been conjugated to iRNAs in order to enhance the activity, cellular distribution or cellular uptake of the iRNA, and procedures for performing such conjugations are available in the scientific literature. Such non-ligand moieties have included lipid moieties, such as cholesterol (Kubo, T. et al.,  Biochem. Biophys. Res. Comm.,  2007, 365(1):54-61; Letsinger et al.,  Proc. Natl. Acad. Sci. USA,  1989, 86:6553), cholic acid (Manoharan et al.,  Bioorg. Med. Chem. Lett.,  1994, 4:1053), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al.,  Ann. N.Y. Acad. Sci.,  1992, 660:306; Manoharan et al.,  Bioorg. Med. Chem. Let.,  1993, 3:2765), a thiocholesterol (Oberhauser et al.,  Nucl. Acids Res.,  1992, 20:533), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al.,  EMBO J.,  1991, 10:111; Kabanov et al.,  FEBS Lett.,  1990, 259:327; Svinarchuk et al.,  Biochimie,  1993, 75:49), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al.,  Tetrahedron Lett.,  1995, 36:3651; Shea et al.,  Nucl. Acids Res.,  1990, 18:3777), a polyamine or a polyethylene glycol chain (Manoharan et al.,  Nucleosides  &amp;  Nucleotides,  1995, 14:969), or adamantane acetic acid (Manoharan et al.,  Tetrahedron Lett.,  1995, 36:3651), a palmityl moiety (Mishra et al.,  Biochim. Biophys. Acta,  1995, 1264:229), or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al.,  J. Pharmacol. Exp. Ther.,  1996, 277:923). Representative United States patents that teach the preparation of such RNA conjugates have been listed above. Typical conjugation protocols involve the synthesis of an RNAs bearing an aminolinker at one or more positions of the sequence. The amino group is then reacted with the molecule being conjugated using appropriate coupling or activating reagents. The conjugation reaction can be performed either with the RNA still bound to the solid support or following cleavage of the RNA, in solution phase. Purification of the RNA conjugate by HPLC typically affords the pure conjugate. 
     V. Delivery of an iRNA of the Invention 
     The delivery of an iRNA of the invention to a cell e.g., a cell within a subject, such as a human subject (e.g., a subject in need thereof, such as a subject having a disease, disorder or condition associated with HDV infection) can be achieved in a number of different ways. For example, delivery may be performed by contacting a cell with an iRNA of the invention either in vitro or in vivo. In vivo delivery may also be performed directly by administering a composition comprising an iRNA, e.g., a dsRNA, to a subject. Alternatively, in vivo delivery may be performed indirectly by administering one or more vectors that encode and direct the expression of the iRNA. These alternatives are discussed further below. 
     In general, any method of delivering a nucleic acid molecule (in vitro or in vivo) can be adapted for use with an iRNA of the invention (see e.g., Akhtar S. and Julian R L. (1992)  Trends Cell. Biol.  2(5):139-144 and WO94/02595, which are incorporated herein by reference in their entireties). For in vivo delivery, factors to consider in order to deliver an iRNA molecule include, for example, biological stability of the delivered molecule, prevention of non-specific effects, and accumulation of the delivered molecule in the target tissue. The non-specific effects of an iRNA can be minimized by local administration, for example, by direct injection or implantation into a tissue or topically administering the preparation. Local administration to a treatment site maximizes local concentration of the agent, limits the exposure of the agent to systemic tissues that can otherwise be harmed by the agent or that can degrade the agent, and permits a lower total dose of the iRNA molecule to be administered. Several studies have shown successful knockdown of gene products when an iRNA is administered locally. For example, intraocular delivery of a VEGF dsRNA by intravitreal injection in cynomolgus monkeys (Tolentino, M J., et al (2004)  Retina  24:132-138) and subretinal injections in mice (Reich, S J., et al (2003)  Mol. Vis.  9:210-216) were both shown to prevent neovascularization in an experimental model of age-related macular degeneration. In addition, direct intratumoral injection of a dsRNA in mice reduces tumor volume (Pille, J., et al (2005)  Mol. Ther.  11:267-274) and can prolong survival of tumor-bearing mice (Kim, W J., et al (2006)  Mol. Ther.  14:343-350; Li, S., et al (2007)  Mol. Ther.  15:515-523). RNA interference has also shown success with local delivery to the CNS by direct injection (Dorn, G., et al. (2004)  Nucleic Acids  32:e49; Tan, P H., et al (2005)  Gene Ther.  12:59-66; Makimura, H., et al (2002)  BMC Neurosci.  3:18; Shishkina, G T., et al (2004)  Neuroscience  129:521-528; Thakker, E R., et al (2004)  Proc. Natl. Acad. Sci. U.S.A.  101:17270-17275; Akaneya, Y., et al (2005)  J. Neurophysiol.  93:594-602) and to the lungs by intranasal administration (Howard, K A., et al (2006)  Mol. Ther.  14:476-484; Zhang, X., et al (2004)  J. Biol. Chem.  279:10677-10684; Bitko, V., et al (2005)  Nat. Med.  11:50-55). For administering an iRNA systemically for the treatment of a disease, the RNA can be modified or alternatively delivered using a drug delivery system; both methods act to prevent the rapid degradation of the dsRNA by endo- and exo-nucleases in vivo. Modification of the RNA or the pharmaceutical carrier can also permit targeting of the iRNA composition to the target tissue and avoid undesirable off-target effects. iRNA molecules can be modified by chemical conjugation to lipophilic groups such as cholesterol to enhance cellular uptake and prevent degradation. For example, an iRNA directed against ApoB conjugated to a lipophilic cholesterol moiety was injected systemically into mice and resulted in knockdown of apoB mRNA in both the liver and jejunum (Soutschek, J., et al (2004)  Nature  432:173-178). Conjugation of an iRNA to an aptamer has been shown to inhibit tumor growth and mediate tumor regression in a mouse model of prostate cancer (McNamara, J O., et al (2006)  Nat. Biotechnol.  24:1005-1015). In an alternative embodiment, the iRNA can be delivered using drug delivery systems such as a nanoparticle, a dendrimer, a polymer, liposomes, or a cationic delivery system. Positively charged cationic delivery systems facilitate binding of an iRNA molecule (negatively charged) and also enhance interactions at the negatively charged cell membrane to permit efficient uptake of an iRNA by the cell. Cationic lipids, dendrimers, or polymers can either be bound to an iRNA, or induced to form a vesicle or micelle (see e.g., Kim S H., et al (2008)  Journal of Controlled Release  129(2):107-116) that encases an iRNA. The formation of vesicles or micelles further prevents degradation of the iRNA when administered systemically. Methods for making and administering cationic-iRNA complexes are well within the abilities of one skilled in the art (see e.g., Sorensen, D R., et al (2003)  J. Mol. Biol  327:761-766; Verma, U N., et al (2003) Clin.  Cancer Res.  9:1291-1300; Arnold, A S et al (2007)  J. Hypertens.  25:197-205, which are incorporated herein by reference in their entirety). Some non-limiting examples of drug delivery systems useful for systemic delivery of iRNAs include DOTAP (Sorensen, D R., et al (2003), supra; Verma, U N., et al (2003), supra), Oligofectamine, “solid nucleic acid lipid particles” (Zimmermann, T S., et al (2006)  Nature  441:111-114), cardiolipin (Chien, P Y., et al (2005)  Cancer Gene Ther.  12:321-328; Pal, A., et al (2005)  Int J. Oncol.  26:1087-1091), polyethyleneimine (Bonnet M E., et al (2008)  Pharm. Res . August 16 Epub ahead of print; Aigner, A. (2006)  J. Biomed. Biotechnol.  71659), Arg-Gly-Asp (RGD) peptides (Liu, S. (2006)  Mol. Pharm.  3:472-487), and polyamidoamines (Tomalia, D A., et al (2007)  Biochem. Soc. Trans.  35:61-67; Yoo, H., et al (1999)  Pharm. Res.  16:1799-1804). In some embodiments, an iRNA forms a complex with cyclodextrin for systemic administration. Methods for administration and pharmaceutical compositions of iRNAs and cyclodextrins can be found in U.S. Pat. No. 7,427,605, which is herein incorporated by reference in its entirety. 
     A. Vector Encoded iRNAs of the Invention 
     iRNA targeting the HDV gene can be expressed from transcription units inserted into DNA or RNA vectors (see, e.g., Couture, A, et al.,  TIG.  (1996), 12:5-10; Skillern, A., et al., International PCT Publication No. WO 00/22113, Conrad, International PCT Publication No. WO 00/22114, and Conrad, U.S. Pat. No. 6,054,299). Expression can be transient (on the order of hours to weeks) or sustained (weeks to months or longer), depending upon the specific construct used and the target tissue or cell type. These transgenes can be introduced as a linear construct, a circular plasmid, or a viral vector, which can be an integrating or non-integrating vector. The transgene can also be constructed to permit it to be inherited as an extrachromosomal plasmid (Gassmann, et al.,  Proc. Natl. Acad. Sci. USA  (1995) 92:1292). 
     The individual strand or strands of an iRNA can be transcribed from a promoter on an expression vector. Where two separate strands are to be expressed to generate, for example, a dsRNA, two separate expression vectors can be co-introduced (e.g., by transfection or infection) into a target cell. Alternatively each individual strand of a dsRNA can be transcribed by promoters both of which are located on the same expression plasmid. In one embodiment, a dsRNA is expressed as inverted repeat polynucleotides joined by a linker polynucleotide sequence such that the dsRNA has a stem and loop structure. 
     iRNA expression vectors are generally DNA plasmids or viral vectors. Expression vectors compatible with eukaryotic cells, preferably those compatible with vertebrate cells, can be used to produce recombinant constructs for the expression of an iRNA as described herein. Eukaryotic cell expression vectors are well known in the art and are available from a number of commercial sources. Typically, such vectors are provided containing convenient restriction sites for insertion of the desired nucleic acid segment. Delivery of iRNA expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that allows for introduction into a desired target cell. 
     iRNA expression plasmids can be transfected into target cells as a complex with cationic lipid carriers (e.g., Oligofectamine) or non-cationic lipid-based carriers (e.g., Transit-TKO™). Multiple lipid transfections for iRNA-mediated knockdowns targeting different regions of a target RNA over a period of a week or more are also contemplated by the invention. Successful introduction of vectors into host cells can be monitored using various known methods. For example, transient transfection can be signaled with a reporter, such as a fluorescent marker, such as Green Fluorescent Protein (GFP). Stable transfection of cells ex vivo can be ensured using markers that provide the transfected cell with resistance to specific environmental factors (e.g., antibiotics and drugs), such as hygromycin B resistance. 
     Viral vector systems which can be utilized with the methods and compositions described herein include, but are not limited to, (a) adenovirus vectors; (b) retrovirus vectors, including but not limited to lentiviral vectors, moloney murine leukemia virus, etc.; (c) adeno-associated virus vectors; (d) herpes simplex virus vectors; (e) SV 40 vectors; (f) polyoma virus vectors; (g) papilloma virus vectors; (h) picornavirus vectors; (i) pox virus vectors such as an orthopox, e.g., vaccinia virus vectors or avipox, e.g. canary pox or fowl pox; and (j) a helper-dependent or gutless adenovirus. Replication-defective viruses can also be advantageous. Different vectors will or will not become incorporated into the cells&#39; genome. The constructs can include viral sequences for transfection, if desired. Alternatively, the construct can be incorporated into vectors capable of episomal replication, e.g. EPV and EBV vectors. Constructs for the recombinant expression of an iRNA will generally require regulatory elements, e.g., promoters, enhancers, etc., to ensure the expression of the iRNA in target cells. Other aspects to consider for vectors and constructs are further described below. 
     Vectors useful for the delivery of an iRNA will include regulatory elements (promoter, enhancer, etc.) sufficient for expression of the iRNA in the desired target cell or tissue. The regulatory elements can be chosen to provide either constitutive or regulated/inducible expression. 
     Expression of the iRNA can be precisely regulated, for example, by using an inducible regulatory sequence that is sensitive to certain physiological regulators, e.g., circulating glucose levels, or hormones (Docherty et al., 1994 , FASEB J.  8:20-24). Such inducible expression systems, suitable for the control of dsRNA expression in cells or in mammals include, for example, regulation by ecdysone, by estrogen, progesterone, tetracycline, chemical inducers of dimerization, and isopropyl-beta-D1-thiogalactopyranoside (IPTG). A person skilled in the art would be able to choose the appropriate regulatory/promoter sequence based on the intended use of the iRNA transgene. 
     Viral vectors that contain nucleic acid sequences encoding an iRNA can be used. For example, a retroviral vector can be used (see Miller et al.,  Meth. Enzymol.  217:581-599 (1993)). These retroviral vectors contain the components necessary for the correct packaging of the viral genome and integration into the host cell DNA. The nucleic acid sequences encoding an iRNA are cloned into one or more vectors, which facilitate delivery of the nucleic acid into a patient. More detail about retroviral vectors can be found, for example, in Boesen et al.,  Biotherapy  6:291-302 (1994), which describes the use of a retroviral vector to deliver the mdr1 gene to hematopoietic stem cells in order to make the stem cells more resistant to chemotherapy. Other references illustrating the use of retroviral vectors in gene therapy are: Clowes et al.,  J. Clin. Invest.  93:644-651 (1994); Kiem et al.,  Blood  83:1467-1473 (1994); Salmons and Gunzberg,  Human Gene Therapy  4:129-141 (1993); and Grossman and Wilson,  Curr. Opin. in Genetics and Devel.  3:110-114 (1993). Lentiviral vectors contemplated for use include, for example, the HIV based vectors described in U.S. Pat. Nos. 6,143,520; 5,665,557; and 5,981,276, which are herein incorporated by reference. 
     Adenoviruses are also contemplated for use in delivery of iRNAs of the invention. Adenoviruses are especially attractive vehicles, e.g., for delivering genes to respiratory epithelia. Adenoviruses naturally infect respiratory epithelia where they cause a mild disease. Other targets for adenovirus-based delivery systems are liver, the central nervous system, endothelial cells, and muscle. Adenoviruses have the advantage of being capable of infecting non-dividing cells. Kozarsky and Wilson,  Current Opinion in Genetics and Development  3:499-503 (1993) present a review of adenovirus-based gene therapy. Bout et al.,  Human Gene Therapy  5:3-10 (1994) demonstrated the use of adenovirus vectors to transfer genes to the respiratory epithelia of rhesus monkeys. Other instances of the use of adenoviruses in gene therapy can be found in Rosenfeld et al.,  Science  252:431-434 (1991); Rosenfeld et al.,  Cell  68:143-155 (1992); Mastrangeli et al.,  J. Clin. Invest.  91:225-234 (1993); PCT Publication WO94/12649; and Wang, et al.,  Gene Therapy  2:775-783 (1995). A suitable AV vector for expressing an iRNA featured in the invention, a method for constructing the recombinant AV vector, and a method for delivering the vector into target cells, are described in Xia H et al. (2002),  Nat. Biotech.  20: 1006-1010. 
     Adeno-associated virus (AAV) vectors may also be used to delivery an iRNA of the invention (Walsh et al., Proc. Soc. Exp. Biol. Med. 204:289-300 (1993); U.S. Pat. No. 5,436,146). In one embodiment, the iRNA can be expressed as two separate, complementary single-stranded RNA molecules from a recombinant AAV vector having, for example, either the U6 or H1 RNA promoters, or the cytomegalovirus (CMV) promoter. Suitable AAV vectors for expressing the dsRNA featured in the invention, methods for constructing the recombinant AV vector, and methods for delivering the vectors into target cells are described in Samulski R et al. (1987),  J. Virol.  61: 3096-3101; Fisher K J et al. (1996),  J. Virol,  70: 520-532; Samulski R et al. (1989),  J. Virol.  63: 3822-3826; U.S. Pat. Nos. 5,252,479; 5,139,941; International Patent Application No. WO 94/13788; and International Patent Application No. WO 93/24641, the entire disclosures of which are herein incorporated by reference. 
     Another viral vector suitable for delivery of an iRNA of the invention is a pox virus such as a vaccinia virus, for example an attenuated vaccinia such as Modified Virus Ankara (MVA) or NYVAC, an avipox such as fowl pox or canary pox. 
     The tropism of viral vectors can be modified by pseudotyping the vectors with envelope proteins or other surface antigens from other viruses, or by substituting different viral capsid proteins, as appropriate. For example, lentiviral vectors can be pseudotyped with surface proteins from vesicular stomatitis virus (VSV), rabies, Ebola, Mokola, and the like. AAV vectors can be made to target different cells by engineering the vectors to express different capsid protein serotypes; see, e.g., Rabinowitz J E et al. (2002),  J Virol  76:791-801, the entire disclosure of which is herein incorporated by reference. 
     The pharmaceutical preparation of a vector can include the vector in an acceptable diluent, or can include a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells which produce the gene delivery system. 
     VI. Pharmaceutical Compositions of the Invention 
     The present invention also includes pharmaceutical compositions and formulations which include the iRNAs of the invention. In one embodiment, provided herein are pharmaceutical compositions containing an iRNA, as described herein, and a pharmaceutically acceptable carrier. The pharmaceutical compositions containing the iRNA are useful for treating a disease or disorder associated with the expression or activity of an HDV gene. Such pharmaceutical compositions are formulated based on the mode of delivery. One example is compositions that are formulated for systemic administration via parenteral delivery, e.g., by subcutaneous, intramuscularly (IM), (SC) or intravenous (IV) delivery. Another example is compositions that are formulated for direct delivery into the brain parenchyma, e.g., by infusion into the brain, such as by continuous pump infusion. The pharmaceutical compositions of the invention may be administered in dosages sufficient to inhibit expression of an HDV gene. 
     In one embodiment, an iRNA agent of the invention is administered to a subject as a weight-based dose. A “weight-based dose” (e.g., a dose in mg/kg) is a dose of the iRNA agent that will change depending on the subject&#39;s weight. In another embodiment, an iRNA agent is administered to a subject as a fixed dose. A “fixed dose” (e.g., a dose in mg) means that one dose of an iRNA agent is used for all subjects regardless of any specific subject-related factors, such as weight. In one particular embodiment, a fixed dose of an iRNA agent of the invention is based on a predetermined weight or age. 
     In general, a suitable dose of an iRNA of the invention will be in the range of about 0.001 to about 200.0 milligrams per kilogram body weight of the recipient per day, generally in the range of about 1 to 50 mg per kilogram body weight per day. For example, the dsRNA can be administered at about 0.01 mg/kg, about 0.05 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 3 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, or about 50 mg/kg per single dose. 
     For example, the dsRNA may be administered at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or about 10 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     In another embodiment, the dsRNA is administered at a dose of about 0.1 to about 50 mg/kg, about 0.25 to about 50 mg/kg, about 0.5 to about 50 mg/kg, about 0.75 to about 50 mg/kg, about 1 to about 50 mg/kg, about 1.5 to about 50 mg/kg, about 2 to about 50 mg/kg, about 2.5 to about 50 mg/kg, about 3 to about 50 mg/kg, about 3.5 to about 50 mg/kg, about 4 to about 50 mg/kg, about 4.5 to about 50 mg/kg, about 5 to about 50 mg/kg, about 7.5 to about 50 mg/kg, about 10 to about 50 mg/kg, about 15 to about 50 mg/kg, about 20 to about 50 mg/kg, about 20 to about 50 mg/kg, about 25 to about 50 mg/kg, about 25 to about 50 mg/kg, about 30 to about 50 mg/kg, about 35 to about 50 mg/kg, about 40 to about 50 mg/kg, about 45 to about 50 mg/kg, about 0.1 to about 45 mg/kg, about 0.25 to about 45 mg/kg, about 0.5 to about 45 mg/kg, about 0.75 to about 45 mg/kg, about 1 to about 45 mg/kg, about 1.5 to about 45 mg/kg, about 2 to about 45 mg/kg, about 2.5 to about 45 mg/kg, about 3 to about 45 mg/kg, about 3.5 to about 45 mg/kg, about 4 to about 45 mg/kg, about 4.5 to about 45 mg/kg, about 5 to about 45 mg/kg, about 7.5 to about 45 mg/kg, about 10 to about 45 mg/kg, about 15 to about 45 mg/kg, about 20 to about 45 mg/kg, about 20 to about 45 mg/kg, about 25 to about 45 mg/kg, about 25 to about 45 mg/kg, about 30 to about 45 mg/kg, about 35 to about 45 mg/kg, about 40 to about 45 mg/kg, about 0.1 to about 40 mg/kg, about 0.25 to about 40 mg/kg, about 0.5 to about 40 mg/kg, about 0.75 to about 40 mg/kg, about 1 to about 40 mg/kg, about 1.5 to about 40 mg/kg, about 2 to about 40 mg/kg, about 2.5 to about 40 mg/kg, about 3 to about 40 mg/kg, about 3.5 to about 40 mg/kg, about 4 to about 40 mg/kg, about 4.5 to about 40 mg/kg, about 5 to about 40 mg/kg, about 7.5 to about 40 mg/kg, about 10 to about 40 mg/kg, about 15 to about 40 mg/kg, about 20 to about 40 mg/kg, about 20 to about 40 mg/kg, about 25 to about 40 mg/kg, about 25 to about 40 mg/kg, about 30 to about 40 mg/kg, about 35 to about 40 mg/kg, about 0.1 to about 30 mg/kg, about 0.25 to about 30 mg/kg, about 0.5 to about 30 mg/kg, about 0.75 to about 30 mg/kg, about 1 to about 30 mg/kg, about 1.5 to about 30 mg/kg, about 2 to about 30 mg/kg, about 2.5 to about 30 mg/kg, about 3 to about 30 mg/kg, about 3.5 to about 30 mg/kg, about 4 to about 30 mg/kg, about 4.5 to about 30 mg/kg, about 5 to about 30 mg/kg, about 7.5 to about 30 mg/kg, about 10 to about 30 mg/kg, about 15 to about 30 mg/kg, about 20 to about 30 mg/kg, about 20 to about 30 mg/kg, about 25 to about 30 mg/kg, about 0.1 to about 20 mg/kg, about 0.25 to about 20 mg/kg, about 0.5 to about 20 mg/kg, about 0.75 to about 20 mg/kg, about 1 to about 20 mg/kg, about 1.5 to about 20 mg/kg, about 2 to about 20 mg/kg, about 2.5 to about 20 mg/kg, about 3 to about 20 mg/kg, about 3.5 to about 20 mg/kg, about 4 to about 20 mg/kg, about 4.5 to about 20 mg/kg, about 5 to about 20 mg/kg, about 7.5 to about 20 mg/kg, about 10 to about 20 mg/kg, or about 15 to about 20 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     For example, the dsRNA may be administered at a dose of about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or about 10 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     In another embodiment, the dsRNA is administered at a dose of about 0.5 to about 50 mg/kg, about 0.75 to about 50 mg/kg, about 1 to about 50 mg/kg, about 1.5 to about 50 mg/kg, about 2 to about 50 mg/kg, about 2.5 to about 50 mg/kg, about 3 to about 50 mg/kg, about 3.5 to about 50 mg/kg, about 4 to about 50 mg/kg, about 4.5 to about 50 mg/kg, about 5 to about 50 mg/kg, about 7.5 to about 50 mg/kg, about 10 to about 50 mg/kg, about 15 to about 50 mg/kg, about 20 to about 50 mg/kg, about 20 to about 50 mg/kg, about 25 to about 50 mg/kg, about 25 to about 50 mg/kg, about 30 to about 50 mg/kg, about 35 to about 50 mg/kg, about 40 to about 50 mg/kg, about 45 to about 50 mg/kg, about 0.5 to about 45 mg/kg, about 0.75 to about 45 mg/kg, about 1 to about 45 mg/kg, about 1.5 to about 45 mg/kg, about 2 to about 45 mg/kg, about 2.5 to about 45 mg/kg, about 3 to about 45 mg/kg, about 3.5 to about 45 mg/kg, about 4 to about 45 mg/kg, about 4.5 to about 45 mg/kg, about 5 to about 45 mg/kg, about 7.5 to about 45 mg/kg, about 10 to about 45 mg/kg, about 15 to about 45 mg/kg, about 20 to about 45 mg/kg, about 20 to about 45 mg/kg, about 25 to about 45 mg/kg, about 25 to about 45 mg/kg, about 30 to about 45 mg/kg, about 35 to about 45 mg/kg, about 40 to about 45 mg/kg, about 0.5 to about 40 mg/kg, about 0.75 to about 40 mg/kg, about 1 to about 40 mg/kg, about 1.5 to about 40 mg/kg, about 2 to about 40 mg/kg, about 2.5 to about 40 mg/kg, about 3 to about 40 mg/kg, about 3.5 to about 40 mg/kg, about 4 to about 40 mg/kg, about 4.5 to about 40 mg/kg, about 5 to about 40 mg/kg, about 7.5 to about 40 mg/kg, about 10 to about 40 mg/kg, about 15 to about 40 mg/kg, about 20 to about 40 mg/kg, about 20 to about 40 mg/kg, about 25 to about 40 mg/kg, about 25 to about 40 mg/kg, about 30 to about 40 mg/kg, about 35 to about 40 mg/kg, about 0.5 to about 30 mg/kg, about 0.75 to about 30 mg/kg, about 1 to about 30 mg/kg, about 1.5 to about 30 mg/kg, about 2 to about 30 mg/kg, about 2.5 to about 30 mg/kg, about 3 to about 30 mg/kg, about 3.5 to about 30 mg/kg, about 4 to about 30 mg/kg, about 4.5 to about 30 mg/kg, about 5 to about 30 mg/kg, about 7.5 to about 30 mg/kg, about 10 to about 30 mg/kg, about 15 to about 30 mg/kg, about 20 to about 30 mg/kg, about 20 to about 30 mg/kg, about 25 to about 30 mg/kg, about 0.5 to about 20 mg/kg, about 0.75 to about 20 mg/kg, about 1 to about 20 mg/kg, about 1.5 to about 20 mg/kg, about 2 to about 20 mg/kg, about 2.5 to about 20 mg/kg, about 3 to about 20 mg/kg, about 3.5 to about 20 mg/kg, about 4 to about 20 mg/kg, about 4.5 to about 20 mg/kg, about 5 to about 20 mg/kg, about 7.5 to about 20 mg/kg, about 10 to about 20 mg/kg, or about 15 to about 20 mg/kg. In one embodiment, the dsRNA is administered at a dose of about 10 mg/kg to about 30 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     For example, subjects can be administered, e.g., subcutaneously, intramuscularly, or intravenously, a single therapeutic amount of iRNA, such as about 0.1, 0.125, 0.15, 0.175, 0.2, 0.225, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, 0.975, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 31, 32, 33, 34, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or about 50 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     In some embodiments, subjects are administered, e.g., subcutaneously, intramuscularly, or intravenously, multiple doses of a therapeutic amount of iRNA, such as a dose about 0.1, 0.125, 0.15, 0.175, 0.2, 0.225, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, 0.975, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 31, 32, 33, 34, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or about 50 mg/kg. A multi-dose regimine may include administration of a therapeutic amount of iRNA daily, such as for two days, three days, four days, five days, six days, seven days, or longer. 
     In other embodiments, subjects are administered, e.g., subcutaneously, intramuscularly, or intravenously, a repeat dose of a therapeutic amount of iRNA, such as a dose about 0.1, 0.125, 0.15, 0.175, 0.2, 0.225, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, 0.975, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 31, 32, 33, 34, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or about 50 mg/kg. A repeat-dose regimine may include administration of a therapeutic amount of iRNA on a regular basis, such as every other day, every third day, every fourth day, twice a week, once a week, every other week, or once a month. 
     In certain embodiments, for example, when a composition of the invention comprises a dsRNA as described herein and a lipid, subjects can be administered a therapeutic amount of iRNA, such as about 0.01 mg/kg to about 5 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.05 mg/kg to about 5 mg/kg, about 0.05 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 5 mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 0.2 mg/kg to about 5 mg/kg, about 0.2 mg/kg to about 10 mg/kg, about 0.3 mg/kg to about 5 mg/kg, about 0.3 mg/kg to about 10 mg/kg, about 0.4 mg/kg to about 5 mg/kg, about 0.4 mg/kg to about 10 mg/kg, about 0.5 mg/kg to about 5 mg/kg, about 0.5 mg/kg to about 10 mg/kg, about 1 mg/kg to about 5 mg/kg, about 1 mg/kg to about 10 mg/kg, about 1.5 mg/kg to about 5 mg/kg, about 1.5 mg/kg to about 10 mg/kg, about 2 mg/kg to about about 2.5 mg/kg, about 2 mg/kg to about 10 mg/kg, about 3 mg/kg to about 5 mg/kg, about 3 mg/kg to about 10 mg/kg, about 3.5 mg/kg to about 5 mg/kg, about 4 mg/kg to about 5 mg/kg, about 4.5 mg/kg to about 5 mg/kg, about 4 mg/kg to about 10 mg/kg, about 4.5 mg/kg to about 10 mg/kg, about 5 mg/kg to about 10 mg/kg, about 5.5 mg/kg to about 10 mg/kg, about 6 mg/kg to about 10 mg/kg, about 6.5 mg/kg to about 10 mg/kg, about 7 mg/kg to about 10 mg/kg, about 7.5 mg/kg to about 10 mg/kg, about 8 mg/kg to about 10 mg/kg, about 8.5 mg/kg to about 10 mg/kg, about 9 mg/kg to about 10 mg/kg, or about 9.5 mg/kg to about 10 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     For example, the dsRNA may be administered at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or about 10 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     In certain embodiments of the invention, for example, when a double-stranded RNAi agent includes a modification (e.g., one or more motifs of three identical modifications on three consecutive nucleotides), including one such motif at or near the cleavage site of the agent, six phosphorothioate linkages, and a ligand, such an agent is administered at a dose of about 0.01 to about 0.5 mg/kg, about 0.01 to about 0.4 mg/kg, about 0.01 to about 0.3 mg/kg, about 0.01 to about 0.2 mg/kg, about 0.01 to about 0.1 mg/kg, about 0.01 mg/kg to about 0.09 mg/kg, about 0.01 mg/kg to about 0.08 mg/kg, about 0.01 mg/kg to about 0.07 mg/kg, about 0.01 mg/kg to about 0.06 mg/kg, about 0.01 mg/kg to about 0.05 mg/kg, about 0.02 to about 0.5 mg/kg, about 0.02 to about 0.4 mg/kg, about 0.02 to about 0.3 mg/kg, about 0.02 to about 0.2 mg/kg, about 0.02 to about 0.1 mg/kg, about 0.02 mg/kg to about 0.09 mg/kg, about 0.02 mg/kg to about 0.08 mg/kg, about 0.02 mg/kg to about 0.07 mg/kg, about 0.02 mg/kg to about 0.06 mg/kg, about 0.02 mg/kg to about 0.05 mg/kg, about 0.03 to about 0.5 mg/kg, about 0.03 to about 0.4 mg/kg, about 0.03 to about 0.3 mg/kg, about 0.03 to about 0.2 mg/kg, about 0.03 to about 0.1 mg/kg, about 0.03 mg/kg to about 0.09 mg/kg, about 0.03 mg/kg to about 0.08 mg/kg, about 0.03 mg/kg to about 0.07 mg/kg, about 0.03 mg/kg to about 0.06 mg/kg, about 0.03 mg/kg to about 0.05 mg/kg, about 0.04 to about 0.5 mg/kg, about 0.04 to about 0.4 mg/kg, about 0.04 to about 0.3 mg/kg, about 0.04 to about 0.2 mg/kg, about 0.04 to about 0.1 mg/kg, about 0.04 mg/kg to about 0.09 mg/kg, about 0.04 mg/kg to about 0.08 mg/kg, about 0.04 mg/kg to about 0.07 mg/kg, about 0.04 mg/kg to about 0.06 mg/kg, about 0.05 to about 0.5 mg/kg, about 0.05 to about 0.4 mg/kg, about 0.05 to about 0.3 mg/kg, about 0.05 to about 0.2 mg/kg, about 0.05 to about 0.1 mg/kg, about 0.05 mg/kg to about 0.09 mg/kg, about 0.05 mg/kg to about 0.08 mg/kg, or about 0.05 mg/kg to about 0.07 mg/kg. Values and ranges intermediate to the foregoing recited values are also intended to be part of this invention, e.g., the RNAi agent may be administered to the subject at a dose of about 0.015 mg/kg to about 0.45 mg/kg. 
     For example, the RNAi agent, e.g., RNAi agent in a pharmaceutical composition, may be administered at a dose of about 0.01 mg/kg, 0.0125 mg/kg, 0.015 mg/kg, 0.0175 mg/kg, 0.02 mg/kg, 0.0225 mg/kg, 0.025 mg/kg, 0.0275 mg/kg, 0.03 mg/kg, 0.0325 mg/kg, 0.035 mg/kg, 0.0375 mg/kg, 0.04 mg/kg, 0.0425 mg/kg, 0.045 mg/kg, 0.0475 mg/kg, 0.05 mg/kg, 0.0525 mg/kg, 0.055 mg/kg, 0.0575 mg/kg, 0.06 mg/kg, 0.0625 mg/kg, 0.065 mg/kg, 0.0675 mg/kg, 0.07 mg/kg, 0.0725 mg/kg, 0.075 mg/kg, 0.0775 mg/kg, 0.08 mg/kg, 0.0825 mg/kg, 0.085 mg/kg, 0.0875 mg/kg, 0.09 mg/kg, 0.0925 mg/kg, 0.095 mg/kg, 0.0975 mg/kg, 0.1 mg/kg, 0.125 mg/kg, 0.15 mg/kg, 0.175 mg/kg, 0.2 mg/kg, 0.225 mg/kg, 0.25 mg/kg, 0.275 mg/kg, 0.3 mg/kg, 0.325 mg/kg, 0.35 mg/kg, 0.375 mg/kg, 0.4 mg/kg, 0.425 mg/kg, 0.45 mg/kg, 0.475 mg/kg, or about 0.5 mg/kg. Values intermediate to the foregoing recited values are also intended to be part of this invention. 
     In some embodiments, the RNAi agent is administered as a fixed dose of between about 100 mg to about 900 mg, e.g., between about 100 mg to about 850 mg, between about 100 mg to about 800 mg, between about 100 mg to about 750 mg, between about 100 mg to about 700 mg, between about 100 mg to about 650 mg, between about 100 mg to about 600 mg, between about 100 mg to about 550 mg, between about 100 mg to about 500 mg, between about 200 mg to about 850 mg, between about 200 mg to about 800 mg, between about 200 mg to about 750 mg, between about 200 mg to about 700 mg, between about 200 mg to about 650 mg, between about 200 mg to about 600 mg, between about 200 mg to about 550 mg, between about 200 mg to about 500 mg, between about 300 mg to about 850 mg, between about 300 mg to about 800 mg, between about 300 mg to about 750 mg, between about 300 mg to about 700 mg, between about 300 mg to about 650 mg, between about 300 mg to about 600 mg, between about 300 mg to about 550 mg, between about 300 mg to about 500 mg, between about 400 mg to about 850 mg, between about 400 mg to about 800 mg, between about 400 mg to about 750 mg, between about 400 mg to about 700 mg, between about 400 mg to about 650 mg, between about 400 mg to about 600 mg, between about 400 mg to about 550 mg, or between about 400 mg to about 500 mg. 
     In some embodiments, the RNAi agent is administered as a fixed dose of about 100 mg, about 125 mg, about 150 mg, about 175 mg, 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, or about 900 mg. 
     The pharmaceutical composition can be administered by intravenous infusion over a period of time, such as over a 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21, 22, 23, 24, or about a 25 minute period. The administration may be repeated, for example, on a regular basis, such as weekly, biweekly (i.e., every two weeks) for one month, two months, three months, four months or longer. After an initial treatment regimen, the treatments can be administered on a less frequent basis. For example, after administration weekly or biweekly for three months, administration can be repeated once per month, for six months or a year or longer. 
     The pharmaceutical composition can be administered once daily, or the iRNA can be administered as two, three, or more sub-doses at appropriate intervals throughout the day or even using continuous infusion or delivery through a controlled release formulation. In that case, the iRNA contained in each sub-dose must be correspondingly smaller in order to achieve the total daily dosage. The dosage unit can also be compounded for delivery over several days, e.g., using a conventional sustained release formulation which provides sustained release of the iRNA over a several day period. Sustained release formulations are well known in the art and are particularly useful for delivery of agents at a particular site, such as could be used with the agents of the present invention. In this embodiment, the dosage unit contains a corresponding multiple of the daily dose. 
     In other embodiments, a single dose of the pharmaceutical compositions can be long lasting, such that subsequent doses are administered at not more than 3, 4, or 5 day intervals, or at not more than 1, 2, 3, or 4 week intervals. In some embodiments of the invention, a single dose of the pharmaceutical compositions of the invention is administered once per week. In other embodiments of the invention, a single dose of the pharmaceutical compositions of the invention is administered bi-monthly. In some embodiments of the invention, a single dose of the pharmaceutical compositions of the invention is administered once per month, once every other month, or once quarterly (i.e., every three months). 
     The skilled artisan will appreciate that certain factors can influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a composition can include a single treatment or a series of treatments. Estimates of effective dosages and in vivo half-lives for the individual iRNAs encompassed by the invention can be made using conventional methodologies or on the basis of in vivo testing using an appropriate animal model, as described elsewhere herein. 
     The pharmaceutical compositions of the present invention can be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (e.g., by a transdermal patch), pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; subdermal, e.g., via an implanted device; or intracranial, e.g., by intraparenchymal, intrathecal or intraventricular, administration. 
     The iRNA can be delivered in a manner to target a particular tissue, such as the liver (e.g., the hepatocytes of the liver). 
     Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like can be necessary or desirable. Coated condoms, gloves and the like can also be useful. Suitable topical formulations include those in which the iRNAs featured in the invention are in admixture with a topical delivery agent such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelating agents and surfactants. Suitable lipids and liposomes include neutral (e.g., dioleoylphosphatidyl DOPE ethanolamine, dimyristoylphosphatidyl choline DMPC, distearolyphosphatidyl choline) negative (e.g., dimyristoylphosphatidyl glycerol DMPG) and cationic (e.g., dioleoyltetramethylaminopropyl DOTAP and dioleoylphosphatidyl ethanolamine DOTMA). iRNAs featured in the invention can be encapsulated within liposomes or can form complexes thereto, in particular to cationic liposomes. Alternatively, iRNAs can be complexed to lipids, in particular to cationic lipids. Suitable fatty acids and esters include but are not limited to arachidonic acid, oleic 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, 1-dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, or a C 1-20  alkyl ester (e.g., isopropylmyristate IPM), monoglyceride, diglyceride or pharmaceutically acceptable salt thereof). Topical formulations are described in detail in U.S. Pat. No. 6,747,014, which is incorporated herein by reference. 
     A. iRNA Formulations Comprising Membranous Molecular Assemblies 
     An iRNA for use in the compositions and methods of the invention can be formulated for delivery in a membranous molecular assembly, e.g., a liposome or a micelle. As used herein, the term “liposome” refers to a vesicle composed of amphiphilic lipids arranged in at least one bilayer, e.g., one bilayer or a plurality of bilayers. Liposomes include unilamellar and multilamellar vesicles that have a membrane formed from a lipophilic material and an aqueous interior. The aqueous portion contains the iRNA composition. The lipophilic material isolates the aqueous interior from an aqueous exterior, which typically does not include the iRNA composition, although in some examples, it may. Liposomes are useful for the transfer and delivery of active ingredients to the site of action. Because the liposomal membrane is structurally similar to biological membranes, when liposomes are applied to a tissue, the liposomal bilayer fuses with bilayer of the cellular membranes. As the merging of the liposome and cell progresses, the internal aqueous contents that include the iRNA are delivered into the cell where the iRNA can specifically bind to a target RNA and can mediate iRNA. In some cases the liposomes are also specifically targeted, e.g., to direct the iRNA to particular cell types. 
     A liposome containing an iRNA agent can be prepared by a variety of methods. In one example, the lipid component of a liposome is dissolved in a detergent so that micelles are formed with the lipid component. For example, the lipid component can be an amphipathic cationic lipid or lipid conjugate. The detergent can have a high critical micelle concentration and may be nonionic. Exemplary detergents include cholate, CHAPS, octylglucoside, deoxycholate, and lauroyl sarcosine. The iRNA agent preparation is then added to the micelles that include the lipid component. The cationic groups on the lipid interact with the iRNA agent and condense around the iRNA agent to form a liposome. After condensation, the detergent is removed, e.g., by dialysis, to yield a liposomal preparation of iRNA agent. 
     If necessary a carrier compound that assists in condensation can be added during the condensation reaction, e.g., by controlled addition. For example, the carrier compound can be a polymer other than a nucleic acid (e.g., spermine or spermidine). pH can also adjusted to favor condensation. 
     Methods for producing stable polynucleotide delivery vehicles, which incorporate a polynucleotide/cationic lipid complex as structural components of the delivery vehicle, are further described in, e.g., WO 96/37194, the entire contents of which are incorporated herein by reference. Liposome formation can also include one or more aspects of exemplary methods described in Felgner, P. L. et al.,  Proc. Natl. Acad. Sci., USA  8:7413-7417, 1987; U.S. Pat. Nos. 4,897,355; 5,171,678; Bangham, et al.  M. Mol. Biol.  23:238, 1965; Olson, et al.  Biochim. Biophys. Acta  557:9, 1979; Szoka, et al.  Proc. Natl. Acad. Sci.  75: 4194, 1978; Mayhew, et al.  Biochim. Biophys. Acta  775:169, 1984; Kim, et al.  Biochim. Biophys. Acta  728:339, 1983; and Fukunaga, et al.  Endocrinol.  115:757, 1984. Commonly used techniques for preparing lipid aggregates of appropriate size for use as delivery vehicles include sonication and freeze-thaw plus extrusion (see, e.g., Mayer, et al.  Biochim. Biophys. Acta  858:161, 1986). Microfluidization can be used when consistently small (50 to 200 nm) and relatively uniform aggregates are desired (Mayhew, et al.  Biochim. Biophys. Acta  775:169, 1984). These methods are readily adapted to packaging iRNA agent preparations into liposomes. 
     Liposomes fall into two broad classes. Cationic liposomes are positively charged liposomes which interact with the negatively charged nucleic acid molecules to form a stable complex. The positively charged nucleic acid/liposome complex binds to the negatively charged cell surface and is internalized in an endosome. Due to the acidic pH within the endosome, the liposomes are ruptured, releasing their contents into the cell cytoplasm (Wang et al.,  Biochem. Biophys. Res. Commun.,  1987, 147, 980-985). 
     Liposomes which are pH-sensitive or negatively-charged, entrap nucleic acids rather than complex with it. Since both the nucleic acid and the lipid are similarly charged, repulsion rather than complex formation occurs. Nevertheless, some nucleic acid is entrapped within the aqueous interior of these liposomes. pH-sensitive liposomes have been used to deliver nucleic acids encoding the thymidine kinase gene to cell monolayers in culture. Expression of the exogenous gene was detected in the target cells (Zhou et al.,  Journal of Controlled Release,  1992, 19, 269-274). 
     One major type of liposomal composition includes phospholipids other than naturally-derived phosphatidylcholine. Neutral liposome compositions, for example, can be formed from dimyristoyl phosphatidylcholine (DMPC) or dipalmitoyl phosphatidylcholine (DPPC). Anionic liposome compositions generally are formed from dimyristoyl phosphatidylglycerol, while anionic fusogenic liposomes are formed primarily from dioleoyl phosphatidylethanolamine (DOPE). Another type of liposomal composition is formed from phosphatidylcholine (PC) such as, for example, soybean PC, and egg PC. Another type is formed from mixtures of phospholipid and/or phosphatidylcholine and/or cholesterol. 
     Examples of other methods to introduce liposomes into cells in vitro and in vivo include U.S. Pat. Nos. 5,283,185; 5,171,678; WO 94/00569; WO 93/24640; WO 91/16024; Felgner,  J. Biol. Chem.  269:2550, 1994; Nabel,  Proc. Natl. Acad. Sci.  90:11307, 1993; Nabel,  Human Gene Ther.  3:649, 1992; Gershon,  Biochem.  32:7143, 1993; and Strauss  EMBO J.  11:417, 1992. 
     Non-ionic liposomal systems have also been examined to determine their utility in the delivery of drugs to the skin, in particular systems comprising non-ionic surfactant and cholesterol. Non-ionic liposomal formulations comprising Novasome™ I (glyceryl dilaurate/cholesterol/polyoxyethylene-10-stearyl ether) and Novasome™ II (glyceryl distearate/cholesterol/polyoxyethylene-10-stearyl ether) were used to deliver cyclosporin-A into the dermis of mouse skin. Results indicated that such non-ionic liposomal systems were effective in facilitating the deposition of cyclosporine A into different layers of the skin (Hu et al.  S.T.P. Pharma. Sci.,  1994, 4(6) 466). 
     Liposomes also include “sterically stabilized” liposomes, a term which, as used herein, refers to liposomes comprising one or more specialized lipids that, when incorporated into liposomes, result in enhanced circulation lifetimes relative to liposomes lacking such specialized lipids. Examples of sterically stabilized liposomes are those in which part of the vesicle-forming lipid portion of the liposome (A) comprises one or more glycolipids, such as monosialoganglioside G M1 , or (B) is derivatized with one or more hydrophilic polymers, such as a polyethylene glycol (PEG) moiety. While not wishing to be bound by any particular theory, it is thought in the art that, at least for sterically stabilized liposomes containing gangliosides, sphingomyelin, or PEG-derivatized lipids, the enhanced circulation half-life of these sterically stabilized liposomes derives from a reduced uptake into cells of the reticuloendothelial system (RES) (Allen 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) reported the ability of monosialoganglioside G M1 , galactocerebroside sulfate and phosphatidylinositol to improve blood half-lives of liposomes. These findings were expounded upon by Gabizon et al. ( Proc. Natl. Acad. Sci. U.S.A.,  1988, 85, 6949). U.S. Pat. No. 4,837,028 and WO 88/04924, both to Allen et al., disclose liposomes comprising (1) sphingomyelin and (2) the ganglioside G M1  or a galactocerebroside sulfate ester. U.S. Pat. No. 5,543,152 (Webb et al.) discloses liposomes comprising sphingomyelin. Liposomes comprising 1,2-sn-dimyristoylphosphatidylcholine are disclosed in WO 97/13499 (Lim et al). 
     In one embodiment, cationic liposomes are used. Cationic liposomes possess the advantage of being able to fuse to the cell membrane. Non-cationic liposomes, although not able to fuse as efficiently with the plasma membrane, are taken up by macrophages in vivo and can be used to deliver iRNA agents to macrophages. 
     Further advantages of liposomes include: liposomes obtained from natural phospholipids are biocompatible and biodegradable; liposomes can incorporate a wide range of water and lipid soluble drugs; liposomes can protect encapsulated iRNA agents in their internal compartments from metabolism and degradation (Rosoff, in “Pharmaceutical Dosage Forms,” Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 245). Important considerations in the preparation of liposome formulations are the lipid surface charge, vesicle size and the aqueous volume of the liposomes. 
     A positively charged synthetic cationic lipid, N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA) can be used to form small liposomes that interact spontaneously with nucleic acid to form lipid-nucleic acid complexes which are capable of fusing with the negatively charged lipids of the cell membranes of tissue culture cells, resulting in delivery of iRNA agent (see, e.g., Felgner, P. L. et al., Proc. Natl. Acad. Sci., USA 8:7413-7417, 1987 and U.S. Pat. No. 4,897,355 for a description of DOTMA and its use with DNA). 
     A DOTMA analogue, 1,2-bis(oleoyloxy)-3-(trimethylammonia)propane (DOTAP) can be used in combination with a phospholipid to form DNA-complexing vesicles. Lipofectin™ Bethesda Research Laboratories, Gaithersburg, Md.) is an effective agent for the delivery of highly anionic nucleic acids into living tissue culture cells that comprise positively charged DOTMA liposomes which interact spontaneously with negatively charged polynucleotides to form complexes. When enough positively charged liposomes are used, the net charge on the resulting complexes is also positive. Positively charged complexes prepared in this way spontaneously attach to negatively charged cell surfaces, fuse with the plasma membrane, and efficiently deliver functional nucleic acids into, for example, tissue culture cells. Another commercially available cationic lipid, 1,2-bis(oleoyloxy)-3,3-(trimethylammonia)propane (“DOTAP”) (Boehringer Mannheim, Indianapolis, Ind.) differs from DOTMA in that the oleoyl moieties are linked by ester, rather than ether linkages. 
     Other reported cationic lipid compounds include those that have been conjugated to a variety of moieties including, for example, carboxyspermine which has been conjugated to one of two types of lipids and includes compounds such as 5-carboxyspermylglycine dioctaoleoylamide (“DOGS”) (Transfectam™, Promega, Madison, Wis.) and dipalmitoylphosphatidylethanolamine 5-carboxyspermyl-amide (“DPPES”) (see, e.g., U.S. Pat. No. 5,171,678). 
     Another cationic lipid conjugate includes derivatization of the lipid with cholesterol (“DC-Chol”) which has been formulated into liposomes in combination with DOPE (See, Gao, X. and Huang, L.,  Biochim. Biophys. Res. Commun.  179:280, 1991). Lipopolylysine, made by conjugating polylysine to DOPE, has been reported to be effective for transfection in the presence of serum (Zhou, X. et al.,  Biochim. Biophys. Acta  1065:8, 1991). For certain cell lines, these liposomes containing conjugated cationic lipids, are said to exhibit lower toxicity and provide more efficient transfection than the DOTMA-containing compositions. Other commercially available cationic lipid products include DMRIE and DMRIE-HP (Vical, La Jolla, Calif.) and Lipofectamine (DOSPA) (Life Technology, Inc., Gaithersburg, Md.). Other cationic lipids suitable for the delivery of oligonucleotides are described in WO 98/39359 and WO 96/37194. 
     Liposomal formulations are particularly suited for topical administration, liposomes present several advantages over other formulations. Such advantages include reduced side effects related to high systemic absorption of the administered drug, increased accumulation of the administered drug at the desired target, and the ability to administer iRNA agent into the skin. In some implementations, liposomes are used for delivering iRNA agent to epidermal cells and also to enhance the penetration of iRNA agent into dermal tissues, e.g., into skin. For example, the liposomes can be applied topically. Topical delivery of drugs formulated as liposomes to the skin has been documented (see, e.g., Weiner et al.,  Journal of Drug Targeting,  1992, vol. 2, 405-410 and du Plessis et al.,  Antiviral Research,  18, 1992, 259-265; Mannino, R. J. and Fould-Fogerite, S.,  Biotechniques  6:682-690, 1988; Itani, T. et al.  Gene  56:267-276. 1987; Nicolau, C. et al.  Meth. Enz.  149:157-176, 1987; Straubinger, R. M. and Papahadjopoulos, D.  Meth. Enz.  101:512-527, 1983; Wang, C. Y. and Huang, L.,  Proc. Natl. Acad. Sci. USA  84:7851-7855, 1987). 
     Non-ionic liposomal systems have also been examined to determine their utility in the delivery of drugs to the skin, in particular systems comprising non-ionic surfactant and cholesterol. Non-ionic liposomal formulations comprising Novasome I (glyceryl dilaurate/cholesterol/polyoxyethylene-10-stearyl ether) and Novasome II (glyceryl distearate/cholesterol/polyoxyethylene-10-stearyl ether) were used to deliver a drug into the dermis of mouse skin. Such formulations with iRNA agent are useful for treating a dermatological disorder. 
     Liposomes that include iRNA can be made highly deformable. Such deformability can enable the liposomes to penetrate through pore that are smaller than the average radius of the liposome. For example, transfersomes are a type of deformable liposomes. 
     Transferosomes can be made by adding surface edge activators, usually surfactants, to a standard liposomal composition. Transfersomes that include iRNA agent can be delivered, for example, subcutaneously by infection in order to deliver iRNA agent to keratinocytes in the skin. In order to cross intact mammalian skin, 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. In addition, due to the lipid properties, these transferosomes can be self-optimizing (adaptive to the shape of pores, e.g., in the skin), self-repairing, and can frequently reach their targets without fragmenting, and often self-loading. 
     Other formulations amenable to the present invention are described in, for example, PCT Publication No. WO 2008/042973, the entire contents of which are incorporated herein by reference. 
     Transfersomes are yet another type of liposomes, and are highly deformable lipid aggregates which are attractive candidates for drug delivery vehicles. Transfersomes can be described as lipid droplets which are so highly deformable that they are easily able to penetrate through pores which are smaller than the droplet. Transfersomes are adaptable to the environment in which they are used, e.g., they are self-optimizing (adaptive to the shape of pores in the skin), self-repairing, frequently reach their targets without fragmenting, and often self-loading. To make transfersomes it is possible to add surface edge-activators, usually surfactants, to a standard liposomal composition. Transfersomes have been used to deliver serum albumin to the skin. The transfersome-mediated delivery of serum albumin has been shown to be as effective as 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 of classifying and ranking the properties of the many different types of surfactants, both natural and synthetic, is by the use of the hydrophile/lipophile balance (HLB). The nature of the hydrophilic group (also known as the “head”) provides the most useful means for categorizing the different surfactants used in formulations (Rieger, in “Pharmaceutical Dosage Forms”, Marcel Dekker, Inc., New York, N.Y., 1988, p. 285). 
     If the surfactant molecule is not ionized, it is classified as a nonionic surfactant. Nonionic surfactants find wide application in pharmaceutical and cosmetic products and are usable over a wide range of pH values. In general their HLB values range from 2 to about 18 depending on their structure. Nonionic surfactants include nonionic esters 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 block polymers are also included in this class. The polyoxyethylene surfactants are the most popular members of the nonionic surfactant class. 
     If the surfactant molecule carries a negative charge when it is dissolved or dispersed in water, the surfactant is classified as anionic. Anionic surfactants include carboxylates such as soaps, acyl lactylates, acyl amides of amino acids, esters of sulfuric acid 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 class are the alkyl sulfates and the soaps. 
     If the surfactant molecule carries a positive charge when it is dissolved or dispersed in water, the surfactant is classified as cationic. Cationic surfactants include quaternary ammonium salts and ethoxylated amines. The quaternary ammonium salts are the most used members of this class. 
     If the surfactant molecule has the ability to carry either a positive or negative charge, the surfactant is classified as amphoteric. Amphoteric surfactants include acrylic acid derivatives, 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). 
     The iRNA for use in the methods of the invention can also be provided as micellar formulations. “Micelles” are defined herein as a particular type of molecular assembly in which amphipathic molecules are arranged in a spherical structure such that all the hydrophobic portions of the molecules are directed inward, leaving the hydrophilic portions in contact with the surrounding aqueous phase. The converse arrangement exists if the environment is hydrophobic. 
     A mixed micellar formulation suitable for delivery through transdermal membranes may be prepared by mixing an aqueous solution of the siRNA composition, an alkali metal C 8  to C 22  alkyl sulphate, and a micelle forming compounds. Exemplary micelle forming compounds include lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linoleic acid, linolenic acid, monoolein, monooleates, monolaurates, borage oil, evening of primrose oil, menthol, trihydroxy oxo cholanyl glycine and pharmaceutically acceptable salts thereof, glycerin, polyglycerin, lysine, polylysine, triolein, polyoxyethylene ethers and analogues thereof, polidocanol alkyl ethers and analogues thereof, chenodeoxycholate, deoxycholate, and mixtures thereof. The micelle forming compounds may be added at the same time or after addition of the alkali metal alkyl sulphate. Mixed micelles will form with substantially any kind of mixing of the ingredients but vigorous mixing in order to provide smaller size micelles. 
     In one method a first micellar composition is prepared which contains the siRNA composition and at least the alkali metal alkyl sulphate. The first micellar composition is then mixed with at least three micelle forming compounds to form a mixed micellar composition. In another method, the micellar composition is prepared by mixing the siRNA composition, the alkali metal alkyl sulphate and at least one of the micelle forming compounds, followed by addition of the remaining micelle forming compounds, with vigorous mixing. 
     Phenol and/or m-cresol may be added to the mixed micellar composition to stabilize the formulation and protect against bacterial growth. Alternatively, phenol and/or m-cresol may be added with the micelle forming ingredients. An isotonic agent such as glycerin may also be added after formation of the mixed micellar composition. 
     For delivery of the micellar formulation as a spray, the formulation can be put into an aerosol dispenser and the dispenser is charged with a propellant. The propellant, which is under pressure, is in liquid form in the dispenser. The ratios of the ingredients are adjusted so that the aqueous and propellant phases become one, i.e., there is one phase. If there are two phases, it is necessary to shake the dispenser prior to dispensing a portion of the contents, e.g., through a metered valve. The dispensed dose of pharmaceutical agent is propelled from the metered valve in a fine spray. 
     Propellants may include hydrogen-containing chlorofluorocarbons, hydrogen-containing fluorocarbons, dimethyl ether and diethyl ether. In certain embodiments, HFA 134a (1,1,1,2 tetrafluoroethane) may be used. 
     The specific concentrations of the essential ingredients can be determined by relatively straightforward experimentation. For absorption through the oral cavities, it is often desirable to increase, e.g., at least double or triple, the dosage for through injection or administration through the gastrointestinal tract. 
     B. Lipid Particles 
     iRNAs, e.g., dsRNAs of in the invention may be fully encapsulated in a lipid formulation, e.g., a LNP, or other nucleic acid-lipid particle. 
     As used herein, the term “LNP” refers to a stable nucleic acid-lipid particle. LNPs typically contain a cationic lipid, a non-cationic lipid, and a lipid that prevents aggregation of the particle (e.g., a PEG-lipid conjugate). LNPs are extremely useful for systemic applications, as they exhibit extended circulation lifetimes following intravenous (i.v.) injection and accumulate at distal sites (e.g., sites physically separated from the administration site). LNPs include “pSPLP,” which include an encapsulated condensing agent-nucleic acid complex as set forth in PCT Publication No. WO 00/03683. The particles of the present invention typically have a mean diameter of about 50 nm to about 150 nm, more typically about 60 nm to about 130 nm, more typically about 70 nm to about 110 nm, most typically about 70 nm to about 90 nm, and are substantially nontoxic. In addition, the nucleic acids when present in the nucleic acid-lipid particles of the present invention are resistant in aqueous solution to degradation with a nuclease. Nucleic acid-lipid particles and their method of preparation are disclosed in, e.g., U.S. Pat. Nos. 5,976,567; 5,981,501; 6,534,484; 6,586,410; 6,815,432; U.S. Publication No. 2010/0324120 and PCT Publication No. WO 96/40964. 
     In one embodiment, the lipid to drug ratio (mass/mass ratio) (e.g., lipid to dsRNA ratio) will be in the range of from about 1:1 to about 50:1, from about 1:1 to about 25:1, from about 3:1 to about 15:1, from about 4:1 to about 10:1, from about 5:1 to about 9:1, or about 6:1 to about 9:1. Ranges intermediate to the above recited ranges are also contemplated to be part of the invention. 
     The cationic lipid can be, for example, N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N—(I-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N—(I-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), N,N-dimethyl-2,3-dioleyloxy)propylamine (DODMA), 1,2-DiLinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), 1,2-Dilinoleylcarbamoyloxy-3-dimethylaminopropane (DLin-C-DAP), 1,2-Dilinoleyoxy-3-(dimethylamino)acetoxypropane (DLin-DAC), 1,2-Dilinoleyoxy-3-morpholinopropane (DLin-MA), 1,2-Dilinoleoyl-3-dimethylaminopropane (DLinDAP), 1,2-Dilinoleylthio-3-dimethylaminopropane (DLin-S-DMA), 1-Linoleoyl-2-linoleyloxy-3-dimethylaminopropane (DLin-2-DMAP), 1,2-Dilinoleyloxy-3-trimethylaminopropane chloride salt (DLin-TMA.Cl), 1,2-Dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.Cl), 1,2-Dilinoleyloxy-3-(N-methylpiperazino)propane (DLin-MPZ), or 3-(N,N-Dilinoleylamino)-1,2-propanediol (DLinAP), 3-(N,N-Dioleylamino)-1,2-propanedio (DOAP), 1,2-Dilinoleyloxo-3-(2-N,N-dimethylamino)ethoxypropane (DLin-EG-DMA), 1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLinDMA), 2,2-Dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA) or analogs thereof, (3aR,5s,6aS)—N,N-dimethyl-2,2-di((9Z,12Z)-octadeca-9,12-dienyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-5-amine (ALN100), (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (MC3), 1,1′-(2-(4-(2-((2-(bis(2-hydroxydodecyl)amino)ethyl)(2-hydroxydodecyl)amino)ethyl)piperazin-1-yl)ethylazanediyl)didodecan-2-ol (Tech GI), or a mixture thereof. The cationic lipid can comprise from about 20 mol % to about 50 mol % or about 40 mol % of the total lipid present in the particle. 
     In another embodiment, the compound 2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane can be used to prepare lipid-siRNA nanoparticles. Synthesis of 2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane is described in U.S. provisional patent application No. 61/107,998 filed on Oct. 23, 2008, which is herein incorporated by reference. 
     In one embodiment, the lipid-siRNA particle includes 40% 2, 2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane: 10% DSPC: 40% Cholesterol: 10% PEG-C-DOMG (mole percent) with a particle size of 63.0±20 nm and a 0.027 siRNA/Lipid Ratio. 
     The ionizable/non-cationic lipid can be an anionic lipid or a neutral lipid including, but not limited to, distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidyl-ethanolamine (DSPE), 16-O-monomethyl PE, 16-O-dimethyl PE, 18-1-trans PE, 1-stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), cholesterol, or a mixture thereof. The non-cationic lipid can be from about 5 mol % to about 90 mol %, about 10 mol %, or about 58 mol % if cholesterol is included, of the total lipid present in the particle. 
     The conjugated lipid that inhibits aggregation of particles can be, for example, a polyethyleneglycol (PEG)-lipid including, without limitation, a PEG-diacylglycerol (DAG), a PEG-dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG-ceramide (Cer), or a mixture thereof. The PEG-DAA conjugate can be, for example, a PEG-dilauryloxypropyl (Ci 2 ), a PEG-dimyristyloxypropyl (Ci 4 ), a PEG-dipalmityloxypropyl (Ci 6 ), or a PEG-distearyloxypropyl (C] 8 ). The conjugated lipid that prevents aggregation of particles can be from 0 mol % to about 20 mol % or about 2 mol % of the total lipid present in the particle. 
     In some embodiments, the nucleic acid-lipid particle further includes cholesterol at, e.g., about 10 mol % to about 60 mol % or about 48 mol % of the total lipid present in the particle. 
     In one embodiment, the lipidoid ND98.4HCl (MW 1487) (see U.S. patent application Ser. No. 12/056,230, filed Mar. 26, 2008, which is incorporated herein by reference), Cholesterol (Sigma-Aldrich), and PEG-Ceramide C16 (Avanti Polar Lipids) can be used to prepare lipid-dsRNA nanoparticles (i.e., LNP01 particles). Stock solutions of each in ethanol can be prepared as follows: ND98, 133 mg/ml; Cholesterol, 25 mg/ml, PEG-Ceramide C16, 100 mg/ml. The ND98, Cholesterol, and PEG-Ceramide C16 stock solutions can then be combined in a, e.g., 42:48:10 molar ratio. The combined lipid solution can be mixed with aqueous dsRNA (e.g., in sodium acetate pH 5) such that the final ethanol concentration is about 35-45% and the final sodium acetate concentration is about 100-300 mM. Lipid-dsRNA nanoparticles typically form spontaneously upon mixing. Depending on the desired particle size distribution, the resultant nanoparticle mixture can be extruded through a polycarbonate membrane (e.g., 100 nm cut-off) using, for example, a thermobarrel extruder, such as Lipex Extruder (Northern Lipids, Inc). In some cases, the extrusion step can be omitted. Ethanol removal and simultaneous buffer exchange can be accomplished by, for example, dialysis or tangential flow filtration. Buffer can be exchanged with, for example, phosphate buffered saline (PBS) at about pH 7, e.g., about pH 6.9, about pH 7.0, about pH 7.1, about pH 7.2, about pH 7.3, or about pH 7.4. 
     
       
         
         
             
             
         
       
     
     LNP01 formulations are described, e.g., in International Application Publication No. WO 2008/042973, which is hereby incorporated by reference. 
     Additional exemplary lipid-dsRNA formulations are described in Table 1. 
     
       
         
           
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                   
                   
                 cationic lipid/non-cationic 
               
               
                   
                   
                 lipid/cholesterol/PEG-lipid  
               
               
                   
                 Ionizable/Cationic Lipid 
                 conjugate Lipid:siRNA ratio 
               
               
                   
               
             
            
               
                 SNALP-1 
                 1,2-Dilinolenyloxy-N,N- 
                 DLinDMA/DPPC/Cholesterol/ 
               
               
                   
                 dimethylaminopropane  
                 PEG-cDMA 
               
               
                   
                 (DLinDMA) 
                 (57.1/7.1/34.4/1.4) 
               
               
                   
                   
                 lipid:siRNA~7:1 
               
               
                 2-XTC 
                 2,2-Dilinoleyl-4- 
                 XTC/DPPC/Cholesterol/ 
               
               
                   
                 dimethylaminoethyl- 
                 PEG-cDMA 
               
               
                   
                 [1,3]-dioxolane (XTC) 
                 57.1/7.1/34.4/1.4 
               
               
                   
                   
                 lipid:siRNA~7:1 
               
               
                 LNP05 
                 2,2-Dilinoleyl-4- 
                 XTC/DSPC/Cholesterol/ 
               
               
                   
                 dimethylaminoethyl- 
                 PEG-DMG 
               
               
                   
                 [1,3]-dioxolane (XTC) 
                 57.5/7.5/31.5/3.5 
               
               
                   
                   
                 lipid:siRNA~6:1 
               
               
                 LNP06 
                 2,2-Dilinoleyl-4- 
                 XTC/DSPC/Cholesterol/ 
               
               
                   
                 dimethylaminoethyl- 
                 PEG-DMG 
               
               
                   
                 [1,3]-dioxolane (XTC) 
                 57.5/7.5/31.5/3.5 
               
               
                   
                   
                 lipid:siRNA~11:1 
               
               
                 LNP07 
                 2,2-Dilinoleyl-4- 
                 XTC/DSPC/Cholesterol/ 
               
               
                   
                 dimethylaminoethyl- 
                 PEG-DMG 
               
               
                   
                 [1,3]-dioxolane (XTC)  
                 60/7.5/31/1.5, 
               
               
                   
                   
                 lipid:siRNA~6:1 
               
               
                 LNP08 
                 2,2-Dilinoleyl-4- 
                 XTC/DSPC/Cholesterol/ 
               
               
                   
                 dimethylaminoethyl- 
                 PEG-DMG 
               
               
                   
                 [1,3]-dioxolane (XTC) 
                 60/7.5/31/1.5, 
               
               
                   
                   
                 lipid:siRNA~11:1 
               
               
                 LNP09 
                 2,2-Dilinoleyl-4- 
                 XTC/DSPC/Cholesterol/ 
               
               
                   
                 dimethylaminoethyl- 
                 PEG-DMG 
               
               
                   
                 [1,3]-dioxolane (XTC) 
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA 10:1 
               
               
                 LNP10 
                 (3aR,5s,6aS)-N,N-dimethyl- 
                 ALN100/DSPC/Cholesterol/ 
               
               
                   
                 2,2-di((9Z,12Z)-octadeca- 
                 PEG-DMG 
               
               
                   
                 9,12-dienyl)tetrahydro- 
                 50/10/38.5/1.5 
               
               
                   
                 3aH-cyclopenta[d] 
                 Lipid: siRNA 10:1 
               
               
                   
                 [1,3]dioxol-5-amine 
                   
               
               
                   
                 (ALN100) 
                   
               
               
                 LNP11 
                 (6Z,9Z,28Z,31Z)- 
                 MC-3/DSPC/Cholesterol/ 
               
               
                   
                 heptatriaconta- 
                 PEG-DMG 
               
               
                   
                 6,9,28,31-tetraen- 
                 50/10/38.5/1.5 
               
               
                   
                 19-yl 4-(dimethylamino) 
                 Lipid:siRNA 10:1 
               
               
                   
                 butanoate (MC3) 
                   
               
               
                 LNP12 
                 1,1&#39;-(2-(4-(2-((2-(bis(2- 
                 Tech G1/DSPC/ 
               
               
                   
                 hydroxydodecyl) 
                 Cholesterol/PEG-DMG 
               
               
                   
                 amino)ethyl)(2- 
                 50/10/38.5/1.5 
               
               
                   
                 hydroxydodecyl)amino) 
                 Lipid:siRNA 10:1 
               
               
                   
                 ethyl)piperazin- 
                   
               
               
                   
                 1-yl)ethylazanediyl) 
                   
               
               
                   
                 didodecan-2-ol 
                   
               
               
                   
                 (Tech G1) 
                   
               
               
                 LNP13 
                 XTC 
                 XTC/DSPC/Chol/ 
               
               
                   
                   
                 PEG-DMG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA: 33:1 
               
               
                 LNP14 
                 MC3 
                 MC3/DSPC/Chol/ 
               
               
                   
                   
                 PEG-DMG 
               
               
                   
                   
                 40/15/40/5 
               
               
                   
                   
                 Lipid:siRNA: 11:1 
               
               
                 LNP15 
                 MC3 
                 MC3/DSPC/Chol/ 
               
               
                   
                   
                 PEG-DSG/GalNAc- 
               
               
                   
                   
                 PEG-DSG/ 
               
               
                   
                   
                 50/10/35/4.5/0.5 
               
               
                   
                   
                 Lipid:siRNA: 11:1 
               
               
                 LNP16 
                 MC3 
                 MC3/DSPC/Chol/ 
               
               
                   
                   
                 PEG-DMG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA: 7:1 
               
               
                 LNP17 
                 MC3 
                 MC3/DSPC/Chol/ 
               
               
                   
                   
                 PEG-DSG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA: 10:1 
               
               
                 LNP18 
                 MC3 
                 MC3/DSPC/Chol/ 
               
               
                   
                   
                 PEG-DMG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA: 12:1 
               
               
                 LNP19 
                 MC3 
                 MC3/DSPC/Chol/ 
               
               
                   
                   
                 PEG-DMG 
               
               
                   
                   
                 50/10/35/5 
               
               
                   
                   
                 Lipid:siRNA: 8:1 
               
               
                 LNP20 
                 MC3 
                 MC3/DSPC/Chol/ 
               
               
                   
                   
                 PEG-DPG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA: 10:1 
               
               
                 LNP21 
                 C12-200 
                 C12-200/DSPC/Chol/ 
               
               
                   
                   
                 PEG-DSG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA: 7:1 
               
               
                 LNP22 
                 XTC 
                 XTC/DSPC/Chol/ 
               
               
                   
                   
                 PEG-DSG 
               
               
                   
                   
                 50/10/38.5/1.5 
               
               
                   
                   
                 Lipid:siRNA: 10:1 
               
               
                   
               
               
                 DSPC: distearoylphosphatidylcholine 
               
               
                 DPPC: dipalmitoylphosphatidylcholine 
               
               
                 PEG-DMG: PEG-didimyristoyl glycerol (C14-PEG, or PEG-C14) (PEG with avg mol wt of 2000) 
               
               
                 PEG-DSG: PEG-distyryl glycerol (C18-PEG, or PEG-C18) (PEG with avg mol wt of 2000) 
               
               
                 PEG-cDMA: PEG-carbamoyl-1,2-dimyristyloxypropylamine (PEG with avg mol wt of 2000) 
               
               
                 SNALP (1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLinDMA)) comprising formulations are described in International PublicationNo. W02009/127060, filed Apr. 15, 2009, which is hereby incorporated by reference. 
               
               
                 XTC e.g., comprising formulations are described, in PCT Publication No. WO 2010/088537, the entire contents of which are incorporated herein by reference. 
               
               
                 MC3 comprising formulations are described, e.g., in U.S. Publication No. 2010/0324120, filed Jun. 10, 2010, the entire contents of which are incorporated herein by reference. 
               
               
                 ALNY-100 comprising formulations are described, e.g., PCT Publication No. WO 2010/054406, the entire contents of which are incorporated herein by reference. 
               
               
                 C12-200 comprising formulations are described in PCT Publication No. WO 2010/129709, the entire contents of which are incorporated herein by reference. 
               
            
           
         
       
     
     Compositions and formulations for oral administration include powders or granules, microparticulates, nanoparticulates, suspensions or solutions in water or non-aqueous media, capsules, gel capsules, sachets, tablets or minitablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders can be desirable. In some embodiments, oral formulations are those in which dsRNAs featured in the invention are administered in conjunction with one or more penetration enhancer surfactants and chelators. Suitable surfactants include fatty acids and/or esters or salts thereof, bile acids and/or salts thereof. Suitable bile acids/salts include chenodeoxycholic acid (CDCA) and ursodeoxychenodeoxycholic acid (UDCA), cholic acid, dehydrocholic acid, deoxycholic acid, glucholic acid, glycholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, sodium tauro-24,25-dihydro-fusidate and sodium glycodihydrofusidate. Suitable fatty acids include arachidonic acid, undecanoic acid, oleic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin, glyceryl 1-monocaprate, 1-dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, or a monoglyceride, a diglyceride or a pharmaceutically acceptable salt thereof (e.g., sodium). In some embodiments, combinations of penetration enhancers are used, for example, fatty acids/salts in combination with bile acids/salts. One exemplary combination is the sodium salt of lauric acid, capric acid and UDCA. Further penetration enhancers include polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether. DsRNAs featured in the invention can be delivered orally, in granular form including sprayed dried particles, or complexed to form micro or nanoparticles. DsRNA complexing agents include poly-amino acids; polyimines; polyacrylates; polyalkylacrylates, polyoxethanes, polyalkylcyanoacrylates; cationized gelatins, albumins, starches, acrylates, polyethyleneglycols (PEG) and starches; polyalkylcyanoacrylates; DEAE-derivatized polyimines, pollulans, celluloses and starches. Suitable complexing agents include chitosan, N-trimethylchitosan, poly-L-lysine, polyhistidine, polyornithine, polyspermines, protamine, polyvinylpyridine, polythiodiethylaminomethylethylene P(TDAE), polyaminostyrene (e.g., p-amino), poly(methylcyanoacrylate), poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly(isobutylcyanoacrylate), poly(isohexylcynaoacrylate), DEAE-methacrylate, DEAE-hexylacrylate, DEAE-acrylamide, DEAE-albumin and DEAE-dextran, polymethylacrylate, polyhexylacrylate, poly(D,L-lactic acid), poly(DL-lactic-co-glycolic acid (PLGA), alginate, and polyethyleneglycol (PEG). Oral formulations for dsRNAs and their preparation are described in detail in U.S. Pat. No. 6,887,906, US Publn. No. 20030027780, and U.S. Pat. No. 6,747,014, each of which is incorporated herein by reference. 
     Compositions and formulations for parenteral, intraparenchymal (into the brain), intrathecal, intraventricular or intrahepatic administration can include sterile aqueous solutions which can also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. 
     Pharmaceutical compositions of the present invention include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions can be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids and self-emulsifying semisolids. Particularly preferred are formulations that target the liver when treating hepatic disorders such as hepatic carcinoma. 
     The pharmaceutical formulations of the present invention, which can conveniently be presented in unit dosage form, can be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association 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 into 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 aqueous, non-aqueous or mixed media. Aqueous suspensions can further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension can also contain stabilizers. 
     C. Additional Formulations 
     i. Emulsions 
     The compositions of the present invention can be prepared and formulated as emulsions. Emulsions are typically heterogeneous systems of one liquid dispersed in another in the form of droplets usually exceeding 0.1 μm in diameter (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199; 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 2, p. 335; Higuchi et al., in Remington&#39;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 with each other. In general, emulsions can be of either the water-in-oil (w/o) or the oil-in-water (o/w) variety. When an aqueous phase is finely divided into and dispersed as minute droplets into a bulk oily phase, the resulting composition is called a water-in-oil (w/o) emulsion. Alternatively, when an oily phase is finely divided into and dispersed as minute droplets into a bulk aqueous phase, the resulting composition is called an oil-in-water (o/w) emulsion. Emulsions can contain additional components in addition to the dispersed phases, and the active drug which can be present as a solution in either the aqueous phase, oily phase or itself as a separate phase. Pharmaceutical excipients such as emulsifiers, stabilizers, dyes, and anti-oxidants can also be present in emulsions as needed. Pharmaceutical emulsions can also be multiple emulsions that are comprised of more than two phases such as, for example, in the case of oil-in-water-in-oil (o/w/o) and water-in-oil-in-water (w/o/w) emulsions. Such complex formulations often provide certain advantages that simple binary emulsions do not. Multiple emulsions in which individual oil droplets of an o/w emulsion enclose small water droplets constitute a w/o/w emulsion. Likewise a system of oil droplets enclosed in globules of water stabilized in an oily continuous phase provides an o/w/o emulsion. 
     Emulsions are characterized by little or no thermodynamic stability. Often, the dispersed or discontinuous phase of the emulsion is well dispersed into the external or continuous phase and maintained in this form through the means of emulsifiers or the viscosity of the formulation. Either of the phases of the emulsion can be a semisolid or a solid, as is the case of emulsion-style ointment bases and creams. Other means of stabilizing emulsions entail the use of emulsifiers that can be incorporated into either phase of the emulsion. Emulsifiers can broadly be classified into four categories: synthetic surfactants, naturally occurring emulsifiers, absorption bases, and finely dispersed solids (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). 
     Synthetic surfactants, also known as surface active agents, have found wide applicability in the formulation of emulsions and have been reviewed in the literature (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), Marcel Dekker, Inc., New York, N.Y., 1988, volume 1, p. 199). Surfactants are typically amphiphilic and comprise a hydrophilic and a hydrophobic portion. The ratio of the hydrophilic to the hydrophobic nature of the surfactant has been termed the hydrophile/lipophile balance (HLB) and is a valuable tool in categorizing and selecting surfactants in the preparation of formulations. Surfactants can be classified into different classes based on the nature of the hydrophilic group: nonionic, anionic, cationic and amphoteric (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y. Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285). 
     Naturally occurring emulsifiers used in emulsion formulations include lanolin, beeswax, phosphatides, lecithin and acacia. Absorption bases possess hydrophilic properties such that they can soak up water to form w/o emulsions yet retain their semisolid consistencies, such as anhydrous lanolin and hydrophilic petrolatum. Finely divided solids have also been used as good emulsifiers especially in combination with surfactants and in viscous preparations. These include polar inorganic solids, such as heavy metal hydroxides, nonswelling clays such as bentonite, attapulgite, hectorite, kaolin, montmorillonite, colloidal aluminum silicate and colloidal magnesium aluminum silicate, pigments and nonpolar solids such as carbon or glyceryl tristearate. 
     A large variety of non-emulsifying materials are also included in emulsion formulations and contribute to the properties of 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, N.Y., 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 (for example, acacia, agar, alginic acid, carrageenan, guar gum, karaya gum, and tragacanth), cellulose derivatives (for example, carboxymethylcellulose and carboxypropylcellulose), and synthetic polymers (for example, carbomers, cellulose ethers, and carboxyvinyl polymers). These disperse or swell in water to form colloidal solutions that stabilize emulsions by forming strong interfacial films around the dispersed-phase droplets and by increasing the viscosity of the external phase. 
     Since emulsions often contain a number of ingredients such as carbohydrates, proteins, sterols and phosphatides that can readily support the growth of microbes, these formulations often incorporate preservatives. Commonly used preservatives included in 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. Antioxidants used can be free 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 dermatological, oral and parenteral routes and methods for their manufacture have been reviewed in the literature (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Emulsion formulations for oral delivery have been very widely used because of ease of formulation, as well as efficacy from an absorption and bioavailability standpoint (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Mineral-oil base laxatives, oil-soluble vitamins and high fat nutritive preparations are among the materials that have commonly been administered orally as o/w emulsions. 
     ii. Microemulsions 
     In one embodiment of the present invention, the compositions of iRNAs and nucleic acids are formulated as microemulsions. A microemulsion can be defined as a system of water, oil and amphiphile which is a single optically isotropic and thermodynamically stable liquid solution (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., 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. Therefore, 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 Release of Drugs: Polymers and Aggregate Systems, Rosoff, M., Ed., 1989, VCH Publishers, New York, pages 185-215). Microemulsions commonly are prepared via a combination of three to five components that include oil, water, surfactant, cosurfactant and electrolyte. Whether the microemulsion is of the water-in-oil (w/o) or an oil-in-water (o/w) type is dependent on the properties of the oil and surfactant used and on the structure and geometric packing of the polar heads and hydrocarbon tails of the surfactant molecules (Schott, in Remington&#39;s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, p. 271). 
     The phenomenological approach utilizing phase diagrams has been extensively studied and has yielded a comprehensive knowledge, to one skilled in the art, of how to formulate microemulsions (see e.g., Ansel&#39;s Pharmaceutical Dosage Forms and Drug Delivery Systems, Allen, L V., Popovich N G., and Ansel H C., 2004, Lippincott Williams &amp; Wilkins (8th ed.), New York, N.Y.; 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 drugs in a formulation of thermodynamically stable droplets that are formed spontaneously. 
     Surfactants used in the preparation of microemulsions include, but are not limited to, ionic surfactants, non-ionic 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 cosurfactants. The cosurfactant, usually a short-chain alcohol such as ethanol, 1-propanol, and 1-butanol, serves to increase the interfacial fluidity by penetrating into the surfactant film and consequently creating a disordered film because of the void space generated among surfactant molecules. Microemulsions can, however, be prepared without the use of cosurfactants and alcohol-free self-emulsifying microemulsion systems are known in the art. The aqueous phase can typically be, but is not limited to, water, an aqueous solution of the drug, glycerol, PEG300, PEG400, polyglycerols, propylene glycols, and derivatives of ethylene glycol. The oil phase can include, but is not limited to, materials such as Captex 300, Captex 355, Capmul MCM, fatty acid esters, medium chain (C8-C12) mono, di, and tri-glycerides, polyoxyethylated glyceryl fatty acid esters, fatty alcohols, polyglycolized glycerides, saturated polyglycolized C8-C10 glycerides, vegetable oils and silicone oil. 
     Microemulsions are particularly of interest from the standpoint of drug solubilization and the enhanced absorption of drugs. Lipid based microemulsions (both o/w and w/o) have been proposed to enhance the oral bioavailability of drugs, including peptides (see e.g., U.S. Pat. Nos. 6,191,105; 7,063,860; 7,070,802; 7,157,099; Constantinides et al., Pharmaceutical Research, 1994, 11, 1385-1390; Ritschel, Meth. Find. Exp. Clin. Pharmacol., 1993, 13, 205). Microemulsions afford advantages of improved drug solubilization, protection of drug from enzymatic hydrolysis, possible enhancement of drug absorption due to surfactant-induced alterations in membrane fluidity and permeability, ease of preparation, ease of oral administration over solid dosage forms, improved clinical potency, and decreased toxicity (see e.g., U.S. Pat. Nos. 6,191,105; 7,063,860; 7,070,802; 7,157,099; 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 are brought together at ambient temperature. This can be particularly advantageous when formulating thermolabile drugs, peptides or iRNAs. Microemulsions have also been effective in the transdermal delivery of active components in both cosmetic and pharmaceutical applications. It is expected that the microemulsion compositions and formulations of the present invention will facilitate the increased systemic absorption of iRNAs and nucleic acids from the gastrointestinal tract, as well as improve the local cellular uptake of iRNAs and nucleic acids. 
     Microemulsions of the present invention can 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 enhance the absorption of the iRNAs and nucleic acids of the present invention. Penetration enhancers used in the microemulsions of the present invention can be classified as belonging to one of five broad categories—surfactants, 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 above. 
     iii. Microparticles 
     An iRNA agent of the invention may be incorporated into a particle, e.g., a microparticle. Microparticles can be produced by spray-drying, but may also be produced by other methods including lyophilization, evaporation, fluid bed drying, vacuum drying, or a combination of these techniques. 
     iv. Penetration Enhancers 
     In one embodiment, the present invention employs various penetration enhancers to effect the efficient delivery of nucleic acids, particularly iRNAs, to the skin of animals. Most drugs are present in solution in both ionized and nonionized forms. However, usually only lipid soluble or lipophilic drugs readily cross cell membranes. It has been discovered that even non-lipophilic drugs can cross cell membranes if the membrane to be crossed is treated with a penetration enhancer. In addition to aiding the diffusion of non-lipophilic drugs across cell membranes, penetration enhancers also enhance the permeability of lipophilic drugs. 
     Penetration enhancers can be classified as belonging to one of five broad categories, i.e., surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (see e.g., Malmsten, M. Surfactants and polymers in drug delivery, Informa Health Care, New York, N.Y., 2002; Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 92). Each of the above mentioned classes of penetration enhancers are described below in greater detail. 
     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 absorption of iRNAs through the mucosa is enhanced. 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) (see e.g., Malmsten, M. Surfactants and polymers in drug delivery, Informa Health Care, New York, N.Y., 2002; 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). 
     Various fatty acids and their derivatives which 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, C1-20 alkyl esters thereof (e.g., methyl, isopropyl and t-butyl), and mono- and di-glycerides thereof (i.e., oleate, laurate, caprate, myristate, palmitate, stearate, linoleate, etc.) (see e.g., Touitou, E., et al. Enhancement in Drug Delivery, CRC Press, Danvers, Mass., 2006; Lee et al., Critical Reviews in Therapeutic Drug Carrier 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). 
     The physiological role of bile includes the facilitation of dispersion and absorption of lipids and fat-soluble vitamins (see e.g., Malmsten, M. Surfactants and polymers in drug delivery, Informa Health Care, New York, N.Y., 2002; Brunton, Chapter 38 in: Goodman &amp; Gilman&#39;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 their synthetic derivatives. Suitable bile salts include, for example, cholic acid (or its pharmaceutically acceptable sodium salt, sodium cholate), dehydrocholic acid (sodium dehydrocholate), deoxycholic acid (sodium deoxycholate), glucholic acid (sodium glucholate), glycholic acid (sodium glycocholate), glycodeoxycholic acid (sodium glycodeoxycholate), taurocholic acid (sodium taurocholate), taurodeoxycholic acid (sodium taurodeoxycholate), chenodeoxycholic acid (sodium chenodeoxycholate), ursodeoxycholic acid (UDCA), sodium tauro-24,25-dihydro-fusidate (STDHF), sodium glycodihydrofusidate and polyoxyethylene-9-lauryl ether (POE) (see e.g., Malmsten, M. Surfactants and polymers in drug delivery, Informa Health Care, New York, N.Y., 2002; Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Swinyard, Chapter 39 In: Remington&#39;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, as used in connection with the present invention, can be defined as compounds that remove metallic ions from solution by forming complexes therewith, with the result that absorption of iRNAs through the mucosa is enhanced. With regards to their use as penetration enhancers in the present invention, chelating agents have the added advantage of also serving as DNase inhibitors, as most characterized DNA nucleases require a divalent metal ion for catalysis and are thus inhibited by chelating agents (Jarrett, J. Chromatogr., 1993, 618, 315-339). Suitable chelating agents include but are not limited to disodium ethylenediaminetetraacetate (EDTA), citric acid, salicylates (e.g., sodium salicylate, 5-methoxysalicylate and homovanilate), N-acyl derivatives of collagen, laureth-9 and N-amino acyl derivatives of beta-diketones (enamines)(see e.g., Katdare, A. et al., Excipient development for pharmaceutical, biotechnology, and drug delivery, CRC Press, Danvers, Mass., 2006; 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 Rel., 1990, 14, 43-51). 
     As used herein, non-chelating non-surfactant penetration enhancing compounds can be defined as compounds that demonstrate insignificant activity as chelating agents or as surfactants but that nonetheless enhance absorption of iRNAs through the alimentary mucosa (see e.g., Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33). This class of penetration enhancers includes, for example, unsaturated cyclic ureas, 1-alkyl- and 1-alkenylazacyclo-alkanone derivatives (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92); and non-steroidal anti-inflammatory agents such as diclofenac sodium, indomethacin and phenylbutazone (Yamashita et al., J. Pharm. Pharmacol., 1987, 39, 621-626). 
     Agents that enhance uptake of iRNAs at the cellular level can also be added to the pharmaceutical and other compositions of the present invention. For example, cationic lipids, such as lipofectin (Junichi et al, U.S. 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 enhance the cellular uptake of dsRNAs. Examples of commercially available transfection reagents include, for example Lipofectamine™ (Invitrogen; Carlsbad, Calif.), Lipofectamine 2000™ (Invitrogen; Carlsbad, Calif.), 293Fectin™ (Invitrogen; Carlsbad, Calif.), Cellfectin™ (Invitrogen; Carlsbad, Calif.), DMRIE-C™ (Invitrogen; Carlsbad, Calif.), FreeStyle™ MAX (Invitrogen; Carlsbad, Calif.), Lipofectamine™ 2000 CD (Invitrogen; Carlsbad, Calif.), Lipofectamine™ (Invitrogen; Carlsbad, Calif.), iRNAMAX (Invitrogen; Carlsbad, Calif.), Oligofectamine™ (Invitrogen; Carlsbad, Calif.), Optifect™ (Invitrogen; Carlsbad, Calif.), X-tremeGENE Q2 Transfection Reagent (Roche; Grenzacherstrasse, Switzerland), DOTAP Liposomal Transfection Reagent (Grenzacherstrasse, Switzerland), DOSPER Liposomal Transfection Reagent (Grenzacherstrasse, Switzerland), or Fugene (Grenzacherstrasse, Switzerland), Transfectam® Reagent (Promega; Madison, Wis.), TransFast™ Transfection Reagent (Promega; Madison, Wis.), Tfx™-20 Reagent (Promega; Madison, Wis.), Tfx™-50 Reagent (Promega; Madison, Wis.), DreamFect™ (OZ Biosciences; Marseille, France), EcoTransfect (OZ Biosciences; Marseille, France), TransPass a  D1 Transfection Reagent (New England Biolabs; Ipswich, Mass., USA), LyoVec™/LipoGen™ (Invitrogen; San Diego, Calif., USA), PerFectin Transfection Reagent (Genlantis; San Diego, Calif., USA), NeuroPORTER Transfection Reagent (Genlantis; San Diego, Calif., USA), GenePORTER Transfection reagent (Genlantis; San Diego, Calif., USA), GenePORTER 2 Transfection reagent (Genlantis; San Diego, Calif., USA), Cytofectin Transfection Reagent (Genlantis; San Diego, Calif., USA), BaculoPORTER Transfection Reagent (Genlantis; San Diego, Calif., USA), TroganPORTER™ transfection Reagent (Genlantis; San Diego, Calif., USA), RiboFect (Bioline; Taunton, Mass., USA), PlasFect (Bioline; Taunton, Mass., USA), UniFECTOR (B-Bridge International; Mountain View, Calif., USA), SureFECTOR (B-Bridge International; Mountain View, Calif., USA), or HiFect™ (B-Bridge International, Mountain View, Calif., USA), among others. 
     Other agents can be utilized to enhance the penetration of the administered nucleic acids, including glycols such as ethylene glycol and propylene glycol, pyrrols such as 2-pyrrol, azones, and terpenes such as limonene and menthone. 
     v. 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 (i.e., does not possess 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, degrading the biologically active nucleic acid or promoting its removal from circulation. The coadministration of a nucleic acid and a carrier compound, typically with an excess of the latter substance, can result in a substantial reduction of 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 hepatic tissue can be reduced when it is coadministered with polyinosinic acid, dextran sulfate, polycytidic acid or 4-acetamido-4′isothiocyano-stilbene-2,2′-disulfonic acid (Miyao et al., DsRNA Res. Dev., 1995, 5, 115-121; Takakura et al., DsRNA &amp; Nucl. Acid Drug Dev., 1996, 6, 177-183. 
     vi. 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 can be liquid or solid and is selected, with the planned manner of administration in mind, so as to provide for the desired bulk, consistency, etc., when combined with a nucleic acid and the other components of a given pharmaceutical composition. Typical pharmaceutical carriers include, but are not limited to, binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.); fillers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc.); lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic 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., sodium lauryl sulphate, etc). 
     Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration which do not deleteriously 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 can include sterile and 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 can also contain buffers, diluents and other suitable additives. Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration which do not deleteriously 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, hydroxymethylcellulose, polyvinylpyrrolidone and the like. 
     vii. Other Components 
     The compositions of the present invention can additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions can contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or can contain additional materials useful in physically formulating various 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, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the nucleic acid(s) of the formulation. 
     Aqueous suspensions can contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension can also contain stabilizers. 
     In some embodiments, pharmaceutical compositions featured in the invention include (a) one or more iRNA compounds and (b) one or more agents which function by a non-iRNA mechanism and which are useful in treating an HDV infection. Examples of such agents include, but are not limited to antiviral agents aimed at suppressing or destroying HDV and/or HBV by interfering with viral replication; and immune modulators aimed at helping the human immune system mount a defense against the virus. In contrast, immune modulators, such as corticosteroids, which induce an enhanced expression of virus and viral antigens, and a suppression of T-lymphocyte function, or adenine arabinoside, acyclovir, or dideoxyinosine, are not beneficial for the treatment of chronic hepatitis B and/or chronic hepatitis D. Suitable agents are discussed in more detail below. 
     Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds that exhibit high therapeutic indices are preferred. 
     The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of compositions featured herein in the invention lies generally within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the methods featured in 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 circulating plasma concentration range of the compound or, when appropriate, of the polypeptide product of a target sequence (e.g., achieving a decreased concentration of the polypeptide) that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography. 
     In addition to their administration, as discussed above, the iRNAs featured in the invention can be administered in combination with other known agents effective in treatment of pathological processes mediated by HDV expression. In any event, the administering physician can adjust the amount and timing of iRNA administration on the basis of results observed using standard measures of efficacy known in the art or described herein. 
     VII. Methods of the Invention 
     The present invention provides therapeutic and prophylactic methods which include administering to a subject having an HDV infection and/or HDV-associated disease, disorder, and/or condition, or prone to developing, an HDV-associated disease, disorder, and/or condition (e.g., CHB), compositions comprising an iRNA agent, or pharmaceutical compositions comprising an iRNA agent, or vectors comprising an iRNA of the invention. 
     The methods of the invention are useful for treating a subject having an HDV infection, e.g., a subject that would benefit from reduction in HDV gene expression and/or HDV replication. In one aspect, the present invention provides methods of reducing the level of Hepatis B virus ccc DNA in a subject infected with HDV. In another aspect, the present invention provides methods of reducing the level of HDV antigen, e.g., HBsAg and/or HBeAg, in a subject infected with HDV. In another aspect, the present invention provides methods of reducing the viral load of HDV in a subject infected with HDV. The present invention also provides methods of reducing the level of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) in a subject infected with HDV. In one aspect, the present invention provides methods for increasing the level of anti-HDV antibodies in a subject infected with HDV. In another aspect, the present invention provides methods of treating a subject having an HDV infection. In one aspect, the present invention provides methods of treating a subject having an HDV-associated disease, e.g., acute hepatitis D; hepatitis B virus infection, acute hepatitis B, acute fulminant hepatitis D; chronic hepatitis D; liver fibrosis; end-stage liver disease; hepatocellular carcinoma. The treatment methods (and uses) of the invention include administering to the subject, e.g., a human, a therapeutically effective amount of an iRNA agent of the invention targeting an HDV gene or a pharmaceutical composition comprising an iRNA agent of the invention targeting an HDV gene or a vector of the invention comprising an iRNA agent targeting an HDV gene. 
     In one aspect, the invention provides methods of preventing at least one symptom in a subject having an HDV infection, 
     In another aspect, the present invention provides uses of a therapeutically effective amount of an iRNA agent of the invention for treating a subject, e.g., a subject that would benefit from a reduction and/or inhibition of HDV gene expression. 
     In a further aspect, the present invention provides uses of an iRNA agent, e.g., a dsRNA, of the invention targeting an HDV gene or pharmaceutical composition comprising an iRNA agent targeting an HDV gene in the manufacture of a medicament for treating a subject, e.g., a subject that would benefit from a reduction and/or inhibition of HDV gene expression and/or HDV replication, such as a subject having a disorder that would benefit from reduction in HDV gene expression, e.g., a HDV-associated disease. 
     In another aspect, the invention provides uses of an iRNA, e.g., a dsRNA, of the invention for preventing at least one symptom in a subject suffering from a disorder that would benefit from a reduction and/or inhibition of HDV gene expression and/or HDV replication. 
     In a further aspect, the present invention provides uses of an iRNA agent of the invention in the manufacture of a medicament for preventing at least one symptom in a subject suffering from a disorder that would benefit from a reduction and/or inhibition of HDV gene expression and/or HDV replication, such as a HDV-associated disease. 
     In one embodiment, an iRNA agent targeting HDV is administered to a subject having an HDV infection and/or an HDV-associated disease such that the expression of one or more HDV genes, HDV antigen levels, and/or HDV viral load levels, e.g., in a cell, tissue, blood or other tissue or fluid of the subject are reduced by at least about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 62%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least about 99% or more when the dsRNA agent is administered to the subject. 
     In one embodiment, an iRNA agent targeting HDV is administered to a subject having an HDV infection and/or an HDV-associated disease such that the level of anti-HDV antibodies, e.g., in a cell, tissue, blood or other tissue or fluid of the subject are increased by at least about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 62%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least about 99% or more when the dsRNA agent is administered to the subject. 
     The methods and uses of the invention include administering a composition described herein such that expression of the target HDV gene is decreased, such as for about 1, 2, 3, 4 5, 6, 7, 8, 12, 16, 18, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, or about 80 hours. In one embodiment, expression of the target HDV gene is decreased for an extended duration, e.g., at least about two, three, four, five, six, seven days or more, e.g., about one week, two weeks, three weeks, or about four weeks or longer. 
     Administration of the dsRNA according to the methods and uses of the invention may result in a reduction of the severity, signs, symptoms, and/or markers of such diseases or disorders in a patient with an HDV infection and/or HDV-associated disease. By “reduction” in this context is meant a statistically significant decrease in such level. The reduction can be, for example, at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 100%. 
     Efficacy of treatment or prevention of disease can be assessed, for example by measuring disease progression, disease remission, symptom severity, reduction in pain, quality of life, dose of a medication required to sustain a treatment effect, level of a disease marker or any other measurable parameter appropriate for a given disease being treated or targeted for prevention. It is well within the ability of one skilled in the art to monitor efficacy of treatment or prevention by measuring any one of such parameters, or any combination of parameters. For example, efficacy of treatment of CHB may be assessed, for example, by periodic monitoring of viral load and transaminase levels. Comparison of the later readings with the initial readings provide a physician an indication of whether the treatment is effective. It is well within the ability of one skilled in the art to monitor efficacy of treatment or prevention by measuring any one of such parameters, or any combination of parameters. In connection with the administration of an iRNA targeting HDV or pharmaceutical composition thereof, “effective against” an HDV-associated disease indicates that administration in a clinically appropriate manner results in a beneficial effect for at least a statistically significant fraction of patients, such as improvement of symptoms, a cure, a reduction in disease, extension of life, improvement in quality of life, or other effect generally recognized as positive by medical doctors familiar with treating HDV infection and/or an HDV-associated disease and the related causes. 
     A treatment or preventive effect is evident when there is a statistically significant improvement in one or more parameters of disease status, or by a failure to worsen or to develop symptoms where they would otherwise be anticipated. As an example, a favorable change of at least 10% in a measurable parameter of disease, and preferably at least 20%, 30%, 40%, 50% or more can be indicative of effective treatment. Efficacy for a given iRNA drug or formulation of that drug can also be judged using an experimental animal model for the given disease as known in the art. When using an experimental animal model, efficacy of treatment is evidenced when a statistically significant reduction in a marker or symptom is observed. 
     Subjects can be administered a therapeutic amount of iRNA, such as about 0.01 mg/kg, 0.02 mg/kg, 0.03 mg/kg, 0.04 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.15 mg/kg, 0.2 mg/kg, 0.25 mg/kg, 0.3 mg/kg, 0.35 mg/kg, 0.4 mg/kg, 0.45 mg/kg, 0.5 mg/kg, 0.55 mg/kg, 0.6 mg/kg, 0.65 mg/kg, 0.7 mg/kg, 0.75 mg/kg, 0.8 mg/kg, 0.85 mg/kg, 0.9 mg/kg, 0.95 mg/kg, 1.0 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2.0 mg/kg, 2.1 mg/kg, 2.2 mg/kg, 2.3 mg/kg, 2.4 mg/kg, 2.5 mg/kg dsRNA, 2.6 mg/kg dsRNA, 2.7 mg/kg dsRNA, 2.8 mg/kg dsRNA, 2.9 mg/kg dsRNA, 3.0 mg/kg dsRNA, 3.1 mg/kg dsRNA, 3.2 mg/kg dsRNA, 3.3 mg/kg dsRNA, 3.4 mg/kg dsRNA, 3.5 mg/kg dsRNA, 3.6 mg/kg dsRNA, 3.7 mg/kg dsRNA, 3.8 mg/kg dsRNA, 3.9 mg/kg dsRNA, 4.0 mg/kg dsRNA, 4.1 mg/kg dsRNA, 4.2 mg/kg dsRNA, 4.3 mg/kg dsRNA, 4.4 mg/kg dsRNA, 4.5 mg/kg dsRNA, 4.6 mg/kg dsRNA, 4.7 mg/kg dsRNA, 4.8 mg/kg dsRNA, 4.9 mg/kg dsRNA, 5.0 mg/kg dsRNA, 5.1 mg/kg dsRNA, 5.2 mg/kg dsRNA, 5.3 mg/kg dsRNA, 5.4 mg/kg dsRNA, 5.5 mg/kg dsRNA, 5.6 mg/kg dsRNA, 5.7 mg/kg dsRNA, 5.8 mg/kg dsRNA, 5.9 mg/kg dsRNA, 6.0 mg/kg dsRNA, 6.1 mg/kg dsRNA, 6.2 mg/kg dsRNA, 6.3 mg/kg dsRNA, 6.4 mg/kg dsRNA, 6.5 mg/kg dsRNA, 6.6 mg/kg dsRNA, 6.7 mg/kg dsRNA, 6.8 mg/kg dsRNA, 6.9 mg/kg dsRNA, 7.0 mg/kg dsRNA, 7.1 mg/kg dsRNA, 7.2 mg/kg dsRNA, 7.3 mg/kg dsRNA, 7.4 mg/kg dsRNA, 7.5 mg/kg dsRNA, 7.6 mg/kg dsRNA, 7.7 mg/kg dsRNA, 7.8 mg/kg dsRNA, 7.9 mg/kg dsRNA, 8.0 mg/kg dsRNA, 8.1 mg/kg dsRNA, 8.2 mg/kg dsRNA, 8.3 mg/kg dsRNA, 8.4 mg/kg dsRNA, 8.5 mg/kg dsRNA, 8.6 mg/kg dsRNA, 8.7 mg/kg dsRNA, 8.8 mg/kg dsRNA, 8.9 mg/kg dsRNA, 9.0 mg/kg dsRNA, 9.1 mg/kg dsRNA, 9.2 mg/kg dsRNA, 9.3 mg/kg dsRNA, 9.4 mg/kg dsRNA, 9.5 mg/kg dsRNA, 9.6 mg/kg dsRNA, 9.7 mg/kg dsRNA, 9.8 mg/kg dsRNA, 9.9 mg/kg dsRNA, 9.0 mg/kg dsRNA, 10 mg/kg dsRNA, 15 mg/kg dsRNA, 20 mg/kg dsRNA, 25 mg/kg dsRNA, 30 mg/kg dsRNA, 35 mg/kg dsRNA, 40 mg/kg dsRNA, 45 mg/kg dsRNA, or about 50 mg/kg dsRNA. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     In certain embodiments, for example, when a composition of the invention comprises a dsRNA as described herein and a lipid, subjects can be administered a therapeutic amount of iRNA, such as about 0.01 mg/kg to about 5 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.05 mg/kg to about 5 mg/kg, about 0.05 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 5 mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 0.2 mg/kg to about 5 mg/kg, about 0.2 mg/kg to about 10 mg/kg, about 0.3 mg/kg to about 5 mg/kg, about 0.3 mg/kg to about 10 mg/kg, about 0.4 mg/kg to about 5 mg/kg, about 0.4 mg/kg to about 10 mg/kg, about 0.5 mg/kg to about 5 mg/kg, about 0.5 mg/kg to about 10 mg/kg, about 1 mg/kg to about 5 mg/kg, about 1 mg/kg to about 10 mg/kg, about 1.5 mg/kg to about 5 mg/kg, about 1.5 mg/kg to about 10 mg/kg, about 2 mg/kg to about 2.5 mg/kg, about 2 mg/kg to about 10 mg/kg, about 3 mg/kg to about 5 mg/kg, about 3 mg/kg to about 10 mg/kg, about 3.5 mg/kg to about 5 mg/kg, about 4 mg/kg to about 5 mg/kg, about 4.5 mg/kg to about 5 mg/kg, about 4 mg/kg to about 10 mg/kg, about 4.5 mg/kg to about 10 mg/kg, about 5 mg/kg to about 10 mg/kg, about 5.5 mg/kg to about 10 mg/kg, about 6 mg/kg to about 10 mg/kg, about 6.5 mg/kg to about 10 mg/kg, about 7 mg/kg to about 10 mg/kg, about 7.5 mg/kg to about 10 mg/kg, about 8 mg/kg to about 10 mg/kg, about 8.5 mg/kg to about 10 mg/kg, about 9 mg/kg to about 10 mg/kg, or about 9.5 mg/kg to about 10 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     For example, the dsRNA may be administered at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or about 10 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     In other embodiments, for example, when a composition of the invention comprises a dsRNA as described herein and an N-acetylgalactosamine, subjects can be administered a therapeutic amount of iRNA, such as a dose of about 0.1 to about 50 mg/kg, about 0.25 to about 50 mg/kg, about 0.5 to about 50 mg/kg, about 0.75 to about 50 mg/kg, about 1 to about 50 mg/kg, about 1.5 to about 50 mg/kg, about 2 to about 50 mg/kg, about 2.5 to about 50 mg/kg, about 3 to about 50 mg/kg, about 3.5 to about 50 mg/kg, about 4 to about 50 mg/kg, about 4.5 to about 50 mg/kg, about 5 to about 50 mg/kg, about 7.5 to about 50 mg/kg, about 10 to about 50 mg/kg, about 15 to about 50 mg/kg, about 20 to about 50 mg/kg, about 20 to about 50 mg/kg, about 25 to about 50 mg/kg, about 25 to about 50 mg/kg, about 30 to about 50 mg/kg, about 35 to about 50 mg/kg, about 40 to about 50 mg/kg, about 45 to about 50 mg/kg, about 0.1 to about 45 mg/kg, about 0.25 to about 45 mg/kg, about 0.5 to about 45 mg/kg, about 0.75 to about 45 mg/kg, about 1 to about 45 mg/kg, about 1.5 to about 45 mg/kg, about 2 to about 45 mg/kg, about 2.5 to about 45 mg/kg, about 3 to about 45 mg/kg, about 3.5 to about 45 mg/kg, about 4 to about 45 mg/kg, about 4.5 to about 45 mg/kg, about 5 to about 45 mg/kg, about 7.5 to about 45 mg/kg, about 10 to about 45 mg/kg, about 15 to about 45 mg/kg, about 20 to about 45 mg/kg, about 20 to about 45 mg/kg, about 25 to about 45 mg/kg, about 25 to about 45 mg/kg, about 30 to about 45 mg/kg, about 35 to about 45 mg/kg, about 40 to about 45 mg/kg, about 0.1 to about 40 mg/kg, about 0.25 to about 40 mg/kg, about 0.5 to about 40 mg/kg, about 0.75 to about 40 mg/kg, about 1 to about 40 mg/kg, about 1.5 to about 40 mg/kg, about 2 to about 40 mg/kg, about 2.5 to about 40 mg/kg, about 3 to about 40 mg/kg, about 3.5 to about 40 mg/kg, about 4 to about 40 mg/kg, about 4.5 to about 40 mg/kg, about 5 to about 40 mg/kg, about 7.5 to about 40 mg/kg, about 10 to about 40 mg/kg, about 15 to about 40 mg/kg, about 20 to about 40 mg/kg, about 20 to about 40 mg/kg, about 25 to about 40 mg/kg, about 25 to about 40 mg/kg, about 30 to about 40 mg/kg, about 35 to about 40 mg/kg, about 0.1 to about 30 mg/kg, about 0.25 to about 30 mg/kg, about 0.5 to about 30 mg/kg, about 0.75 to about 30 mg/kg, about 1 to about 30 mg/kg, about 1.5 to about 30 mg/kg, about 2 to about 30 mg/kg, about 2.5 to about 30 mg/kg, about 3 to about 30 mg/kg, about 3.5 to about 30 mg/kg, about 4 to about 30 mg/kg, about 4.5 to about 30 mg/kg, about 5 to about 30 mg/kg, about 7.5 to about 30 mg/kg, about 10 to about 30 mg/kg, about 15 to about 30 mg/kg, about 20 to about 30 mg/kg, about 20 to about 30 mg/kg, about 25 to about 30 mg/kg, about 0.1 to about 20 mg/kg, about 0.25 to about 20 mg/kg, about 0.5 to about 20 mg/kg, about 0.75 to about 20 mg/kg, about 1 to about 20 mg/kg, about 1.5 to about 20 mg/kg, about 2 to about 20 mg/kg, about 2.5 to about 20 mg/kg, about 3 to about 20 mg/kg, about 3.5 to about 20 mg/kg, about 4 to about 20 mg/kg, about 4.5 to about 20 mg/kg, about 5 to about 20 mg/kg, about 7.5 to about 20 mg/kg, about 10 to about 20 mg/kg, or about 15 to about 20 mg/kg. In one embodiment, when a composition of the invention comprises a dsRNA as described herein and an N-acetylgalactosamine, subjects can be administered a therapeutic amount of about 10 to about 30 mg/kg of dsRNA. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     For example, subjects can be administered a therapeutic amount of iRNA, such as about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 31, 32, 33, 34, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or about 50 mg/kg. Values and ranges intermediate to the recited values are also intended to be part of this invention. 
     In certain embodiments of the invention, for example, when a double-stranded RNAi agent includes a modification (e.g., one or more motifs of three identical modifications on three consecutive nucleotides), including one such motif at or near the cleavage site of the agent, six phosphorothioate linkages, and a ligand, such an agent is administered at a dose of about 0.01 to about 0.5 mg/kg, about 0.01 to about 0.4 mg/kg, about 0.01 to about 0.3 mg/kg, about 0.01 to about 0.2 mg/kg, about 0.01 to about 0.1 mg/kg, about 0.01 mg/kg to about 0.09 mg/kg, about 0.01 mg/kg to about 0.08 mg/kg, about 0.01 mg/kg to about 0.07 mg/kg, about 0.01 mg/kg to about 0.06 mg/kg, about 0.01 mg/kg to about 0.05 mg/kg, about 0.02 to about 0.5 mg/kg, about 0.02 to about 0.4 mg/kg, about 0.02 to about 0.3 mg/kg, about 0.02 to about 0.2 mg/kg, about 0.02 to about 0.1 mg/kg, about 0.02 mg/kg to about 0.09 mg/kg, about 0.02 mg/kg to about 0.08 mg/kg, about 0.02 mg/kg to about 0.07 mg/kg, about 0.02 mg/kg to about 0.06 mg/kg, about 0.02 mg/kg to about 0.05 mg/kg, about 0.03 to about 0.5 mg/kg, about 0.03 to about 0.4 mg/kg, about 0.03 to about 0.3 mg/kg, about 0.03 to about 0.2 mg/kg, about 0.03 to about 0.1 mg/kg, about 0.03 mg/kg to about 0.09 mg/kg, about 0.03 mg/kg to about 0.08 mg/kg, about 0.03 mg/kg to about 0.07 mg/kg, about 0.03 mg/kg to about 0.06 mg/kg, about 0.03 mg/kg to about 0.05 mg/kg, about 0.04 to about 0.5 mg/kg, about 0.04 to about 0.4 mg/kg, about 0.04 to about 0.3 mg/kg, about 0.04 to about 0.2 mg/kg, about 0.04 to about 0.1 mg/kg, about 0.04 mg/kg to about 0.09 mg/kg, about 0.04 mg/kg to about 0.08 mg/kg, about 0.04 mg/kg to about 0.07 mg/kg, about 0.04 mg/kg to about 0.06 mg/kg, about 0.05 to about 0.5 mg/kg, about 0.05 to about 0.4 mg/kg, about 0.05 to about 0.3 mg/kg, about 0.05 to about 0.2 mg/kg, about 0.05 to about 0.1 mg/kg, about 0.05 mg/kg to about 0.09 mg/kg, about 0.05 mg/kg to about 0.08 mg/kg, or about 0.05 mg/kg to about 0.07 mg/kg. Values and ranges intermediate to the foregoing recited values are also intended to be part of this invention, e.g., the RNAi agent may be administered to the subject at a dose of about 0.015 mg/kg to about 0.45 mg/kg. 
     For example, the RNAi agent, e.g., RNAi agent in a pharmaceutical composition, may be administered at a dose of about 0.01 mg/kg, 0.0125 mg/kg, 0.015 mg/kg, 0.0175 mg/kg, 0.02 mg/kg, 0.0225 mg/kg, 0.025 mg/kg, 0.0275 mg/kg, 0.03 mg/kg, 0.0325 mg/kg, 0.035 mg/kg, 0.0375 mg/kg, 0.04 mg/kg, 0.0425 mg/kg, 0.045 mg/kg, 0.0475 mg/kg, 0.05 mg/kg, 0.0525 mg/kg, 0.055 mg/kg, 0.0575 mg/kg, 0.06 mg/kg, 0.0625 mg/kg, 0.065 mg/kg, 0.0675 mg/kg, 0.07 mg/kg, 0.0725 mg/kg, 0.075 mg/kg, 0.0775 mg/kg, 0.08 mg/kg, 0.0825 mg/kg, 0.085 mg/kg, 0.0875 mg/kg, 0.09 mg/kg, 0.0925 mg/kg, 0.095 mg/kg, 0.0975 mg/kg, 0.1 mg/kg, 0.125 mg/kg, 0.15 mg/kg, 0.175 mg/kg, 0.2 mg/kg, 0.225 mg/kg, 0.25 mg/kg, 0.275 mg/kg, 0.3 mg/kg, 0.325 mg/kg, 0.35 mg/kg, 0.375 mg/kg, 0.4 mg/kg, 0.425 mg/kg, 0.45 mg/kg, 0.475 mg/kg, or about 0.5 mg/kg. Values intermediate to the foregoing recited values are also intended to be part of this invention. 
     In some embodiments, the RNAi agent is administered as a fixed dose of between about 100 mg to about 900 mg, e.g., between about 100 mg to about 850 mg, between about 100 mg to about 800 mg, between about 100 mg to about 750 mg, between about 100 mg to about 700 mg, between about 100 mg to about 650 mg, between about 100 mg to about 600 mg, between about 100 mg to about 550 mg, between about 100 mg to about 500 mg, between about 200 mg to about 850 mg, between about 200 mg to about 800 mg, between about 200 mg to about 750 mg, between about 200 mg to about 700 mg, between about 200 mg to about 650 mg, between about 200 mg to about 600 mg, between about 200 mg to about 550 mg, between about 200 mg to about 500 mg, between about 300 mg to about 850 mg, between about 300 mg to about 800 mg, between about 300 mg to about 750 mg, between about 300 mg to about 700 mg, between about 300 mg to about 650 mg, between about 300 mg to about 600 mg, between about 300 mg to about 550 mg, between about 300 mg to about 500 mg, between about 400 mg to about 850 mg, between about 400 mg to about 800 mg, between about 400 mg to about 750 mg, between about 400 mg to about 700 mg, between about 400 mg to about 650 mg, between about 400 mg to about 600 mg, between about 400 mg to about 550 mg, or between about 400 mg to about 500 mg. 
     In some embodiments, the RNAi agent is administered as a fixed dose of about 100 mg, about 125 mg, about 150 mg, about 175 mg, 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, or about 900 mg. 
     The iRNA can be administered by intravenous infusion over a period of time, such as over a 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or about a 25 minute period. The administration may be repeated, for example, on a regular basis, such as weekly, biweekly (i.e., every two weeks) for one month, two months, three months, four months or longer. After an initial treatment regimen, the treatments can be administered on a less frequent basis. For example, after administration weekly or biweekly for three months, administration can be repeated once per month, for six months or a year or longer. 
     Administration of the iRNA can reduce the presence of serum and/or liver HDV DNA, the presence of serum and/or liver HDV antigen e.g., in a cell, tissue, blood, urine or other compartment of the patient by at least about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 72%, 73%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least about 99% or more, e.g., to below the level of detection of the assay. 
     Before administration of a full dose of the iRNA, patients can be administered a smaller dose, such as a 5% infusion, and monitored for adverse effects, such as an allergic reaction. In another example, the patient can be monitored for unwanted immunostimulatory effects, such as increased cytokine (e.g., TNF-alpha or INF-alpha) levels. 
     The methods of treatment of HDV can further comprise treatment of HBV using any method known in the art. In certain embodiments, methods of treatment of HBV comprise administration of an iRNA compound, e.g., an iRNA agent targeting an HBV gene as provided herein. 
     Owing to the inhibitory effects on HDV expression, a composition according to the invention or a pharmaceutical composition prepared therefrom can enhance the quality of life. 
     An iRNA of the invention may be administered in “naked” form, where the modified or unmodified iRNA agent is directly suspended in aqueous or suitable buffer solvent, as a “free iRNA.” A free iRNA is administered in the absence of a pharmaceutical composition. The free iRNA may be in a suitable buffer solution. The buffer solution may comprise acetate, citrate, prolamine, carbonate, or phosphate, or any combination thereof. In one embodiment, the buffer solution is phosphate buffered saline (PBS). The pH and osmolarity of the buffer solution containing the iRNA can be adjusted such that it is suitable for administering to a subject. 
     Alternatively, an iRNA of the invention may be administered as a pharmaceutical composition, such as a dsRNA liposomal formulation. 
     Subjects that would benefit from a reduction and/or inhibition of HDV gene expression are those having an HDV infection and/or an HDV-associated disease or disorder as described herein. 
     Treatment of a subject that would benefit from a reduction and/or inhibition of HDV gene expression includes therapeutic and prophylactic treatment. 
     The invention further provides methods and uses of an iRNA agent or a pharmaceutical composition thereof for treating a subject that would benefit from reduction and/or inhibition of HDV gene expression, e.g., a subject having a HDV-associated disease, in combination with other pharmaceuticals and/or other therapeutic methods, e.g., with known pharmaceuticals and/or known therapeutic methods, such as, for example, those which are currently employed for treating these disorders. 
     For example, a subject administered a first RNAi agent or a first and second RNAi agent targeting HDV may further be administered one or more iRNA agents targeting HBV and/or one or more agents which function by a non-iRNA mechanism and which are useful in treating an HBV and/or an HDV infection. Exemplary agents include immune modulators which stimulate the immune system by, for example, enhancing T-cell helper activity, maturation of B lymphocytes, inhibiting T-cell suppressors, and enhancing HLA type I expression. Suitable immune modulators include interferons which have a variety of properties that include antiviral, immunomodulatory, and antiproliferative effects. 
     For example, the current treatment for chronic hepatitis B is interferon therapy. Interferon therapy is administered to subjects who have a documented HBV infection for at least six months, elevated liver enzymes (AST and ALT) and an actively dividing virus in their blood (HBeAg, and/or HBV DNA positive tests). Interferon-α therapy produces a long-term, sustained remission of the disease in about 35% of those with chronic hepatitis B, with normalization of liver enzymes and loss of the three markers for an active infection (HBeAg, HBV DNA, and HBsAg). Subjects with an acute HBV infection, end stage cirrhosis or other major medical problems are typically not treated with interferon. 
     In addition, interferon therapy for patients with HBV-related cirrhosis decreases significantly the hepatocellular carcinoma (HCC) rate, particularly in patients with a larger amount of serum HBV DNA. In patients with HBeAg-positive compensated cirrhosis, virological and biochemical remission following interferon therapy is associated with improved survival. In patients with chronic HBV infection, the clearance of HBeAg after treatment with interferon-α is associated with improved clinical outcomes. 
     The standard duration of therapy is considered 16 weeks. Patients who exhibit a low level of viral replication at the end of the standard regimen benefit most from prolonged treatment. 
     Thus, in some embodiments, an iRNA targeting one or more HDV genes is administered in combination with, e.g., an agent useful in treating an HDV-associated disease as described elsewhere herein. 
     For example, additional therapeutics and therapeutic methods suitable for treating a subject that would benefit from reduction in HDV expression, e.g., a subject having a HDV-associated disease, include an iRNA agent targeting a different portion of the HDV genome, an antiviral agent, a nucleotide analog, a nucleoside analog, a reverse transcriptase inhibitor (e.g., Tenofovir disoproxil fumarate (TDF), Tenofovir alafenamide, Lamivudine, Adefovir dipivoxil, Entecavir (ETV), Telbivudine, AGX-1009, emtricitabine, clevudine, ritonavir, dipivoxil, lobucavir, famvir, FTC, N-Acetyl-Cysteine (NAC), PC1323, theradigm-HBV, thymosin-alpha, and ganciclovir), an immune stimulator (e.g., pegylated interferon alfa 2a (PEG-IFN-α2a), Interferon alfa-2b, a recombinant human interleukin-7, and aToll-like receptor 7 (TLR7) agonist), a therapeutic vaccine (e.g., GS-4774, DV-601, and TG1050), a viral entry inhibitor (e.g., Myrcludex), an oligonucleotide that inhibits the secretion or release of HbsAg (e.g., REP 9AC), a capsid inhibitor (e.g., Bay41-4109 and NVR-1221), a cccDNA inhibitor (e.g., IHVR-25), or other therapeutic agents and/or procedures, e.g., liver transplant, chemotherapy, for treating a HBV-associated disease, a combination of any of the foregoing. 
     In certain embodiments, a first iRNA agent targeting one or more HDV genes is administered in combination with a second iRNA agent targeting a different portion of the HDV genome. For example, the first RNAi agent comprises a first sense strand and a first antisense strand forming a double-stranded region, wherein substantially all of the nucleotides of said first sense strand and substantially all of the nucleotides of the first antisense strand are modified nucleotides, wherein said first sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker; and the second RNAi agent comprises a second sense strand and a second antisense strand forming a double-stranded region, wherein substantially all of the nucleotides of the second sense strand and substantially all of the nucleotides of the second antisense strand are modified nucleotides, wherein the second sense strand is conjugated to a ligand attached at the 3′-terminus, and wherein the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker; wherein the first sense strand comprises a sequences selected from the group consisting of any one of the sense sequences in any one of Tables 11, 12, 31, and 32 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequences), and wherein the first antisense strand comprises a sequence selected from the group consisting of any one of the antisense sequences in any one of Tables 11, 12, 31, and 32 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequences); wherein the second sense strand comprises any one of the sense sequences in any one of Tables 11, 12, 31, and 32 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequence), and wherein the second antisense strand comprises any one of the antisense sequences in any one of Tables 11, 12, 31, and 32 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequence). 
     In one embodiment, the first and second sense strands each independently comprise a sequence selected from the group consisting of any one of the sense sequences from AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequences). 
     In another embodiment, the first and second antisense strands each independently comprise a sequence selected from the group consisting of any one of the antisense sequences from AD-70260.1, AD-70232.1, AD-70249.1, AD-70244.1, AD-70272.1, AD-70228.1, AD-70255.1, AD-70278.1, AD-70295.1, AD-67200.1, AD-67211.1, AD-67199.1, AD-67202.1, AD-67208.1, AD-67210.1, AD-70259.1, AD-70267.1, AD-70272.1, AD-70271.1, AD-70268.1, AD-70269.1, AD-70232.1, AD-70256.1, AD-70257.1, or AD-70275.1 (or a nucleotide sequence which is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical over its entire length to the foregoing nucleotide sequences). 
     In one embodiment, all of the nucleotides of the first and second sense strand and/or all of the nucleotides of the first and second antisense strand comprise a modification. 
     In one embodiment, the at least one of the modified nucleotides is selected from the group consisting of a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an unlocked nucleotide, a conformationally restricted nucleotide, a constrained ethyl nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-O-allyl-modified nucleotide, 2′-C-alkyl-modified nucleotide, 2′-hydroxyl-modified nucleotide, a 2′-methoxyethyl modified nucleotide, a 2′-O-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a tetrahydropyran modified nucleotide, a 1,5-anhydrohexitol modified nucleotide, a cyclohexenyl modified nucleotide, a nucleotide comprising a phosphorothioate group, a nucleotide comprising a methylphosphonate group, a nucleotide comprising a 5′-phosphate, and a nucleotide comprising a 5′-phosphate mimic. 
     A subject administered a first or a first and second RNAi agent may further be administered one or more iRNA agents targeting HBV antiviral agent, a reverse transcriptase inhibitor (e.g., Tenofovir disoproxil fumarate (TDF), Tenofovir alafenamide, Lamivudine, Adefovir dipivoxil, Entecavir (ETV), Telbivudine, and AGX-1009), an immune stimulator (e.g., pegylated interferon alfa 2a (PEG-IFN-α2a), Interferon alfa-2b, a recombinant human interleukin-7, and aToll-like receptor 7 (TLR7) agonist), a therapeutic vaccine (e.g., GS-4774, DV-601, and TG1050), a viral entry inhibitor (e.g., Myrcludex), an oligonucleotide that inhibits the secretion or release of HbsAg (e.g., REP 9AC), a capsid inhibitor (e.g., Bay41-4109 and NVR-1221), a cccDNA inhibitor (e.g., IHVR-25), or other therapeutic agents and/or procedures, e.g., liver transplant, chemotherapy, for treating a HDV-associated disease, a combination of any of the foregoing. 
     In one embodiment, the methods of the invention include administering to a subject having an HDV infection and/or HDV-associated disease a reverse transcriptase inhibitor. In another embodiment, the methods of the invention include administering to a subject having an HDV infection and/or HDV-associate disease a reverse transcriptase inhibitor and an immune stimulator. 
     The iRNA agent and an additional therapeutic agent and/or treatment may be administered at the same time and/or in the same combination, e.g., parenterally, or the additional therapeutic agent can be administered as part of a separate composition or at separate times and/or by another method known in the art or described herein. 
     The present invention also provides methods of using an iRNA agent of the invention and/or a composition containing an iRNA agent of the invention to reduce and/or inhibit HDV expression in a cell. In other aspects, the present invention provides an iRNA of the invention and/or a composition comprising an iRNA of the invention for use in reducing and/or inhibiting HDV gene expression in a cell. In yet other aspects, use of an iRNA of the invention and/or a composition comprising an iRNA of the invention for the manufacture of a medicament for reducing and/or inhibiting HDV gene expression in a cell are provided. In still other aspect, the the present invention provides an iRNA of the invention and/or a composition comprising an iRNA of the invention for use in reducing and/or inhibiting HDV replication in a cell. In yet other aspects, use of an iRNA of the invention and/or a composition comprising an iRNA of the invention for the manufacture of a medicament for reducing and/or inhibiting HDV replication in a cell are provided. The methods and uses include contacting the cell with an iRNA, e.g., a dsRNA, of the invention and maintaining the cell for a time sufficient to obtain degradation of the mRNA transcript of an HDV gene, thereby inhibiting expression of the HDV gene or inhibiting HDV replication in the cell. 
     Reduction in gene expression can be assessed by any methods known in the art. For example, a reduction in the expression of HDV may be determined by determining the mRNA expression level of HDV using methods routine to one of ordinary skill in the art, e.g., Northern blotting, qRT-PCR, by determining the protein level of HDV using methods routine to one of ordinary skill in the art, such as western blotting, immunological techniques, flow cytometry methods, ELISA, and/or by determining a biological activity of HDV. 
     In the methods and uses of the invention the cell may be contacted in vitro or in vivo, i.e., the cell may be within a subject. 
     A cell suitable for treatment using the methods of the invention may be any cell that expresses an HDV gene, e.g., a cell infected with HDV or a cell comprising an expression vector comprising an HDV genome or portion of an HDV gene. A cell suitable for use in the methods and uses of the invention may be a mammalian cell, e.g., a primate cell (such as a human cell or a non-human primate cell, e.g., a monkey cell or a chimpanzee cell), a non-primate cell (such as a cow cell, a pig cell, a camel cell, a llama cell, a horse cell, a goat cell, a rabbit cell, a sheep cell, a hamster, a guinea pig cell, a cat cell, a dog cell, a rat cell, a mouse cell, a lion cell, a tiger cell, a bear cell, or a buffalo cell), a bird cell (e.g., a duck cell or a goose cell), or a whale cell. In one embodiment, the cell is a human cell, e.g., a human liver cell. 
     HDV gene expression may be inhibited in the cell by at least about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 100%, i.e., to below the level of detection of the assay. 
     HDV replication may be inhibited in the cell by at least about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 72%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or about 100%, i.e., to below the level of detection of the assay. 
     The in vivo methods and uses of the invention may include administering to a subject a composition containing an iRNA, where the iRNA includes a nucleotide sequence that is complementary to at least a part of an RNA transcript of the HDV gene of the mammal to be treated. When the organism to be treated is a human, the composition can be administered by any means known in the art including, but not limited to subcutaneous, intravenous, oral, intraperitoneal, or parenteral routes, including intracranial (e.g., intraventricular, intraparenchymal and intrathecal), intramuscular, transdermal, airway (aerosol), nasal, rectal, and topical (including buccal and sublingual) administration. In certain embodiments, the compositions are administered by subcutaneous injection. In some embodiments, the compositions are administered by intravenous infusion or injection. In other embodiments, the compositions are administered by intramuscular injection. 
     In some embodiments, the administration is via a depot injection. A depot injection may release the iRNA in a consistent way over a prolonged time period. Thus, a depot injection may reduce the frequency of dosing needed to obtain a desired effect, e.g., a desired inhibition of HDV, or a therapeutic or prophylactic effect. A depot injection may also provide more consistent serum concentrations. Depot injections may include subcutaneous injections or intramuscular injections. In preferred embodiments, the depot injection is a subcutaneous injection. 
     In some embodiments, the administration is via a pump. The pump may be an external pump or a surgically implanted pump. In certain embodiments, the pump is a subcutaneously implanted osmotic pump. In other embodiments, the pump is an infusion pump. An infusion pump may be used for intravenous, subcutaneous, arterial, or epidural infusions. In preferred embodiments, the infusion pump is a subcutaneous infusion pump. In other embodiments, the pump is a surgically implanted pump that delivers the iRNA to the liver. 
     The mode of administration may be chosen based upon whether local or systemic treatment is desired and based upon the area to be treated. The route and site of administration may be chosen to enhance targeting. 
     In one aspect, the present invention also provides methods for inhibiting the expression of an HDV gene in a mammal, e.g., a human. The present invention also provides a composition comprising an iRNA, e.g., a dsRNA, that targets an HDV gene in a cell of a mammal for use in inhibiting expression of the HDV gene in the mammal. In another aspect, the present invention provides use of an iRNA, e.g., a dsRNA, that targets an HDV gene in a cell of a mammal in the manufacture of a medicament for inhibiting expression of the HDV gene in the mammal. 
     The methods and uses include administering to the mammal, e.g., a human, a composition comprising an iRNA, e.g., a dsRNA, that targets an HDV gene in a cell of the mammal and maintaining the mammal for a time sufficient to obtain degradation of the mRNA transcript of the HDV gene, thereby inhibiting expression of the HDV gene in the mammal. 
     Reduction in gene expression can be assessed in peripheral blood sample of the iRNA-administered subject by any methods known it the art, e.g. qRT-PCR, described herein. Reduction in protein production can be assessed by any methods known it the art and by methods, e.g., ELISA or western blotting, described herein. In one embodiment, a puncture liver biopsy sample serves as the tissue material for monitoring the reduction in HDV gene and/or protein expression. In another embodiment, a blood sample serves as the tissue material for monitoring the reduction in HDV gene and/or protein expression. 
     In one embodiment, verification of RISC medicated cleavage of target in vivo following administration of iRNA agent is done by performing 5′-RACE or modifications of the protocol as known in the art (Lasham A et al., (2010)  Nucleic Acid Res.,  38 (3) p-e19) (Zimmermann et al. (2006)  Nature  441: 111-4). 
     This invention is further illustrated by the following examples which should not be construed as limiting. The entire contents of all references, patents and published patent applications cited throughout this application, as well as the Figures and the Sequence Listing, are hereby incorporated herein by reference. 
     EXAMPLES 
     Example 1. iRNA Synthesis 
     Source of Reagents 
     Where the source of a reagent is not specifically given herein, such reagent can be obtained from any supplier of reagents for molecular biology at a quality/purity standard for application in molecular biology. 
     Transcripts 
     siRNA Design 
     The selection of siRNA designs targeting HBV was driven by two primary factors: a) potency and b), the desire to employ siRNA with near-perfect matches with greater than 90% fractional coverage of the large number of public HBV sequences of all known serotypes (A through H). The coordinates for the siRNA selection were determined relative to the NCBI HBV reference genome sequence NC_003977.1 (GenBank Accession No. GI:21326584 (SEQ ID NO:1). The reverse complement of SEQ ID NO:1 is provided in SEQ ID NO:2. A first set of siRNAs containing structure-activity modifications, including various 2′-O-methyl and 2′-fluoro substitution patterns, centered on two adjacent regions of the HBV genome coding for surface antigen (HbSAg) and the HBV polymerase, were designed, synthesized and screened in-vitro. A second set of siRNAs were designed, synthesized and screened targeting additional target regions with particular attention to positions 1581-1599 of SEQ ID NO:1 that code, in addition to the HbSAg and polymerase, the X gene. 
     The sequence of Hepatitis B virus genomic DNA, complete sequence, isolate 22Y04HCC (GenBank Accession No., GI: 3582357) and its reverse complement are provided in SEQ ID NOs. 3 and 4, respectively. 
     A detailed list of the unmodified HBV sense and antisense strand sequences is shown in Tables 3, 14, 24, and 27. 
     A detailed list of the modified HBV sense and antisense strand sequences is shown in Tables 4, 6, 15, 25, and 28. 
     siRNA Synthesis 
     HBV siRNA sequences were synthesized at 1 μmol scale on Mermade 192 synthesizer (BioAutomation) using the solid support mediated phosphoramidite chemistry. The solid support was controlled pore glass (500 A) loaded with custom GalNAc ligand or universal solid support (AM biochemical). Ancillary synthesis reagents, 2′-F and 2′-O-Methyl RNA and deoxy phosphoramidites were obtained from Thermo-Fisher (Milwaukee, Wis.) and Hongene (China). 2′F 2′-O-Methyl, GNA (glycol nucleic acids), 5′phosphate and abasic modifications were introduced employing the corresponding phosphoramidites. Synthesis of 3′ GalNAc conjugated single strands was performed on a GalNAc modified CPG support. Custom CPG universal solid support was used for the synthesis of antisense single strands. Coupling time for all phosphoramidites (100 mM in acetonitrile) was 5 min employing 5-Ethylthio-1H-tetrazole (ETT) as activator (0.6 M in acetonitrile). Phosphorothioate linkages were generated using a 50 mM solution of 3-((Dimethylamino-methylidene) amino)-3H-1,2,4-dithiazole-3-thione (DDTT, obtained from Chemgenes (Wilmington, Mass., USA)) in anhydrous acetonitrile/pyridine (1:1 v/v). Oxidation time was 3 minutes. All sequences were synthesized with final removal of the DMT group (“DMT off”). 
     Upon completion of the solid phase synthesis, oligoribonucleotides were cleaved from the solid support and deprotected in sealed 96 deep well plates using 200 μL Aqueous Methylamine reagents at 60° C. for 20 minutes. At the end of cleavage and deprotection step, the synthesis plate was allowed to come to room temperature and was precipitated by addition of 1 mL of acetontile: ethanol mixture (9:1). The plates were cooled at −80 C for 2 hrs, supernatant decanted carefully with the aid of a multi channel pipette. The oligonucleotide pellet was re-suspended in 20 mM NaOAc buffer and were desalted using a 5 mL HiTrap size exclusion column (GE Healthcare) on an AKTA Purifier System equipped with an A905 autosampler and a Frac 950 fraction collector. Desalted samples were collected in 96-well plates. Samples from each sequence were analyzed by LC-MS to confirm the identity, UV (260 nm) for quantification and a selected set of samples by IEX chromatography to determine purity. 
     Annealing of HBV single strands was performed on a Tecan liquid handling robot. Equimolar mixture of sense and antisense single strands were combined and annealed in 96 well plates. After combining the complementary single strands, the 96-well plate was sealed tightly and heated in an oven at 100° C. for 10 minutes and allowed to come slowly to room temperature over a period 2-3 hours. The concentration of each duplex was normalized to 10M in 1×PBS. 
     Example 2. In Vitro Screening of siRNA Duplexes 
     Cell Culture and Transfections 
     Cos7 cells (ATCC, Manassas, Va.) were grown to near confluence at 37° C. in an atmosphere of 5% CO2 in DMEM (ATCC) supplemented with 10% FBS, before being released from the plate by trypsinization. Dual-Glo® Luciferaseconstructs generated in the psiCHECK2 plasmid containing approximately 1.1 kb of HBV genomic sequences were transfected into approximately 15×10 4  cells using Lipofectamine 2000 (Invitrogen, Carlsbad Calif. cat #11668-019). For each well of a 96 well plate, 0.2 μl of Lipofectamine was added to 10 ng of plasmid vector in 14.8 μl of Opti-MEM and allowed to complex at room temperature for 15 minutes. The mixture was then added to the cells which were resuspended in 80 μl of fresh complete media. After approximately 24 hours, the media were removed and the cells re-transfected with siRNA. Each siRNA was transfected into cells that had previously been transfected with the psiCHECK2-HBV vector that had a perfect match for the siRNA. siRNA transfection was carried out by adding 14.8 μl of Opti-MEM plus 0.2 μl of Lipofectamine RNAiMax per well (Invitrogen, Carlsbad Calif. cat #13778-150) to 5 μl of siRNA duplexes per well into a 96-well plate and incubated at room temperature for 15 minutes. The mixture was then added to the cells previously transfected with the psiCHECK2-HBV plasmid that had a perfect match to the siRNA sequence. Cells were incubated for 24 hours before luciferase was measured. 
     Single dose experiments were performed at 10 nM and 0.01 nM final duplex concentration. 
     Dual-Glo® Luciferase Assay 
     Twenty-four hours after the siRNAs were transfected, Firefly (transfection control) and Rinella (fused to HBV target sequence) luciferase were measured. First, media was removed from cells. Then Firefly luciferase activity was measured by adding 75 μl of Dual-Glo® Luciferase Reagent equal to the culture medium volume to each well and mix. The mixture was incubated at room temperature for 30 minutes before lunimescense (500 nm) was measured on a Spectramax (Molecular Devices) to detect the Firefly luciferase signal. Renilla luciferase activity was measured by adding 75 μl of room temperature of Dual-Glo® Stop &amp; Glo® Reagent was added to each well and the plates were incubated for 10-15 minutes before luminescence was again measured to determine the Renilla luciferase signal. The Dual-Glo® Stop &amp; Glo® Reagent, quench the firefly luciferase signal and sustain luminescence for the Renilla luciferase reaction. siRNA activity was determined by normalizing the Renilla (HBV) signal to the Firefly (control) signal within each well. The magnitude of siRNA activity was then assessed relative to cells that were transfected with the same vector but were not treated with siRNA or were treated with a non-targeting siRNA. All transfections were done at n=2 or greater. 
     Essentially the same methods were used to screen siRNA targeted to HDV. 
     Table 5 shows the results of a single dose screen in Cos7 cells transfected with the indicated HBV iRNAs. Data are expressed as percent of mRNA remaining relative to negative control. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Abbreviations of nucleotide monomers used in nucleic acid sequence 
               
               
                 representation. It will be understood that these monomers, when present  
               
               
                 in an oligonucleotide, are mutually linked by 5&#39;-3&#39;-phosphodiester bonds. 
               
            
           
           
               
               
            
               
                 Abbreviation 
                 Nucleotide(s) 
               
               
                   
               
               
                 A 
                 Adenosine-3&#39;-phosphate 
               
               
                 Af 
                 2&#39;-fluoroadenosine-3&#39;-phosphate 
               
               
                 Afs 
                 2&#39;-fluoroadenosine-3&#39;-phosphorothioate 
               
               
                 As 
                 adenosine-3&#39;-phosphorothioate 
               
               
                 C 
                 cytidine-3&#39;-phosphate 
               
               
                 Cf 
                 2&#39;-fluorocytidine-3&#39;-phosphate 
               
               
                 Cfs 
                 2&#39;-fluorocytidine-3&#39;-phosphorothioate 
               
               
                 Cs 
                 cytidine-3&#39;-phosphorothioate 
               
               
                 G 
                 guanosine-3&#39;-phosphate 
               
               
                 Gf 
                 2&#39;-fluoroguanosine-3&#39;-phosphate 
               
               
                 Gfs 
                 2&#39;-fluoroguanosine-3&#39;-phosphorothioate 
               
               
                 Gs 
                 guanosine-3&#39;-phosphorothioate 
               
               
                 T 
                 5&#39;-methyluridine-3&#39;-phosphate 
               
               
                 Tf 
                 2&#39;-fluoro-5-methyluridine-3&#39;-phosphate 
               
               
                 Tfs 
                 2&#39;-fluoro-5-methyluridine-3&#39;-phosphorothioate 
               
               
                 Ts 
                 5-methyluridine-3&#39;-phosphorothioate 
               
               
                 U 
                 Uridine-3&#39;-phosphate 
               
               
                 Uf 
                 2&#39;-fluorouridine-3&#39;-phosphate 
               
               
                 Ufs 
                 2&#39;-fluorouridine-3&#39;-phosphorothioate 
               
               
                 Us 
                 uridine-3&#39;-phosphorothioate 
               
               
                 N 
                 any nucleotide (G, A, C, T or U) 
               
               
                 a 
                 2&#39;-O-methyladenosine-3&#39;-phosphate 
               
               
                 as 
                 2&#39;-O-methyladenosine-3&#39;-phosphorothioate 
               
               
                 c 
                 2&#39;-O-methylcytidine-3&#39;-phosphate 
               
               
                 cs 
                 2&#39;-O-methylcytidine-3&#39;-phosphorothioate 
               
               
                 g 
                 2&#39;-O-methylguanosine-3&#39;-phosphate 
               
               
                 gs 
                 2&#39;-O-methylguanosine-3&#39;-phosphorothioate 
               
               
                 t 
                 2&#39;-O-methyl-5-methyluridine-3&#39;-phosphate 
               
               
                 ts 
                 2&#39;-O-methyl-5-methyluridine-3&#39;-phosphorothioate 
               
               
                 u 
                 2&#39;-O-methyluridine-3&#39;-phosphate 
               
               
                 us 
                 2&#39;-O-methyluridine-3&#39;-phosphorothioate 
               
               
                 s 
                 phosphorothioate linkage 
               
               
                 L96 
                 N-[tris(GalNAc-alkyl)-amidodecanoyl)]-4- 
               
               
                   
                 hydroxyprolinol Hyp-(GalNAc-alkyl)3 
               
               
                 (dt) 
                 deoxy-thymine 
               
               
                 Y34 
                 2-hydroxymethyl-tetrahydrofurane-4-methoxy- 
               
               
                   
                 3-phosphate (abasic 2&#39;-OMe furanose) 
               
               
                 Y44 
                 2-hydroxymethyl-tetrahydrofurane-5-phosphate 
               
               
                 (Agn) 
                 Adenosine-glycol nucleic acid (GNA) 
               
               
                 (Tgn) 
                 Thymidine-glycol nucleic acid (GNA) S-Isomer 
               
               
                 (Cgn) 
                 Cytidine-glycol nucleic acid (GNA) 
               
               
                 P 
                 Phosphate 
               
               
                 VP 
                 Vinyl-phosphate 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Unmodified Sense and Antisense Strand Sequences of HBV dsRNAs 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 Sense 
                   
                 SEQ 
                   
                   
                 SEQ 
                 Position 
               
               
                 Duplex 
                 Oligo 
                 Sense Sequence 
                 ID 
                 Antisense 
                 Antisense Sequence 
                 ID 
                 in NC_ 
               
               
                 Name 
                 Name 
                 (5′ to 3′) 
                 NO: 
                 Oligo Name 
                 (5′ to 3′) 
                 NO: 
                 003977.1 
               
               
                   
               
               
                 AD-61522.2 
                 A-123463.2 
                 AGUUAUAUGGAUGAUGUGGUA 
                 121 
                 A-123464.2 
                 UACCACAUCAUCCAUAUAACUGA 
                 556 
                 731_753 
               
               
                   
               
               
                 AD-61547.2 
                 A-123487.2 
                 GGAUGUGUCUGCGGCGUUUUA 
                 122 
                 A-123488.2 
                 UAAAACGCCGCAGACACAUCCAG 
                 557 
                 373_395 
               
               
                   
               
               
                 AD-63938.2 
                 A-127896.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 123 
                 A-127897.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 558 
                 250_272 
               
               
                   
               
               
                 AD-63939.2 
                 A-127909.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 124 
                 A-127906.3 
                 UGAGAGAAGUCCACCACGAGUCU 
                 559 
                 250_272 
               
               
                   
               
               
                 AD-63940.2 
                 A-127917.1 
                 ACUCGUGGUGGACUUCTCUCA 
                 125 
                 A-127906.11 
                 UGAGAGAAGUCCACCACGAGUCU 
                 560 
                 250_272 
               
               
                   
               
               
                 AD-63940.3 
                 A-127917.4 
                 ACUCGUGGUGGACUUCTCUCA 
                 126 
                 A-127906.19 
                 UGAGAGAAGUCCACCACGAGUCU 
                 561 
                 250_272 
               
               
                   
               
               
                 AD-63941.2 
                 A-127905.8 
                 ACUCGUGGUGGACUUCUCUCA 
                 127 
                 A-127925.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 562 
                 250_272 
               
               
                   
               
               
                 AD-63942.2 
                 A-127933.1 
                 UCGUGGUGGACUUCUCUCA 
                 128 
                 A-127934.1 
                 UGAGAGAAGUCCACCACGAGU 
                 563 
                 252_274 
               
               
                   
               
               
                 AD-63943.2 
                 A-127944.2 
                 ACUCGUGGUGGACUUCUCUCA 
                 129 
                 A-127942.2 
                 UGAGAGAAGUCCACCACGAGUCU 
                 564 
                 250_272 
               
               
                   
               
               
                 AD-63945.2 
                 A-127910.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 130 
                 A-127906.4 
                 UGAGAGAAGUCCACCACGAGUCU 
                 565 
                 250_272 
               
               
                   
               
               
                 AD-63946.2 
                 A-127918.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 131 
                 A-127906.12 
                 UGAGAGAAGUCCACCACGAGUCU 
                 566 
                 250_272 
               
               
                   
               
               
                 AD-63947.2 
                 A-127905.9 
                 ACUCGUGGUGGACUUCUCUCA 
                 132 
                 A-127926.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 567 
                 250_272 
               
               
                   
               
               
                 AD-63948.2 
                 A-127935.1 
                 GUGGUGGACUUCUCUCA 
                 133 
                 A-127936.1 
                 UGAGAGAAGUCCACCACGA 
                 568 
                 254_276 
               
               
                   
               
               
                 AD-63949.2 
                 A-127944.3 
                 ACUCGUGGUGGACUUCUCUCA 
                 134 
                 A-127906.14 
                 UGAGAGAAGUCCACCACGAGUCU 
                 569 
                 250_272 
               
               
                   
               
               
                 AD-63950.2 
                 A-127900.1 
                 UCGUGGUGGACUUCUCUCAUU 
                 135 
                 A-127901.1 
                 UGAGAGAAGUCCACCACGAUU 
                 570 
                 252_274 
               
               
                   
               
               
                 AD-63951.2 
                 A-127911.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 136 
                 A-127906.5 
                 UGAGAGAAGUCCACCACGAGUCU 
                 571 
                 250_272 
               
               
                   
               
               
                 AD-63952.2 
                 A-127905.2 
                 ACUCGUGGUGGACUUCUCUCA 
                 137 
                 A-127919.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 572 
                 250_272 
               
               
                   
               
               
                 AD-63953.2 
                 A-127905.10 
                 ACUCGUGGUGGACUUCUCUCA 
                 138 
                 A-127927.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 573 
                 250_272 
               
               
                   
               
               
                 AD-63955.2 
                 A-127945.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 139 
                 A-127940.3 
                 UGAGAGAAGUCCACCACGAGUCU 
                 574 
                 250_272 
               
               
                   
               
               
                 AD-63956.2 
                 A-127902.1 
                 UCGUGGUGGACUUCUCUCA 
                 140 
                 A-127903.1 
                 UGAGAGAAGUCCACCACGAUU 
                 575 
                 252_274 
               
               
                   
               
               
                 AD-63957.2 
                 A-127912.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 141 
                 A-127906.6 
                 UGAGAGAAGUCCACCACGAGUCU 
                 576 
                 250_272 
               
               
                   
               
               
                 AD-63958.2 
                 A-127905.3 
                 ACUCGUGGUGGACUUCUCUCA 
                 142 
                 A-127920.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 577 
                 250_272 
               
               
                   
               
               
                 AD-63959.2 
                 A-127905.11 
                 ACUCGUGGUGGACUUCUCUCA 
                 143 
                 A-127928.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 578 
                 250_272 
               
               
                   
               
               
                 AD-63960.2 
                 A-126619.2 
                 UAUUUCCUAGGGUACAA 
                 144 
                 A-127938.1 
                 UGAGAGAAGUCCACCACGA 
                 579 
                 254_276 
               
               
                   
               
               
                 AD-63961.2 
                 A-127945.2 
                 ACUCGUGGUGGACUUCUCUCA 
                 145 
                 A-127942.3 
                 UGAGAGAAGUCCACCACGAGUCU 
                 580 
                 250_272 
               
               
                   
               
               
                 AD-63962.2 
                 A-127902.2 
                 UCGUGGUGGACUUCUCUCA 
                 146 
                 A-127904.1 
                 UGAGAGAAGUCCACCACGAUU 
                 581 
                 252_274 
               
               
                   
               
               
                 AD-63963.2 
                 A-127913.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 147 
                 A-127906.7 
                 UGAGAGAAGUCCACCACGAGUCU 
                 582 
                 250_272 
               
               
                   
               
               
                 AD-63964.2 
                 A-127905.4 
                 ACUCGUGGUGGACUUCUCUCA 
                 148 
                 A-127921.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 583 
                 250_272 
               
               
                   
               
               
                 AD-63965.2 
                 A-127905.12 
                 ACUCGUGGUGGACUUCUCUCA 
                 149 
                 A-127929.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 584 
                 250_272 
               
               
                   
               
               
                 AD-63966.2 
                 A-127939.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 150 
                 A-127940.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 585 
                 250_272 
               
               
                   
               
               
                 AD-63967.2 
                 A-127945.3 
                 ACUCGUGGUGGACUUCUCUCA 
                 151 
                 A-127906.15 
                 UGAGAGAAGUCCACCACGAGUCU 
                 586 
                 250_272 
               
               
                   
               
               
                 AD-63968.2 
                 A-127905.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 152 
                 A-127906.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 587 
                 250_272 
               
               
                   
               
               
                 AD-63968.2 
                 A-127905.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 153 
                 A-127906.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 588 
                 250_272 
               
               
                   
               
               
                 AD-63968.4 
                 A-127905.15 
                 ACUCGUGGUGGACUUCUCUCA 
                 154 
                 A-127906.17 
                 UGAGAGAAGUCCACCACGAGUCU 
                 589 
                 250_272 
               
               
                   
               
               
                 AD-63968.5 
                 A-127905.17 
                 ACUCGUGGUGGACUUCUCUCA 
                 155 
                 A-127906.18 
                 UGAGAGAAGUCCACCACGAGUCU 
                 590 
                 250_272 
               
               
                   
               
               
                 AD-63969.2 
                 A-127914.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 156 
                 A-127906.8 
                 UGAGAGAAGUCCACCACGAGUCU 
                 591 
                 250_272 
               
               
                   
               
               
                 AD-63970.2 
                 A-127905.5 
                 ACUCGUGGUGGACUUCUCUCA 
                 157 
                 A-127922.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 592 
                 250_272 
               
               
                   
               
               
                 AD-63971.2 
                 A-127905.13 
                 ACUCGUGGUGGACUUCUCUCA 
                 158 
                 A-127930.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 593 
                 250_272 
               
               
                   
               
               
                 AD-63972.2 
                 A-127941.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 159 
                 A-127942.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 594 
                 250_272 
               
               
                   
               
               
                 AD-63973.2 
                 A-127946.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 160 
                 A-127947.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 595 
                 250_272 
               
               
                   
               
               
                 AD-63975.2 
                 A-127915.1 
                 ACUCGUGGUGGACUUCTCUCA 
                 161 
                 A-127906.9 
                 UGAGAGAAGUCCACCACGAGUCU 
                 596 
                 250_272 
               
               
                   
               
               
                 AD-63976.2 
                 A-127905.6 
                 ACUCGUGGUGGACUUCUCUCA 
                 162 
                 A-127923.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 597 
                 250_272 
               
               
                   
               
               
                 AD-63977.2 
                 A-127917.2 
                 ACUCGUGGUGGACUUCTCUCA 
                 163 
                 A-127931.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 598 
                 250_272 
               
               
                   
               
               
                 AD-63978.2 
                 A-127943.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 164 
                 A-127906.13 
                 UGAGAGAAGUCCACCACGAGUCU 
                 599 
                 250_272 
               
               
                   
               
               
                 AD-63979.2 
                 A-127908.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 165 
                 A-127906.2 
                 UGAGAGAAGUCCACCACGAGUCU 
                 600 
                 250_272 
               
               
                   
               
               
                 AD-63980.2 
                 A-127916.1 
                 ACUCGUGGUGGACUUCTCUCA 
                 166 
                 A-127906.10 
                 UGAGAGAAGUCCACCACGAGUCU 
                 601 
                 250_272 
               
               
                   
               
               
                 AD-63981.2 
                 A-127905.7 
                 ACUCGUGGUGGACUUCUCUCA 
                 167 
                 A-127924.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 602 
                 250_272 
               
               
                   
               
               
                 AD-63982.2 
                 A-127917.3 
                 ACUCGUGGUGGACUUCTCUCA 
                 168 
                 A-127932.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 603 
                 250_272 
               
               
                   
               
               
                 AD-63983.2 
                 A-127944.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 169 
                 A-127940.2 
                 UGAGAGAAGUCCACCACGAGUCU 
                 604 
                 250_272 
               
               
                   
               
               
                 AD-63985.2 
                 A-127961.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 170 
                 A-127956.4 
                 AAAUUGAGAGAAGUCCACCACGA 
                 605 
                 254_276 
               
               
                   
               
               
                 AD-63986.2 
                 A-127969.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 171 
                 A-127956.12 
                 AAAUUGAGAGAAGUCCACCACGA 
                 606 
                 254_276 
               
               
                   
               
               
                 AD-63987.2 
                 A-127955.9 
                 GUGGUGGACUUCUCUCAAUUU 
                 172 
                 A-127977.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 607 
                 254_276 
               
               
                   
               
               
                 AD-63988.2 
                 A-127986.1 
                 UGGACUUCUCUCAAUUU 
                 173 
                 A-127987.1 
                 AAAUUGAGAGAAGUCCACC 
                 608 
                 258_280 
               
               
                   
               
               
                 AD-63989.2 
                 A-127996.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 174 
                 A-127992.2 
                 AAAUUGAGAGAAGUCCACCACGA 
                 609 
                 254_276 
               
               
                   
               
               
                 AD-63990.2 
                 A-127950.1 
                 GGUGGACUUCUCUCAAUUUUU 
                 175 
                 A-127951.1 
                 AAAUUGAGAGAAGUCCACCUU 
                 610 
                 256_278 
               
               
                   
               
               
                 AD-63991.2 
                 A-127962.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 176 
                 A-127956.5 
                 AAAUUGAGAGAAGUCCACCACGA 
                 611 
                 254_276 
               
               
                   
               
               
                 AD-63992.2 
                 A-127955.2 
                 GUGGUGGACUUCUCUCAAUUU 
                 177 
                 A-127970.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 612 
                 254_276 
               
               
                   
               
               
                 AD-63993.2 
                 A-127955.10 
                 GUGGUGGACUUCUCUCAAUUU 
                 178 
                 A-127978.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 613 
                 254_276 
               
               
                   
               
               
                 AD-63994.2 
                 A-127984.2 
                 GGUGGACUUCUCUCAAUUU 
                 179 
                 A-127988.1 
                 AAAUUGAGAGAAGUCCACCAC 
                 614 
                 256_278 
               
               
                   
               
               
                 AD-63995.2 
                 A-127996.2 
                 GUGGUGGACUUCUCUCAAUUU 
                 180 
                 A-127993.2 
                 AAAUUGAGAGAAGUCCACCACGA 
                 615 
                 254_276 
               
               
                   
               
               
                 AD-63996.2 
                 A-127952.1 
                 GGUGGACUUCUCUCAAUUU 
                 181 
                 A-127953.1 
                 AAAUUGAGAGAAGUCCACCUU 
                 616 
                 256_278 
               
               
                   
               
               
                 AD-63997.2 
                 A-127963.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 182 
                 A-127956.6 
                 AAAUUGAGAGAAGUCCACCACGA 
                 617 
                 254_276 
               
               
                   
               
               
                 AD-63999.2 
                 A-127955.11 
                 GUGGUGGACUUCUCUCAAUUU 
                 183 
                 A-127979.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 618 
                 254_276 
               
               
                   
               
               
                 AD-64000.2 
                 A-127986.2 
                 UGGACUUCUCUCAAUUU 
                 184 
                 A-127989.1 
                 AAAUUGAGAGAAGUCCACC 
                 619 
                 258_280 
               
               
                   
               
               
                 AD-64001.2 
                 A-127996.3 
                 GUGGUGGACUUCUCUCAAUUU 
                 185 
                 A-127994.2 
                 AAAUUGAGAGAAGUCCACCACGA 
                 620 
                 254_276 
               
               
                   
               
               
                 AD-64002.2 
                 A-127952.2 
                 GGUGGACUUCUCUCAAUUU 
                 186 
                 A-127954.1 
                 AAAUUGAGAGAAGUCCACCUU 
                 621 
                 256_278 
               
               
                   
               
               
                 AD-64003.2 
                 A-127964.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 187 
                 A-127956.7 
                 AAAUUGAGAGAAGUCCACCACGA 
                 622 
                 254_276 
               
               
                   
               
               
                 AD-64004.2 
                 A-127955.4 
                 GUGGUGGACUUCUCUCAAUUU 
                 188 
                 A-127972.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 623 
                 254_276 
               
               
                   
               
               
                 AD-64005.2 
                 A-127955.12 
                 GUGGUGGACUUCUCUCAAUUU 
                 189 
                 A-127980.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 624 
                 254_276 
               
               
                   
               
               
                 AD-64006.2 
                 A-127990.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 190 
                 A-127991.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 625 
                 254_276 
               
               
                   
               
               
                 AD-64007.2 
                 A-127996.4 
                 GUGGUGGACUUCUCUCAAUUU 
                 191 
                 A-127995.2 
                 AAAUUGAGAGAAGUCCACCACGA 
                 626 
                 254_276 
               
               
                   
               
               
                 AD-64008.2 
                 A-127955.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 192 
                 A-127956.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 627 
                 254_276 
               
               
                   
               
               
                 AD-64008.2 
                 A-127955.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 193 
                 A-127956.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 628 
                 254_276 
               
               
                   
               
               
                 AD-64008.4 
                 A-127955.15 
                 GUGGUGGACUUCUCUCAAUUU 
                 194 
                 A-127956.14 
                 AAAUUGAGAGAAGUCCACCACGA 
                 629 
                 254_276 
               
               
                   
               
               
                 AD-64009.2 
                 A-127965.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 195 
                 A-127956.8 
                 AAAUUGAGAGAAGUCCACCACGA 
                 630 
                 254_276 
               
               
                   
               
               
                 AD-64010.2 
                 A-127955.5 
                 GUGGUGGACUUCUCUCAAUUU 
                 196 
                 A-127973.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 631 
                 254_276 
               
               
                   
               
               
                 AD-64011.2 
                 A-127955.13 
                 GUGGUGGACUUCUCUCAAUUU 
                 197 
                 A-127981.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 632 
                 254_276 
               
               
                   
               
               
                 AD-64012.2 
                 A-127990.2 
                 GUGGUGGACUUCUCUCAAUUU 
                 198 
                 A-127992.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 633 
                 254_276 
               
               
                   
               
               
                 AD-64013.2 
                 A-127997.1 
                 GUGGUGGACTTCUCUCAAUUU 
                 199 
                 A-127998.1 
                 AAAUUGAGAGAAGTCCACCACGA 
                 634 
                 254_276 
               
               
                   
               
               
                 AD-64014.2 
                 A-127957.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 200 
                 A-127958.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 635 
                 254_276 
               
               
                   
               
               
                 AD-64015.2 
                 A-127966.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 201 
                 A-127956.9 
                 AAAUUGAGAGAAGUCCACCACGA 
                 636 
                 254_276 
               
               
                   
               
               
                 AD-64016.2 
                 A-127955.6 
                 GUGGUGGACUUCUCUCAAUUU 
                 202 
                 A-127974.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 637 
                 254_276 
               
               
                   
               
               
                 AD-64017.2 
                 A-127968.2 
                 GUGGUGGACUTCUCUCAAUUU 
                 203 
                 A-127982.1 
                 AAAUUGAGAGAAGTCCACCACGA 
                 638 
                 254_276 
               
               
                   
               
               
                 AD-64018.2 
                 A-127990.3 
                 GUGGUGGACUUCUCUCAAUUU 
                 204 
                 A-127993.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 639 
                 254_276 
               
               
                   
               
               
                 AD-64019.2 
                 A-127959.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 205 
                 A-127956.2 
                 AAAUUGAGAGAAGUCCACCACGA 
                 640 
                 254_276 
               
               
                   
               
               
                 AD-M020.2 
                 A-127967.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 206 
                 A-127956.10 
                 AAAUUGAGAGAAGUCCACCACGA 
                 641 
                 254_276 
               
               
                   
               
               
                 AD-M021.2 
                 A-127955.7 
                 GUGGUGGACUUCUCUCAAUUU 
                 207 
                 A-127975.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 642 
                 254_276 
               
               
                   
               
               
                 AD-M022.2 
                 A-127968.3 
                 GUGGUGGACUTCUCUCAAUUU 
                 208 
                 A-127983.1 
                 AAAUUGAGAGAAGTCCACCACGA 
                 643 
                 254_276 
               
               
                   
               
               
                 AD-M023.2 
                 A-127990.4 
                 GUGGUGGACUUCUCUCAAUUU 
                 209 
                 A-127994.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 644 
                 254_276 
               
               
                   
               
               
                 AD-M024.2 
                 A-127960.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 210 
                 A-127956.3 
                 AAAUUGAGAGAAGUCCACCACGA 
                 645 
                 254_276 
               
               
                   
               
               
                 AD-M025.2 
                 A-127968.1 
                 GUGGUGGACUTCUCUCAAUUU 
                 211 
                 A-127956.11 
                 AAAUUGAGAGAAGUCCACCACGA 
                 646 
                 254_276 
               
               
                   
               
               
                 AD-M026.2 
                 A-127955.8 
                 GUGGUGGACUUCUCUCAAUUU 
                 212 
                 A-127976.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 647 
                 254_276 
               
               
                   
               
               
                 AD-64027.2 
                 A-127984.1 
                 GGUGGACUUCUCUCAAUUU 
                 213 
                 A-127985.1 
                 AAAUUGAGAGAAGUCCACCAC 
                 648 
                 256_278 
               
               
                   
               
               
                 AD-64028.2 
                 A-127990.5 
                 GUGGUGGACUUCUCUCAAUUU 
                 214 
                 A-127995.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 649 
                 254_276 
               
               
                   
               
               
                 AD-64272.2 
                 A-128001.2 
                 GUGCACUUCGCUUCACCUCUG 
                 215 
                 A-128002.2 
                 CAGAGGUGAAGCGAAGUGCACAC 
                 650 
                 1577_1599 
               
               
                   
               
               
                 AD-64274.1 
                 A-128363.1 
                 GUUGACAAAAAUCCUCACAAU 
                 216 
                 A-128364.1 
                 AUUGUGAGGAUUUUUGUCAACAA 
                 651 
                 215_237 
               
               
                   
               
               
                 AD-64275.1 
                 A-128377.1 
                 UGUUGACAAAAAUCCUCACAA 
                 217 
                 A-128378.1 
                 UUGUGAGGAUUUUUGUCAACAAG 
                 652 
                 214_236 
               
               
                   
               
               
                 AD-64276.1 
                 A-128393.1 
                 GGUGGACUUCUCUCAAUUUUA 
                 218 
                 A-128394.1 
                 UAAAAUUGAGAGAAGUCCACCAC 
                 653 
                 256_278 
               
               
                   
               
               
                 AD-64277.1 
                 A-128407.1 
                 UCUUUUGGAGUGUGGAUUCGA 
                 219 
                 A-128408.1 
                 UCGAAUCCACACUCCAAAAGACA 
                 654 
                 2259_2281 
               
               
                   
               
               
                 AD-64277.1 
                 A-128407.1 
                 UCUUUUGGAGUGUGGAUUCGA 
                 220 
                 A-128408.1 
                 UCGAAUCCACACUCCAAAAGACA 
                 655 
                 2259_2281 
               
               
                   
               
               
                 AD-64278.1 
                 A-128423.1 
                 ACUGUUCAAGCCUCCAAGCUA 
                 221 
                 A-128424.1 
                 UAGCUUGGAGGCUUGAACAAGAC 
                 656 
                 1857_1879 
               
               
                   
               
               
                 AD-64279.1 
                 A-128435.1 
                 UCUGCCGAUCCAUACUGCGGA 
                 222 
                 A-128436.1 
                 UCCGCAGUAUGGAUCGGCAGAGG 
                 657 
                 1255_1277 
               
               
                   
               
               
                 AD-64280.1 
                 A-128379.1 
                 AUGUGUCUGCGGCGUUUUAUA 
                 223 
                 A-128380.1 
                 UAUAAAACGCCGCAGACACAUCC 
                 658 
                 375_397 
               
               
                   
               
               
                 AD-64281.1 
                 A-128395.1 
                 CCCCGUCUGUGCCUUCUCAUA 
                 224 
                 A-128396.1 
                 UAUGAGAAGGCACAGACGGGGAG 
                 659 
                 1545_1567 
               
               
                   
               
               
                 AD-64282.1 
                 A-128409.1 
                 GCCUAAUCAUCUCUUGUUCAU 
                 225 
                 A-128410.1 
                 AUGAACAAGAGAUGAUUAGCGAG 
                 660 
                 1831_1853 
               
               
                   
               
               
                 AD-64283.1 
                 A-128425.1 
                 UCUAGACUCGUGGUGGACUUC 
                 226 
                 A-128426.1 
                 GAAGUCCACCACGAGUCUAGACU 
                 661 
                 245_267 
               
               
                   
               
               
                 AD-64284.1 
                 A-128437.1 
                 CUGCCGAUCCAUACUGCGGAA 
                 227 
                 A-128438.1 
                 UUCCGCAGUAUGGAUCGGCAGAG 
                 662 
                 1256_1278 
               
               
                   
               
               
                 AD-64285.1 
                 A-128365.1 
                 UUUUUCUUGUUGACAAAAAUA 
                 228 
                 A-128366.1 
                 UAUUUUUGUCAACAAGAAAAACC 
                 663 
                 207_229 
               
               
                   
               
               
                 AD-64286.1 
                 A-128381.1 
                 AUCUUCUUGUUGGUUCUUCUA 
                 229 
                 A-128382.1 
                 UAGAAGAACCAACAAGAAGAUGA 
                 664 
                 426_448 
               
               
                   
               
               
                 AD-64289.1 
                 A-128367.1 
                 GUUUUUCUUGUUGACAAAAAU 
                 230 
                 A-128368.1 
                 AUUUUUGUCAACAAGAAAAACCC 
                 665 
                 206_228 
               
               
                   
               
               
                 AD-64290.1 
                 A-128383.1 
                 CUGCCUAAUCAUCUCUUGUUA 
                 231 
                 A-128384.1 
                 UAACAAGAGAUGAUUAGGCAGAG 
                 666 
                 1829_1851 
               
               
                   
               
               
                 AD-64291.1 
                 A-128399.1 
                 UCCUCACAAUACCACAGAGUA 
                 232 
                 A-128400.1 
                 UACUCUGUGGUAUUGUGAGGAUU 
                 667 
                 226_248 
               
               
                   
               
               
                 AD-64292.1 
                 A-128413.1 
                 CUUGUUGACAAAAAUCCUCAA 
                 233 
                 A-128414.1 
                 UUGAGGAUUUUUGUCAACAAGAA 
                 668 
                 212_234 
               
               
                   
               
               
                 AD-64293.1 
                 A-128439.1 
                 GCAACUUUUUCACCUCUGCCU 
                 234 
                 A-128440.1 
                 AGGCAGAGGUGAAAAAGUUGCAU 
                 669 
                 1814_1836 
               
               
                   
               
               
                 AD-64294.1 
                 A-128369.1 
                 GGGAACAAGAGCUACAGCAUA 
                 235 
                 A-128370.1 
                 UAUGCUGUAGCUCUUGUUCCCAA 
                 670 
                 2828_2850 
               
               
                   
               
               
                 AD-64295.1 
                 A-128385.1 
                 CGUGGUGGACUUCUCUCAAUU 
                 236 
                 A-128386.1 
                 AAUUGAGAGAAGUCCACCAGCAG 
                 671 
                 253_275 
               
               
                   
               
               
                 AD-64297.1 
                 A-128415.1 
                 CUGCUGCUAUGCCUCAUCUUA 
                 237 
                 A-128416.1 
                 UAAGAUGAGGCAUAGCAGCAGGA 
                 672 
                 411_433 
               
               
                   
               
               
                 AD-64298.1 
                 A-128427.1 
                 GUUGGAUGUGUCUGCGGCGUU 
                 238 
                 A-128428.1 
                 AACGCCGCAGACACAUCCAACGA 
                 673 
                 370_392 
               
               
                   
               
               
                 AD-64299.1 
                 A-128441.1 
                 UUCAUCCUGCUGCUAUGCCUA 
                 239 
                 A-128442.1 
                 UAGGCAUAGCAGCAGGAUGAAGA 
                 674 
                 405_427 
               
               
                   
               
               
                 AD-64300.1 
                 A-128371.1 
                 UUCUUGUUGACAAAAAUCCUA 
                 240 
                 A-128372.1 
                 UAGGAUUUUUGUCAACAAGAAAA 
                 675 
                 210_232 
               
               
                   
               
               
                 AD-64302.1 
                 A-128417.1 
                 UAUAUGGAUGAUGUGGUAUUA 
                 241 
                 A-128418.1 
                 UAAUACCACAUCAUCCAUAUAAC 
                 676 
                 734_756 
               
               
                   
               
               
                 AD-64303.1 
                 A-128429.1 
                 UUCAUCCUGCUGCUAUGCCUC 
                 242 
                 A-128430.1 
                 GAGGCAUAGCAGCAGGAUGAAGA 
                 677 
                 405_427 
               
               
                   
               
               
                 AD-64304.1 
                 A-128443.1 
                 GUGCACUUCGCUUCACCUCUA 
                 243 
                 A-128444.1 
                 UAGAGGUGAAGCGAAGUGCACAC 
                 678 
                 1577_1599 
               
               
                   
               
               
                 AD-64305.1 
                 A-128373.1 
                 UUGACAAAAAUCCUCACAAUA 
                 244 
                 A-128374.1 
                 UAUUGUGAGGAUUUUUGUCAACA 
                 679 
                 216_238 
               
               
                   
               
               
                 AD-64307.1 
                 A-128403.1 
                 AAGCCUCCAAGCUGUGCCUUA 
                 245 
                 A-128404.1 
                 UAAGGCACAGCUUGGAGGCUUGA 
                 680 
                 1864_1886 
               
               
                   
               
               
                 AD-64308.1 
                 A-128419.1 
                 CCUCUUCAUCCUGCUGCUAUA 
                 246 
                 A-128420.1 
                 UAUAGCAGCAGGAUGAAGAGGAA 
                 681 
                 401_423 
               
               
                   
               
               
                 AD-64309.1 
                 A-128431.1 
                 CCUGCUGCUAUGCCUCAUCUU 
                 247 
                 A-128432.1 
                 AAGAUGAGGCAUAGCAGCAGGAU 
                 682 
                 410_432 
               
               
                   
               
               
                 AD-64310.1 
                 A-128375.1 
                 CAUCUUCUUGUUGGUUCUUCU 
                 248 
                 A-128376.1 
                 AGAAGAACCAACAAGAAGAUGAG 
                 683 
                 425_447 
               
               
                   
               
               
                 AD-64311.1 
                 A-128391.1 
                 CCGUCUGUGCCUUCUCAUCUA 
                 249 
                 A-128392.1 
                 UAGAUGAGAAGGCACAGACGGGG 
                 684 
                 1547_1569 
               
               
                   
               
               
                 AD-64312.1 
                 A-128405.1 
                 CCUCAUCUUCUUGUUGGUUCU 
                 250 
                 A-128406.1 
                 AGAACCAACAAGAAGAUGAGGCA 
                 685 
                 422_444 
               
               
                   
               
               
                 AD-64313.1 
                 A-128421.1 
                 CCACCAAAUGCCCCUAUCUUA 
                 251 
                 A-128422.1 
                 UAAGAUAGGGGCAUUUGGUGGUC 
                 686 
                 2298_2320 
               
               
                   
               
               
                 AD-64314.1 
                 A-128433.1 
                 GCUCCUCUGCCGAUCCAUACU 
                 252 
                 A-128434.1 
                 AGUAUGGAUCGGCAGAGGAGCCA 
                 687 
                 1250_1272 
               
               
                   
               
               
                 AD-64315.1 
                 A-128363.2 
                 GUUGACAAAAAUCCUCACAAU 
                 253 
                 A-128445.1 
                 AUUGUGAGGAUUUUUGUCAACAA 
                 688 
                 215_237 
               
               
                   
               
               
                 AD-64316.1 
                 A-128377.2 
                 UGUUGACAAAAAUCCUCACAA 
                 254 
                 A-128453.1 
                 UUGUGAGGAUUUUUGUCAACAAG 
                 689 
                 214_236 
               
               
                   
               
               
                 AD-64317.1 
                 A-128393.2 
                 GGUGGACUUCUCUCAAUUUUA 
                 255 
                 A-128461.1 
                 UAAAAUUGAGAGAAGUCCACCAC 
                 690 
                 256_278 
               
               
                   
               
               
                 AD-64318.1 
                 A-128407.2 
                 UCUUUUGGAGUGUGGAUUCGA 
                 256 
                 A-128469.1 
                 UCGAAUCCACACUCCAAAAGACA 
                 691 
                 2259_2281 
               
               
                   
               
               
                 AD-64318.1 
                 A-128407.2 
                 UCUUUUGGAGUGUGGAUUCGA 
                 257 
                 A-128469.1 
                 UCGAAUCCACACUCCAAAAGACA 
                 692 
                 2259_2281 
               
               
                   
               
               
                 AD-64319.1 
                 A-128423.2 
                 ACUGUUCAAGCCUCCAAGCUA 
                 258 
                 A-128477.1 
                 UAGCUUGGAGGCUUGAACAAGAC 
                 693 
                 1857_1879 
               
               
                   
               
               
                 AD-64320.1 
                 A-128435.2 
                 UCUGCCGAUCCAUACUGCGGA 
                 259 
                 A-128483.1 
                 UCCGCAGUAUGGAUCGGCAGAGG 
                 694 
                 1255_1277 
               
               
                   
               
               
                 AD-64321.1 
                 A-123463.3 
                 AGUUAUAUGGAUGAUGUGGUA 
                 260 
                 A-128446.1 
                 UACCACAUCAUCCAUAUAACUGA 
                 695 
                 731_753 
               
               
                   
               
               
                 AD-64322.1 
                 A-128379.2 
                 AUGUGUCUGCGGCGUUUUAUA 
                 261 
                 A-128454.1 
                 UAUAAAACGCCGCAGACACAUCC 
                 696 
                 375_397 
               
               
                   
               
               
                 AD-64323.1 
                 A-128395.2 
                 CCCCGUCUGUGCCUUCUCAUA 
                 262 
                 A-128462.1 
                 UAUGAGAAGGCACAGACGGGGAG 
                 697 
                 1545_1567 
               
               
                   
               
               
                 AD-64324.1 
                 A-128409.2 
                 GCCUAAUCAUCUCUUGUUCAU 
                 263 
                 A-128470.1 
                 AUGAACAAGAGAUGAUUAGCGAG 
                 698 
                 1831_1853 
               
               
                   
               
               
                 AD-64325.1 
                 A-128425.2 
                 UCUAGACUCGUGGUGGACUUC 
                 264 
                 A-128478.1 
                 GAAGUCCACCACGAGUCUAGACU 
                 699 
                 245_267 
               
               
                   
               
               
                 AD-64326.1 
                 A-128437.2 
                 CUGCCGAUCCAUACUGCGGAA 
                 265 
                 A-128484.1 
                 UUCCGCAGUAUGGAUCGGCAGAG 
                 700 
                 1256_1278 
               
               
                   
               
               
                 AD-64328.1 
                 A-128381.2 
                 AUCUUCUUGUUGGUUCUUCUA 
                 266 
                 A-128455.1 
                 UAGAAGAACCAACAAGAAGAUGA 
                 701 
                 426_448 
               
               
                   
               
               
                 AD-64330.1 
                 A-128411.2 
                 UUCUCUCAAUUUUCUAGGGGA 
                 267 
                 A-128471.1 
                 UCCCCUAGAAAAUUGAGAGAAGU 
                 702 
                 263_285 
               
               
                   
               
               
                 AD-64331.1 
                 A-127905.16 
                 ACUCGUGGUGGACUUCUCUCA 
                 268 
                 A-127907.2 
                 UGAGAGAAGUCCACCACGAGUCU 
                 703 
                 250_272 
               
               
                   
               
               
                 AD-64332.1 
                 A-128001.3 
                 GUGCACUUCGCUUCACCUCUG 
                 269 
                 A-128485.1 
                 CAGAGGUGAAGCGAAGUGCACAC 
                 704 
                 1577_1599 
               
               
                   
               
               
                 AD-64333.1 
                 A-128367.2 
                 GUUUUUCUUGUUGACAAAAAU 
                 270 
                 A-128448.1 
                 AUUUUUGUCAACAAGAAAAACCC 
                 705 
                 206_228 
               
               
                   
               
               
                 AD-64334.1 
                 A-128383.2 
                 CUGCCUAAUCAUCUCUUGUUA 
                 271 
                 A-128456.1 
                 UAACAAGAGAUGAUUAGGCAGAG 
                 706 
                 1829_1851 
               
               
                   
               
               
                 AD-64335.1 
                 A-128399.2 
                 UCCUCACAAUACCACAGAGUA 
                 272 
                 A-128464.1 
                 UACUCUGUGGUAUUGUGAGGAUU 
                 707 
                 226_248 
               
               
                   
               
               
                 AD-64336.1 
                 A-128413.2 
                 CUUGUUGACAAAAAUCCUCAA 
                 273 
                 A-128472.1 
                 UUGAGGAUUUUUGUCAACAAGAA 
                 708 
                 212_234 
               
               
                   
               
               
                 AD-64337.1 
                 A-127955.16 
                 GUGGUGGACUUCUCUCAAUUU 
                 274 
                 A-127958.2 
                 AAAUUGAGAGAAGUCCACCACGA 
                 709 
                 254_276 
               
               
                   
               
               
                 AD-64338.1 
                 A-128439.2 
                 GCAACUUUUUCACCUCUGCCU 
                 275 
                 A-128486.1 
                 AGGCAGAGGUGAAAAAGUUGCAU 
                 710 
                 1814_1836 
               
               
                   
               
               
                 AD-64339.1 
                 A-128369.2 
                 GGGAACAAGAGCUACAGCAUA 
                 276 
                 A-128449.1 
                 UAUGCUGUAGCUCUUGUUCCCAA 
                 711 
                 2828_2850 
               
               
                   
               
               
                 AD-64341.1 
                 A-128401.2 
                 UCAUCUUCUUGUUGGUUCUUA 
                 277 
                 A-128465.1 
                 UAAGAACCAACAAGAAGAUGAGG 
                 712 
                 424_446 
               
               
                   
               
               
                 AD-64342.1 
                 A-128415.2 
                 CUGCUGCUAUGCCUCAUCUUA 
                 278 
                 A-128473.1 
                 UAAGAUGAGGCAUAGCAGCAGGA 
                 713 
                 411_433 
               
               
                   
               
               
                 AD-64343.1 
                 A-128427.2 
                 GUUGGAUGUGUCUGCGGCGUU 
                 279 
                 A-128479.1 
                 AACGCCGCAGACACAUCCAACGA 
                 714 
                 370_392 
               
               
                   
               
               
                 AD-64344.1 
                 A-128441.2 
                 UUCAUCCUGCUGCUAUGCCUA 
                 280 
                 A-128487.1 
                 UAGGCAUAGCAGCAGGAUGAAGA 
                 715 
                 405_427 
               
               
                   
               
               
                 AD-64345.1 
                 A-128371.2 
                 UUCUUGUUGACAAAAAUCCUA 
                 281 
                 A-128450.1 
                 UAGGAUUUUUGUCAACAAGAAAA 
                 716 
                 210_232 
               
               
                   
               
               
                 AD-64347.1 
                 A-123487.3 
                 GGAUGUGUCUGCGGCGUUUUA 
                 282 
                 A-128466.1 
                 UAAAACGCCGCAGACACAUCCAG 
                 717 
                 373_395 
               
               
                   
               
               
                 AD-64348.1 
                 A-128417.2 
                 UAUAUGGAUGAUGUGGUAUUA 
                 283 
                 A-128474.1 
                 UAAUACCACAUCAUCCAUAUAAC 
                 718 
                 734_756 
               
               
                   
               
               
                 AD-64349.1 
                 A-128429.2 
                 UUCAUCCUGCUGCUAUGCCUC 
                 284 
                 A-128480.1 
                 GAGGCAUAGCAGCAGGAUGAAGA 
                 719 
                 405_427 
               
               
                   
               
               
                 AD-64350.1 
                 A-128443.2 
                 GUGCACUUCGCUUCACCUCUA 
                 285 
                 A-128488.1 
                 UAGAGGUGAAGCGAAGUGCACAC 
                 720 
                 1577_1599 
               
               
                   
               
               
                 AD-64351.1 
                 A-128373.2 
                 UUGACAAAAAUCCUCACAAUA 
                 286 
                 A-128451.1 
                 UAUUGUGAGGAUUUUUGUCAACA 
                 721 
                 216_238 
               
               
                   
               
               
                 AD-64352.1 
                 A-128389.2 
                 CCAAGUGUUUGCUGACGCAAA 
                 287 
                 A-128459.1 
                 UUUGCGUCAGCAAACACUUGGCA 
                 722 
                 1174_1196 
               
               
                   
               
               
                 AD-64352.1 
                 A-128389.2 
                 CCAAGUGUUUGCUGACGCAAA 
                 288 
                 A-128459.1 
                 UUUGCGUCAGCAAACACUUGGCA 
                 723 
                 1174_1196 
               
               
                   
               
               
                 AD-64353.1 
                 A-128403.2 
                 AAGCCUCCAAGCUGUGCCUUA 
                 289 
                 A-128467.1 
                 UAAGGCACAGCUUGGAGGCUUGA 
                 724 
                 1864_1886 
               
               
                   
               
               
                 AD-64354.1 
                 A-128419.2 
                 CCUCUUCAUCCUGCUGCUAUA 
                 290 
                 A-128475.1 
                 UAUAGCAGCAGGAUGAAGAGGAA 
                 725 
                 401_423 
               
               
                   
               
               
                 AD-64355.1 
                 A-128431.2 
                 CCUGCUGCUAUGCCUCAUCUU 
                 291 
                 A-128481.1 
                 AAGAUGAGGCAUAGCAGCAGGAU 
                 726 
                 410_432 
               
               
                   
               
               
                 AD-64356.1 
                 A-128375.2 
                 CAUCUUCUUGUUGGUUCUUCU 
                 292 
                 A-128452.1 
                 AGAAGAACCAACAAGAAGAUGAG 
                 727 
                 425_447 
               
               
                   
               
               
                 AD-64357.1 
                 A-128391.2 
                 CCGUCUGUGCCUUCUCAUCUA 
                 293 
                 A-128460.1 
                 UAGAUGAGAAGGCACAGACGGGG 
                 728 
                 1547_1569 
               
               
                   
               
               
                 AD-64358.1 
                 A-128405.2 
                 CCUCAUCUUCUUGUUGGUUCU 
                 294 
                 A-128468.1 
                 AGAACCAACAAGAAGAUGAGGCA 
                 729 
                 422_444 
               
               
                   
               
               
                 AD-64359.1 
                 A-128421.2 
                 CCACCAAAUGCCCCUAUCUUA 
                 295 
                 A-128476.1 
                 UAAGAUAGGGGCAUUUGGUGGUC 
                 730 
                 2298_2320 
               
               
                   
               
               
                 AD-64360.1 
                 A-128433.2 
                 GCUCCUCUGCCGAUCCAUACU 
                 296 
                 A-128482.1 
                 AGUAUGGAUCGGCAGAGGAGCCA 
                 731 
                 1250_1272 
               
               
                   
               
               
                 AD-64700.1 
                 A-129379.1 
                 ACUCGUGGUGTACUUCUCUCA 
                 297 
                 A-127906.26 
                 UGAGAGAAGUCCACCACGAGUCU 
                 732 
                 250_272 
               
               
                   
               
               
                 AD-64701.1 
                 A-127905.20 
                 ACUCGUGGUGGACUUCUCUCA 
                 298 
                 A-129387.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 733 
                 250_272 
               
               
                   
               
               
                 AD-64702.1 
                 A-127905.28 
                 ACUCGUGGUGGACUUCUCUCA 
                 299 
                 A-129395.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 734 
                 250_272 
               
               
                   
               
               
                 AD-64703.1 
                 A-129376.2 
                 ACUCGUGGUGGACUUCACUCA 
                 300 
                 A-129385.5 
                 UGAGAGAAGTCCACCACGAGUCU 
                 735 
                 250_272 
               
               
                   
               
               
                 AD-64704.1 
                 A-129381.3 
                 ACUCGUGGTGTACUUCACUCA 
                 301 
                 A-129389.6 
                 UGAGAGAAGUCCACCACGAGUCU 
                 736 
                 250_272 
               
               
                   
               
               
                 AD-64705.1 
                 A-129380.1 
                 ACUCGUGGUGTACUUCACUCA 
                 302 
                 A-127906.27 
                 UGAGAGAAGUCCACCACGAGUCU 
                 737 
                 250_272 
               
               
                   
               
               
                 AD-64706.1 
                 A-127905.21 
                 ACUCGUGGUGGACUUCUCUCA 
                 303 
                 A-129388.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 738 
                 250_272 
               
               
                   
               
               
                 AD-64707.1 
                 A-127905.29 
                 ACUCGUGGUGGACUUCUCUCA 
                 304 
                 A-129396.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 739 
                 250_272 
               
               
                   
               
               
                 AD-64708.1 
                 A-129382.2 
                 ACUCGUGGTGGACUUCTCUCA 
                 305 
                 A-129385.6 
                 UGAGAGAAGTCCACCACGAGUCU 
                 740 
                 250_272 
               
               
                   
               
               
                 AD-64709.1 
                 A-129373.4 
                 ACUCGUGGUGGACUUCUCUCA 
                 306 
                 A-129391.2 
                 UGAGAGAAGTCCACCACGAGUCU 
                 741 
                 250_272 
               
               
                   
               
               
                 AD-64710.1 
                 A-129373.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 307 
                 A-127906.20 
                 UGAGAGAAGUCCACCACGAGUCU 
                 742 
                 250_272 
               
               
                   
               
               
                 AD-64711.1 
                 A-129381.1 
                 ACUCGUGGTGTACUUCACUCA 
                 308 
                 A-127906.28 
                 UGAGAGAAGUCCACCACGAGUCU 
                 743 
                 250_272 
               
               
                   
               
               
                 AD-64712.1 
                 A-127905.22 
                 ACUCGUGGUGGACUUCUCUCA 
                 309 
                 A-129389.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 744 
                 250_272 
               
               
                   
               
               
                 AD-64713.1 
                 A-127905.30 
                 ACUCGUGGUGGACUUCUCUCA 
                 310 
                 A-129397.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 745 
                 250_272 
               
               
                   
               
               
                 AD-64714.1 
                 A-129384.2 
                 ACUCGUGGTGGACUUCACUCA 
                 311 
                 A-129385.7 
                 UGAGAGAAGTCCACCACGAGUCU 
                 746 
                 250_272 
               
               
                   
               
               
                 AD-64715.1 
                 A-129376.4 
                 ACUCGUGGUGGACUUCACUCA 
                 312 
                 A-129391.3 
                 UGAGAGAAGTCCACCACGAGUCU 
                 747 
                 250_272 
               
               
                   
               
               
                 AD-64716.1 
                 A-129374.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 313 
                 A-127906.21 
                 UGAGAGAAGUCCACCACGAGUCU 
                 748 
                 250_272 
               
               
                   
               
               
                 AD-64717.1 
                 A-129382.1 
                 ACUCGUGGTGGACUUCTCUCA 
                 314 
                 A-127906.29 
                 UGAGAGAAGUCCACCACGAGUCU 
                 749 
                 250_272 
               
               
                   
               
               
                 AD-64718.1 
                 A-127905.23 
                 ACUCGUGGUGGACUUCUCUCA 
                 315 
                 A-129390.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 750 
                 250_272 
               
               
                   
               
               
                 AD-64719.1 
                 A-127917.5 
                 ACUCGUGGUGGACUUCTCUCA 
                 316 
                 A-129385.2 
                 UGAGAGAAGTCCACCACGAGUCU 
                 751 
                 250_272 
               
               
                   
               
               
                 AD-64720.1 
                 A-129381.2 
                 ACUCGUGGTGTACUUCACUCA 
                 317 
                 A-129385.8 
                 UGAGAGAAGTCCACCACGAGUCU 
                 752 
                 250_272 
               
               
                   
               
               
                 AD-64721.1 
                 A-129382.4 
                 ACUCGUGGTGGACUUCTCUCA 
                 318 
                 A-129391.4 
                 UGAGAGAAGTCCACCACGAGUCU 
                 753 
                 250_272 
               
               
                   
               
               
                 AD-64722.1 
                 A-129375.1 
                 ACUCGUGGUGGACUUCCUCA 
                 319 
                 A-127906.22 
                 UGAGAGAAGUCCACCACGAGUCU 
                 754 
                 250_272 
               
               
                   
               
               
                 AD-64723.1 
                 A-129383.1 
                 ACUCGUGGUGGACUUCTCUCA 
                 320 
                 A-127906.30 
                 UGAGAGAAGUCCACCACGAGUCU 
                 755 
                 250_272 
               
               
                   
               
               
                 AD-64725.1 
                 A-127917.6 
                 ACUCGUGGUGGACUUCTCUCA 
                 321 
                 A-129398.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 756 
                 250_272 
               
               
                   
               
               
                 AD-64726.1 
                 A-129373.3 
                 ACUCGUGGUGGACUUCUCUCA 
                 322 
                 A-129389.2 
                 UGAGAGAAGUCCACCACGAGUCU 
                 757 
                 250_272 
               
               
                   
               
               
                 AD-64727.1 
                 A-129384.4 
                 ACUCGUGGTGGACUUCACUCA 
                 323 
                 A-129391.5 
                 UGAGAGAAGTCCACCACGAGUCU 
                 758 
                 250_272 
               
               
                   
               
               
                 AD-64728.1 
                 A-129376.1 
                 ACUCGUGGUGGACUUCACUCA 
                 324 
                 A-127906.23 
                 UGAGAGAAGUCCACCACGAGUCU 
                 759 
                 250_272 
               
               
                   
               
               
                 AD-64729.1 
                 A-129384.1 
                 ACUCGUGGTGGACUUCACUCA 
                 325 
                 A-127906.31 
                 UGAGAGAAGUCCACCACGAGUCU 
                 760 
                 250_272 
               
               
                   
               
               
                 AD-64730.1 
                 A-127905.25 
                 ACUCGUGGUGGACUUCUCUCA 
                 326 
                 A-129392.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 761 
                 250_272 
               
               
                   
               
               
                 AD-64731.1 
                 A-129399.1 
                 ACUCGUGGUGGACUUCTCUCA 
                 327 
                 A-129385.3 
                 UGAGAGAAGTCCACCACGAGUCU 
                 762 
                 250_272 
               
               
                   
               
               
                 AD-64732.1 
                 A-129376.3 
                 ACUCGUGGUGGACUUCACUCA 
                 328 
                 A-129389.3 
                 UGAGAGAAGUCCACCACGAGUCU 
                 763 
                 250_272 
               
               
                   
               
               
                 AD-64733.1 
                 A-129381.4 
                 ACUCGUGGTGTACUUCACUCA 
                 329 
                 A-129391.6 
                 UGAGAGAAGTCCACCACGAGUCU 
                 764 
                 250_272 
               
               
                   
               
               
                 AD-64734.1 
                 A-129377.1 
                 ACUCGUGGUGGACUUCCCUCA 
                 330 
                 A-127906.24 
                 UGAGAGAAGUCCACCACGAGUCU 
                 765 
                 250_272 
               
               
                   
               
               
                 AD-64735.1 
                 A-127905.18 
                 ACUCGUGGUGGACUUCUCUCA 
                 331 
                 A-129385.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 766 
                 250_272 
               
               
                   
               
               
                 AD-64736.1 
                 A-127905.26 
                 ACUCGUGGUGGACUUCUCUCA 
                 332 
                 A-129393.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 767 
                 250_272 
               
               
                   
               
               
                 AD-64737.1 
                 A-129399.2 
                 ACUCGUGGUGGACUUCTCUCA 
                 333 
                 A-129398.2 
                 UGAGAGAAGTCCACCACGAGUCU 
                 768 
                 250_272 
               
               
                   
               
               
                 AD-64738.1 
                 A-129382.3 
                 ACUCGUGGTGGACUUCTCUCA 
                 334 
                 A-129389.4 
                 UGAGAGAAGUCCACCACGAGUCU 
                 769 
                 250_272 
               
               
                   
               
               
                 AD-64739.1 
                 A-129378.1 
                 ACUCGUGGUGGACUUCGCUCA 
                 335 
                 A-127906.25 
                 UGAGAGAAGUCCACCACGAGUCU 
                 770 
                 250_272 
               
               
                   
               
               
                 AD-64740.1 
                 A-127905.19 
                 ACUCGUGGUGGACUUCUCUCA 
                 336 
                 A-129386.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 771 
                 250_272 
               
               
                   
               
               
                 AD-64741.1 
                 A-127905.27 
                 ACUCGUGGUGGACUUCUCUCA 
                 337 
                 A-129394.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 772 
                 250_272 
               
               
                   
               
               
                 AD-64742.1 
                 A-129373.2 
                 ACUCGUGGUGGACUUCUCUCA 
                 338 
                 A-129385.4 
                 UGAGAGAAGTCCACCACGAGUCU 
                 773 
                 250_272 
               
               
                   
               
               
                 AD-64743.1 
                 A-129384.3 
                 ACUCGUGGTGGACUUCACUCA 
                 339 
                 A-129389.5 
                 UGAGAGAAGUCCACCACGAGUCU 
                 774 
                 250_272 
               
               
                   
               
               
                 AD-61522.2 
                 A-123463.2 
                 AGUUAUAUGGAUGAUGUGGUA 
                 340 
                 A-123464.2 
                 UACCACAUCAUCCAUAUAACUGA 
                 775 
                 731_753 
               
               
                   
               
               
                 AD-61547.2 
                 A-123487.2 
                 GGAUGUGUCUGCGGCGUUUUA 
                 341 
                 A-123488.2 
                 UAAAACGCCGCAGACACAUCCAG 
                 776 
                 373_395 
               
               
                   
               
               
                 AD-63938.2 
                 A-127896.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 342 
                 A-127897.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 777 
                 250_272 
               
               
                   
               
               
                 AD-63939.2 
                 A-127909.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 343 
                 A-127906.3 
                 UGAGAGAAGUCCACCACGAGUCU 
                 778 
                 250_272 
               
               
                   
               
               
                 AD-63940.2 
                 A-127917.1 
                 ACUCGUGGUGGACUUCTCUCA 
                 344 
                 A-127906.11 
                 UGAGAGAAGUCCACCACGAGUCU 
                 779 
                 250_272 
               
               
                   
               
               
                 AD-63941.2 
                 A-127905.8 
                 ACUCGUGGUGGACUUCUCUCA 
                 345 
                 A-127925.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 780 
                 250_272 
               
               
                   
               
               
                 AD-63942.2 
                 A-127933.1 
                 UCGUGGUGGACUUCUCUCA 
                 346 
                 A-127934.1 
                 UGAGAGAAGUCCACCACGAGU 
                 781 
                 252_274 
               
               
                   
               
               
                 AD-63943.2 
                 A-127944.2 
                 ACUCGUGGUGGACUUCUCUCA 
                 347 
                 A-127942.2 
                 UGAGAGAAGUCCACCACGAGUCU 
                 782 
                 250_272 
               
               
                   
               
               
                 AD-63945.2 
                 A-127910.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 348 
                 A-127906.4 
                 UGAGAGAAGUCCACCACGAGUCU 
                 783 
                 250_272 
               
               
                   
               
               
                 AD-63946.2 
                 A-127918.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 349 
                 A-127906.12 
                 UGAGAGAAGUCCACCACGAGUCU 
                 784 
                 250_272 
               
               
                   
               
               
                 AD-63947.2 
                 A-127905.9 
                 ACUCGUGGUGGACUUCUCUCA 
                 350 
                 A-127926.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 785 
                 250_272 
               
               
                   
               
               
                 AD-63948.2 
                 A-127935.1 
                 GUGGUGGACUUCUCUCA 
                 351 
                 A-127936.1 
                 UGAGAGAAGUCCACCACGA 
                 786 
                 254_276 
               
               
                   
               
               
                 AD-63949.2 
                 A-127944.3 
                 ACUCGUGGUGGACUUCUCUCA 
                 352 
                 A-127906.14 
                 UGAGAGAAGUCCACCACGAGUCU 
                 787 
                 250_272 
               
               
                   
               
               
                 AD-63950.2 
                 A-127900.1 
                 UCGUGGUGGACUUCUCUCAUU 
                 353 
                 A-127901.1 
                 UGAGAGAAGUCCACCACGAUU 
                 788 
                 252_274 
               
               
                   
               
               
                 AD-63951.2 
                 A-127911.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 354 
                 A-127906.5 
                 UGAGAGAAGUCCACCACGAGUCU 
                 789 
                 250_272 
               
               
                   
               
               
                 AD-63952.2 
                 A-127905.2 
                 ACUCGUGGUGGACUUCUCUCA 
                 355 
                 A-127919.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 790 
                 250_272 
               
               
                   
               
               
                 AD-63953.2 
                 A-127905.10 
                 ACUCGUGGUGGACUUCUCUCA 
                 356 
                 A-127927.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 791 
                 250_272 
               
               
                   
               
               
                 AD-63955.2 
                 A-127945.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 357 
                 A-127940.3 
                 UGAGAGAAGUCCACCACGAGUCU 
                 792 
                 250_272 
               
               
                   
               
               
                 AD-63956.2 
                 A-127902.1 
                 UCGUGGUGGACUUCUCUCA 
                 358 
                 A-127903.1 
                 UGAGAGAAGUCCACCACGAUU 
                 793 
                 252_274 
               
               
                   
               
               
                 AD-63957.2 
                 A-127912.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 359 
                 A-127906.6 
                 UGAGAGAAGUCCACCACGAGUCU 
                 794 
                 250_272 
               
               
                   
               
               
                 AD-63958.2 
                 A-127905.3 
                 ACUCGUGGUGGACUUCUCUCA 
                 360 
                 A-127920.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 795 
                 250_272 
               
               
                   
               
               
                 AD-63959.2 
                 A-127905.11 
                 ACUCGUGGUGGACUUCUCUCA 
                 361 
                 A-127928.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 796 
                 250_272 
               
               
                   
               
               
                 AD-63960.2 
                 A-126619.2 
                 UAUUUCCUAGGGUACAA 
                 362 
                 A-127938.1 
                 UGAGAGAAGUCCACCACGA 
                 797 
                 254_276 
               
               
                   
               
               
                 AD-63961.2 
                 A-127945.2 
                 ACUCGUGGUGGACUUCUCUCA 
                 363 
                 A-127942.3 
                 UGAGAGAAGUCCACCACGAGUCU 
                 798 
                 250_272 
               
               
                   
               
               
                 AD-63962.2 
                 A-127902.2 
                 UCGUGGUGGACUUCUCUCA 
                 364 
                 A-127904.1 
                 UGAGAGAAGUCCACCACGAUU 
                 799 
                 252_274 
               
               
                   
               
               
                 AD-63963.2 
                 A-127913.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 365 
                 A-127906.7 
                 UGAGAGAAGUCCACCACGAGUCU 
                 800 
                 250_272 
               
               
                   
               
               
                 AD-63964.2 
                 A-127905.4 
                 ACUCGUGGUGGACUUCUCUCA 
                 366 
                 A-127921.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 801 
                 250_272 
               
               
                   
               
               
                 AD-63965.2 
                 A-127905.12 
                 ACUCGUGGUGGACUUCUCUCA 
                 367 
                 A-127929.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 802 
                 250_272 
               
               
                   
               
               
                 AD-63966.2 
                 A-127939.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 368 
                 A-127940.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 803 
                 250_272 
               
               
                   
               
               
                 AD-63967.2 
                 A-127945.3 
                 ACUCGUGGUGGACUUCUCUCA 
                 369 
                 A-127906.15 
                 UGAGAGAAGUCCACCACGAGUCU 
                 804 
                 250_272 
               
               
                   
               
               
                 AD-63968.2 
                 A-127905.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 370 
                 A-127906.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 805 
                 250_272 
               
               
                   
               
               
                 AD-63968.4 
                 A-127905.15 
                 ACUCGUGGUGGACUUCUCUCA 
                 371 
                 A-127906.17 
                 UGAGAGAAGUCCACCACGAGUCU 
                 806 
                 250_272 
               
               
                   
               
               
                 AD-63968.5 
                 A-127905.17 
                 ACUCGUGGUGGACUUCUCUCA 
                 372 
                 A-127906.18 
                 UGAGAGAAGUCCACCACGAGUCU 
                 807 
                 250_272 
               
               
                   
               
               
                 AD-63969.2 
                 A-127914.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 373 
                 A-127906.8 
                 UGAGAGAAGUCCACCACGAGUCU 
                 808 
                 250_272 
               
               
                   
               
               
                 AD-63970.2 
                 A-127905.5 
                 ACUCGUGGUGGACUUCUCUCA 
                 374 
                 A-127922.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 809 
                 250_272 
               
               
                   
               
               
                 AD-63971.2 
                 A-127905.13 
                 ACUCGUGGUGGACUUCUCUCA 
                 375 
                 A-127930.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 810 
                 250_272 
               
               
                   
               
               
                 AD-63972.2 
                 A-127941.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 376 
                 A-127942.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 811 
                 250_272 
               
               
                   
               
               
                 AD-63973.2 
                 A-127946.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 377 
                 A-127947.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 812 
                 250_272 
               
               
                   
               
               
                 AD-63975.2 
                 A-127915.1 
                 ACUCGUGGUGGACUUCTCUCA 
                 378 
                 A-127906.9 
                 UGAGAGAAGUCCACCACGAGUCU 
                 813 
                 250_272 
               
               
                   
               
               
                 AD-63976.2 
                 A-127905.6 
                 ACUCGUGGUGGACUUCUCUCA 
                 379 
                 A-127923.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 814 
                 250_272 
               
               
                   
               
               
                 AD-63977.2 
                 A-127917.2 
                 ACUCGUGGUGGACUUCTCUCA 
                 380 
                 A-127931.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 815 
                 250_272 
               
               
                   
               
               
                 AD-63978.2 
                 A-127943.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 381 
                 A-127906.13 
                 UGAGAGAAGUCCACCACGAGUCU 
                 816 
                 250_272 
               
               
                   
               
               
                 AD-63979.2 
                 A-127908.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 382 
                 A-127906.2 
                 UGAGAGAAGUCCACCACGAGUCU 
                 817 
                 250_272 
               
               
                   
               
               
                 AD-63980.2 
                 A-127916.1 
                 ACUCGUGGUGGACUUCTCUCA 
                 383 
                 A-127906.10 
                 UGAGAGAAGUCCACCACGAGUCU 
                 818 
                 250_272 
               
               
                   
               
               
                 AD-63981.2 
                 A-127905.7 
                 ACUCGUGGUGGACUUCUCUCA 
                 384 
                 A-127924.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 819 
                 250_272 
               
               
                   
               
               
                 AD-63982.2 
                 A-127917.3 
                 ACUCGUGGUGGACUUCTCUCA 
                 385 
                 A-127932.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 820 
                 250_272 
               
               
                   
               
               
                 AD-63983.2 
                 A-127944.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 386 
                 A-127940.2 
                 UGAGAGAAGUCCACCACGAGUCU 
                 821 
                 250_272 
               
               
                   
               
               
                 AD-63985.2 
                 A-127961.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 387 
                 A-127956.4 
                 AAAUUGAGAGAAGUCCACCACGA 
                 822 
                 254_276 
               
               
                   
               
               
                 AD-63986.2 
                 A-127969.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 388 
                 A-127956.12 
                 AAAUUGAGAGAAGUCCACCACGA 
                 823 
                 254_276 
               
               
                   
               
               
                 AD-63987.2 
                 A-127955.9 
                 GUGGUGGACUUCUCUCAAUUU 
                 389 
                 A-127977.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 824 
                 254_276 
               
               
                   
               
               
                 AD-63988.2 
                 A-127986.1 
                 UGGACUUCUCUCAAUUU 
                 390 
                 A-127987.1 
                 AAAUUGAGAGAAGUCCACC 
                 825 
                 258_280 
               
               
                   
               
               
                 AD-63989.2 
                 A-127996.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 391 
                 A-127992.2 
                 AAAUUGAGAGAAGUCCACCACGA 
                 826 
                 254_276 
               
               
                   
               
               
                 AD-63990.2 
                 A-127950.1 
                 GGUGGACUUCUCUCAAUUUUU 
                 392 
                 A-127951.1 
                 AAAUUGAGAGAAGUCCACCUU 
                 827 
                 256_278 
               
               
                   
               
               
                 AD-63991.2 
                 A-127962.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 393 
                 A-127956.5 
                 AAAUUGAGAGAAGUCCACCACGA 
                 828 
                 254_276 
               
               
                   
               
               
                 AD-63992.2 
                 A-127955.2 
                 GUGGUGGACUUCUCUCAAUUU 
                 394 
                 A-127970.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 829 
                 254_276 
               
               
                   
               
               
                 AD-63993.2 
                 A-127955.10 
                 GUGGUGGACUUCUCUCAAUUU 
                 395 
                 A-127978.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 830 
                 254_276 
               
               
                   
               
               
                 AD-63994.2 
                 A-127984.2 
                 GGUGGACUUCUCUCAAUUU 
                 396 
                 A-127988.1 
                 AAAUUGAGAGAAGUCCACCAC 
                 831 
                 256_278 
               
               
                   
               
               
                 AD-63995.2 
                 A-127996.2 
                 GUGGUGGACUUCUCUCAAUUU 
                 397 
                 A-127993.2 
                 AAAUUGAGAGAAGUCCACCACGA 
                 832 
                 254_276 
               
               
                   
               
               
                 AD-63996.2 
                 A-127952.1 
                 GGUGGACUUCUCUCAAUUU 
                 398 
                 A-127953.1 
                 AAAUUGAGAGAAGUCCACCUU 
                 833 
                 256_278 
               
               
                   
               
               
                 AD-63997.2 
                 A-127963.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 399 
                 A-127956.6 
                 AAAUUGAGAGAAGUCCACCACGA 
                 834 
                 254_276 
               
               
                   
               
               
                 AD-63999.2 
                 A-127955.11 
                 GUGGUGGACUUCUCUCAAUUU 
                 400 
                 A-127979.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 835 
                 254_276 
               
               
                   
               
               
                 AD-64000.2 
                 A-127986.2 
                 UGGACUUCUCUCAAUUU 
                 401 
                 A-127989.1 
                 AAAUUGAGAGAAGUCCACC 
                 836 
                 258_280 
               
               
                   
               
               
                 AD-64001.2 
                 A-127996.3 
                 GUGGUGGACUUCUCUCAAUUU 
                 402 
                 A-127994.2 
                 AAAUUGAGAGAAGUCCACCACGA 
                 837 
                 254_276 
               
               
                   
               
               
                 AD-64002.2 
                 A-127952.2 
                 GGUGGACUUCUCUCAAUUU 
                 403 
                 A-127954.1 
                 AAAUUGAGAGAAGUCCACCUU 
                 838 
                 256_278 
               
               
                   
               
               
                 AD-64003.2 
                 A-127964.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 404 
                 A-127956.7 
                 AAAUUGAGAGAAGUCCACCACGA 
                 839 
                 254_276 
               
               
                   
               
               
                 AD-64004.2 
                 A-127955.4 
                 GUGGUGGACUUCUCUCAAUUU 
                 405 
                 A-127972.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 840 
                 254_276 
               
               
                   
               
               
                 AD-64005.2 
                 A-127955.12 
                 GUGGUGGACUUCUCUCAAUUU 
                 406 
                 A-127980.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 841 
                 254_276 
               
               
                   
               
               
                 AD-64006.2 
                 A-127990.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 407 
                 A-127991.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 842 
                 254_276 
               
               
                   
               
               
                 AD-64007.2 
                 A-127996.4 
                 GUGGUGGACUUCUCUCAAUUU 
                 408 
                 A-127995.2 
                 AAAUUGAGAGAAGUCCACCACGA 
                 843 
                 254_276 
               
               
                   
               
               
                 AD-64008.2 
                 A-127955.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 409 
                 A-127956.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 844 
                 254_276 
               
               
                   
               
               
                 AD-64008.4 
                 A-127955.15 
                 GUGGUGGACUUCUCUCAAUUU 
                 410 
                 A-127956.14 
                 AAAUUGAGAGAAGUCCACCACGA 
                 845 
                 254_276 
               
               
                   
               
               
                 AD-64009.2 
                 A-127965.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 411 
                 A-127956.8 
                 AAAUUGAGAGAAGUCCACCACGA 
                 846 
                 254_276 
               
               
                   
               
               
                 AD-64010.2 
                 A-127955.5 
                 GUGGUGGACUUCUCUCAAUUU 
                 412 
                 A-127973.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 847 
                 254_276 
               
               
                   
               
               
                 AD-64011.2 
                 A-127955.13 
                 GUGGUGGACUUCUCUCAAUUU 
                 413 
                 A-127981.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 848 
                 254_276 
               
               
                   
               
               
                 AD-64012.2 
                 A-127990.2 
                 GUGGUGGACUUCUCUCAAUUU 
                 414 
                 A-127992.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 849 
                 254_276 
               
               
                   
               
               
                 AD-64013.2 
                 A-127997.1 
                 GUGGUGGACTTCUCUCAAUUU 
                 415 
                 A-127998.1 
                 AAAUUGAGAGAAGTCCACCACGA 
                 850 
                 254_276 
               
               
                   
               
               
                 AD-64014.2 
                 A-127957.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 416 
                 A-127958.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 851 
                 254_276 
               
               
                   
               
               
                 AD-64015.2 
                 A-127966.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 417 
                 A-127956.9 
                 AAAUUGAGAGAAGUCCACCACGA 
                 852 
                 254_276 
               
               
                   
               
               
                 AD-64016.2 
                 A-127955.6 
                 GUGGUGGACUUCUCUCAAUUU 
                 418 
                 A-127974.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 853 
                 254_276 
               
               
                   
               
               
                 AD-64017.2 
                 A-127968.2 
                 GUGGUGGACUTCUCUCAAUUU 
                 419 
                 A-127982.1 
                 AAAUUGAGAGAAGTCCACCACGA 
                 854 
                 254_276 
               
               
                   
               
               
                 AD-64018.2 
                 A-127990.3 
                 GUGGUGGACUUCUCUCAAUUU 
                 420 
                 A-127993.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 855 
                 254_276 
               
               
                   
               
               
                 AD-64019.2 
                 A-127959.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 421 
                 A-127956.2 
                 AAAUUGAGAGAAGUCCACCACGA 
                 856 
                 254_276 
               
               
                   
               
               
                 AD-64020.2 
                 A-127967.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 422 
                 A-127956.10 
                 AAAUUGAGAGAAGUCCACCACGA 
                 857 
                 254_276 
               
               
                   
               
               
                 AD-64021.2 
                 A-127955.7 
                 GUGGUGGACUUCUCUCAAUUU 
                 423 
                 A-127975.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 858 
                 254_276 
               
               
                   
               
               
                 AD-64022.2 
                 A-127968.3 
                 GUGGUGGACUTCUCUCAAUUU 
                 424 
                 A-127983.1 
                 AAAUUGAGAGAAGTCCACCACGA 
                 859 
                 254_276 
               
               
                   
               
               
                 AD-64023.2 
                 A-127990.4 
                 GUGGUGGACUUCUCUCAAUUU 
                 425 
                 A-127994.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 860 
                 254_276 
               
               
                   
               
               
                 AD-64024.2 
                 A-127960.1 
                 GUGGUGGACUUCUCUCAAUUU 
                 426 
                 A-127956.3 
                 AAAUUGAGAGAAGUCCACCACGA 
                 861 
                 254_276 
               
               
                   
               
               
                 AD-64025.2 
                 A-127968.1 
                 GUGGUGGACUTCUCUCAAUUU 
                 427 
                 A-127956.11 
                 AAAUUGAGAGAAGUCCACCACGA 
                 862 
                 254_276 
               
               
                   
               
               
                 AD-64026.2 
                 A-127955.8 
                 GUGGUGGACUUCUCUCAAUUU 
                 428 
                 A-127976.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 863 
                 254_276 
               
               
                   
               
               
                 AD-64027.2 
                 A-127984.1 
                 GGUGGACUUCUCUCAAUUU 
                 429 
                 A-127985.1 
                 AAAUUGAGAGAAGUCCACCAC 
                 864 
                 256_278 
               
               
                   
               
               
                 AD-64028.2 
                 A-127990.5 
                 GUGGUGGACUUCUCUCAAUUU 
                 430 
                 A-127995.1 
                 AAAUUGAGAGAAGUCCACCACGA 
                 865 
                 254_276 
               
               
                   
               
               
                 AD-64272.2 
                 A-128001.2 
                 GUGCACUUCGCUUCACCUCUG 
                 431 
                 A-128002.2 
                 CAGAGGUGAAGCGAAGUGCACAC 
                 866 
                 1577_1599 
               
               
                   
               
               
                 AD-64274.1 
                 A-128363.1 
                 GUUGACAAAAAUCCUCACAAU 
                 432 
                 A-128364.1 
                 AUUGUGAGGAUUUUUGUCAACAA 
                 867 
                 215_237 
               
               
                   
               
               
                 AD-64275.1 
                 A-128377.1 
                 UGUUGACAAAAAUCCUCACAA 
                 433 
                 A-128378.1 
                 UUGUGAGGAUUUUUGUCAACAAG 
                 868 
                 214_236 
               
               
                   
               
               
                 AD-64276.1 
                 A-128393.1 
                 GGUGGACUUCUCUCAAUUUUA 
                 434 
                 A-128394.1 
                 UAAAAUUGAGAGAAGUCCACCAC 
                 869 
                 256_278 
               
               
                   
               
               
                 AD-64277.1 
                 A-128407.1 
                 UCUUUUGGAGUGUGGAUUCGA 
                 435 
                 A-128408.1 
                 UCGAAUCCACACUCCAAAAGACA 
                 870 
                 2259_2281 
               
               
                   
               
               
                 AD-64277.1 
                 A-128407.1 
                 UCUUUUGGAGUGUGGAUUCGA 
                 436 
                 A-128408.1 
                 UCGAAUCCACACUCCAAAAGACA 
                 871 
                 2259_2281 
               
               
                   
               
               
                 AD-64278.1 
                 A-128423.1 
                 ACUGUUCAAGCCUCCAAGCUA 
                 437 
                 A-128424.1 
                 UAGCUUGGAGGCUUGAACAAGAC 
                 872 
                 1857_1879 
               
               
                   
               
               
                 AD-64279.1 
                 A-128435.1 
                 UCUGCCGAUCCAUACUGCGGA 
                 438 
                 A-128436.1 
                 UCCGCAGUAUGGAUCGGCAGAGG 
                 873 
                 1255_1277 
               
               
                   
               
               
                 AD-64280.1 
                 A-128379.1 
                 AUGUGUCUGCGGCGUUUUAUA 
                 439 
                 A-128380.1 
                 UAUAAAACGCCGCAGACACAUCC 
                 874 
                 375_397 
               
               
                   
               
               
                 AD-64281.1 
                 A-128395.1 
                 CCCCGUCUGUGCCUUCUCAUA 
                 440 
                 A-128396.1 
                 UAUGAGAAGGCACAGACGGGGAG 
                 875 
                 1545_1567 
               
               
                   
               
               
                 AD-64282.1 
                 A-128409.1 
                 GCCUAAUCAUCUCUUGUUCAU 
                 441 
                 A-128410.1 
                 AUGAACAAGAGAUGAUUAGCGAG 
                 876 
                 1831_1853 
               
               
                   
               
               
                 AD-64283.1 
                 A-128425.1 
                 UCUAGACUCGUGGUGGACUUC 
                 442 
                 A-128426.1 
                 GAAGUCCACCACGAGUCUAGACU 
                 877 
                 245_267 
               
               
                   
               
               
                 AD-64284.1 
                 A-128437.1 
                 CUGCCGAUCCAUACUGCGGAA 
                 443 
                 A-128438.1 
                 UUCCGCAGUAUGGAUCGGCAGAG 
                 878 
                 1256_1278 
               
               
                   
               
               
                 AD-64285.1 
                 A-128365.1 
                 UUUUUCUUGUUGACAAAAAUA 
                 444 
                 A-128366.1 
                 UAUUUUUGUCAACAAGAAAAACC 
                 879 
                 207_229 
               
               
                   
               
               
                 AD-64286.1 
                 A-128381.1 
                 AUCUUCUUGUUGGUUCUUCUA 
                 445 
                 A-128382.1 
                 UAGAAGAACCAACAAGAAGAUGA 
                 880 
                 426_448 
               
               
                   
               
               
                 AD-64289.1 
                 A-128367.1 
                 GUUUUUCUUGUUGACAAAAAU 
                 446 
                 A-128368.1 
                 AUUUUUGUCAACAAGAAAAACCC 
                 881 
                 206_228 
               
               
                   
               
               
                 AD-64290.1 
                 A-128383.1 
                 CUGCCUAAUCAUCUCUUGUUA 
                 447 
                 A-128384.1 
                 UAACAAGAGAUGAUUAGGCAGAG 
                 882 
                 1829_1851 
               
               
                   
               
               
                 AD-64291.1 
                 A-128399.1 
                 UCCUCACAAUACCACAGAGUA 
                 448 
                 A-128400.1 
                 UACUCUGUGGUAUUGUGAGGAUU 
                 883 
                 226_248 
               
               
                   
               
               
                 AD-64292.1 
                 A-128413.1 
                 CUUGUUGACAAAAAUCCUCAA 
                 449 
                 A-128414.1 
                 UUGAGGAUUUUUGUCAACAAGAA 
                 884 
                 212_234 
               
               
                   
               
               
                 AD-64293.1 
                 A-128439.1 
                 GCAACUUUUUCACCUCUGCCU 
                 450 
                 A-128440.1 
                 AGGCAGAGGUGAAAAAGUUGCAU 
                 885 
                 1814_1836 
               
               
                   
               
               
                 AD-64294.1 
                 A-128369.1 
                 GGGAACAAGAGCUACAGCAUA 
                 451 
                 A-128370.1 
                 UAUGCUGUAGCUCUUGUUCCCAA 
                 886 
                 2828_2850 
               
               
                   
               
               
                 AD-64295.1 
                 A-128385.1 
                 CGUGGUGGACUUCUCUCAAUU 
                 452 
                 A-128386.1 
                 AAUUGAGAGAAGUCCACCAGCAG 
                 887 
                 253_275 
               
               
                   
               
               
                 AD-64297.1 
                 A-128415.1 
                 CUGCUGCUAUGCCUCAUCUUA 
                 453 
                 A-128416.1 
                 UAAGAUGAGGCAUAGCAGCAGGA 
                 888 
                 411_433 
               
               
                   
               
               
                 AD-64298.1 
                 A-128427.1 
                 GUUGGAUGUGUCUGCGGCGUU 
                 454 
                 A-128428.1 
                 AACGCCGCAGACACAUCCAACGA 
                 889 
                 370_392 
               
               
                   
               
               
                 AD-64299.1 
                 A-128441.1 
                 UUCAUCCUGCUGCUAUGCCUA 
                 455 
                 A-128442.1 
                 UAGGCAUAGCAGCAGGAUGAAGA 
                 890 
                 405_427 
               
               
                   
               
               
                 AD-64300.1 
                 A-128371.1 
                 UUCUUGUUGACAAAAAUCCUA 
                 456 
                 A-128372.1 
                 UAGGAUUUUUGUCAACAAGAAAA 
                 891 
                 210_232 
               
               
                   
               
               
                 AD-64302.1 
                 A-128417.1 
                 UAUAUGGAUGAUGUGGUAUUA 
                 457 
                 A-128418.1 
                 UAAUACCACAUCAUCCAUAUAAC 
                 892 
                 734_756 
               
               
                   
               
               
                 AD-64303.1 
                 A-128429.1 
                 UUCAUCCUGCUGCUAUGCCUC 
                 458 
                 A-128430.1 
                 GAGGCAUAGCAGCAGGAUGAAGA 
                 893 
                 405_427 
               
               
                   
               
               
                 AD-64304.1 
                 A-128443.1 
                 GUGCACUUCGCUUCACCUCUA 
                 459 
                 A-128444.1 
                 UAGAGGUGAAGCGAAGUGCACAC 
                 894 
                 1577_1599 
               
               
                   
               
               
                 AD-64305.1 
                 A-128373.1 
                 UUGACAAAAAUCCUCACAAUA 
                 460 
                 A-128374.1 
                 UAUUGUGAGGAUUUUUGUCAACA 
                 895 
                 216_238 
               
               
                   
               
               
                 AD-64307.1 
                 A-128403.1 
                 AAGCCUCCAAGCUGUGCCUUA 
                 461 
                 A-128404.1 
                 UAAGGCACAGCUUGGAGGCUUGA 
                 896 
                 1864_1886 
               
               
                   
               
               
                 AD-64308.1 
                 A-128419.1 
                 CCUCUUCAUCCUGCUGCUAUA 
                 462 
                 A-128420.1 
                 UAUAGCAGCAGGAUGAAGAGGAA 
                 897 
                 401_423 
               
               
                   
               
               
                 AD-64309.1 
                 A-128431.1 
                 CCUGCUGCUAUGCCUCAUCUU 
                 463 
                 A-128432.1 
                 AAGAUGAGGCAUAGCAGCAGGAU 
                 898 
                 410_432 
               
               
                   
               
               
                 AD-64310.1 
                 A-128375.1 
                 CAUCUUCUUGUUGGUUCUUCU 
                 464 
                 A-128376.1 
                 AGAAGAACCAACAAGAAGAUGAG 
                 899 
                 425_447 
               
               
                   
               
               
                 AD-64311.1 
                 A-128391.1 
                 CCGUCUGUGCCUUCUCAUCUA 
                 465 
                 A-128392.1 
                 UAGAUGAGAAGGCACAGACGGGG 
                 900 
                 1547_1569 
               
               
                   
               
               
                 AD-64312.1 
                 A-128405.1 
                 CCUCAUCUUCUUGUUGGUUCU 
                 466 
                 A-128406.1 
                 AGAACCAACAAGAAGAUGAGGCA 
                 901 
                 422_444 
               
               
                   
               
               
                 AD-64313.1 
                 A-128421.1 
                 CCACCAAAUGCCCCUAUCUUA 
                 467 
                 A-128422.1 
                 UAAGAUAGGGGCAUUUGGUGGUC 
                 902 
                 2298_2320 
               
               
                   
               
               
                 AD-64314.1 
                 A-128433.1 
                 GCUCCUCUGCCGAUCCAUACU 
                 468 
                 A-128434.1 
                 AGUAUGGAUCGGCAGAGGAGCCA 
                 903 
                 1250_1272 
               
               
                   
               
               
                 AD-64315.1 
                 A-128363.2 
                 GUUGACAAAAAUCCUCACAAU 
                 469 
                 A-128445.1 
                 AUUGUGAGGAUUUUUGUCAACAA 
                 904 
                 215_237 
               
               
                   
               
               
                 AD-64316.1 
                 A-128377.2 
                 UGUUGACAAAAAUCCUCACAA 
                 470 
                 A-128453.1 
                 UUGUGAGGAUUUUUGUCAACAAG 
                 905 
                 214_236 
               
               
                   
               
               
                 AD-64317.1 
                 A-128393.2 
                 GGUGGACUUCUCUCAAUUUUA 
                 471 
                 A-128461.1 
                 UAAAAUUGAGAGAAGUCCACCAC 
                 906 
                 256_278 
               
               
                   
               
               
                 AD-64318.1 
                 A-128407.2 
                 UCUUUUGGAGUGUGGAUUCGA 
                 472 
                 A-128469.1 
                 UCGAAUCCACACUCCAAAAGACA 
                 907 
                 2259_2281 
               
               
                   
               
               
                 AD-64318.1 
                 A-128407.2 
                 UCUUUUGGAGUGUGGAUUCGA 
                 473 
                 A-128469.1 
                 UCGAAUCCACACUCCAAAAGACA 
                 908 
                 2259_2281 
               
               
                   
               
               
                 AD-64319.1 
                 A-128423.2 
                 ACUGUUCAAGCCUCCAAGCUA 
                 474 
                 A-128477.1 
                 UAGCUUGGAGGCUUGAACAAGAC 
                 909 
                 1857_1879 
               
               
                   
               
               
                 AD-64320.1 
                 A-128435.2 
                 UCUGCCGAUCCAUACUGCGGA 
                 475 
                 A-128483.1 
                 UCCGCAGUAUGGAUCGGCAGAGG 
                 910 
                 1255_1277 
               
               
                   
               
               
                 AD-64321.1 
                 A-123463.3 
                 AGUUAUAUGGAUGAUGUGGUA 
                 476 
                 A-128446.1 
                 UACCACAUCAUCCAUAUAACUGA 
                 911 
                 731_753 
               
               
                   
               
               
                 AD-64322.1 
                 A-128379.2 
                 AUGUGUCUGCGGCGUUUUAUA 
                 477 
                 A-128454.1 
                 UAUAAAACGCCGCAGACACAUCC 
                 912 
                 375_397 
               
               
                   
               
               
                 AD-64323.1 
                 A-128395.2 
                 CCCCGUCUGUGCCUUCUCAUA 
                 478 
                 A-128462.1 
                 UAUGAGAAGGCACAGACGGGGAG 
                 913 
                 1545_1567 
               
               
                   
               
               
                 AD-64324.1 
                 A-128409.2 
                 GCCUAAUCAUCUCUUGUUCAU 
                 479 
                 A-128470.1 
                 AUGAACAAGAGAUGAUUAGCGAG 
                 914 
                 1831_1853 
               
               
                   
               
               
                 AD-64325.1 
                 A-128425.2 
                 UCUAGACUCGUGGUGGACUUC 
                 480 
                 A-128478.1 
                 GAAGUCCACCACGAGUCUAGACU 
                 915 
                 245_267 
               
               
                   
               
               
                 AD-64326.1 
                 A-128437.2 
                 CUGCCGAUCCAUACUGCGGAA 
                 481 
                 A-128484.1 
                 UUCCGCAGUAUGGAUCGGCAGAG 
                 916 
                 1256_1278 
               
               
                   
               
               
                 AD-64328.1 
                 A-128381.2 
                 AUCUUCUUGUUGGUUCUUCUA 
                 482 
                 A-128455.1 
                 UAGAAGAACCAACAAGAAGAUGA 
                 917 
                 426_448 
               
               
                   
               
               
                 AD-64330.1 
                 A-128411.2 
                 UUCUCUCAAUUUUCUAGGGGA 
                 483 
                 A-128471.1 
                 UCCCCUAGAAAAUUGAGAGAAGU 
                 918 
                 263_285 
               
               
                   
               
               
                 AD-64331.1 
                 A-127905.16 
                 ACUCGUGGUGGACUUCUCUCA 
                 484 
                 A-127907.2 
                 UGAGAGAAGUCCACCACGAGUCU 
                 919 
                 250_272 
               
               
                   
               
               
                 AD-64332.1 
                 A-128001.3 
                 GUGCACUUCGCUUCACCUCUG 
                 485 
                 A-128485.1 
                 CAGAGGUGAAGCGAAGUGCACAC 
                 920 
                 1577_1599 
               
               
                   
               
               
                 AD-64333.1 
                 A-128367.2 
                 GUUUUUCUUGUUGACAAAAAU 
                 486 
                 A-128448.1 
                 AUUUUUGUCAACAAGAAAAACCC 
                 921 
                 206_228 
               
               
                   
               
               
                 AD-64334.1 
                 A-128383.2 
                 CUGCCUAAUCAUCUCUUGUUA 
                 487 
                 A-128456.1 
                 UAACAAGAGAUGAUUAGGCAGAG 
                 922 
                 1829_1851 
               
               
                   
               
               
                 AD-64335.1 
                 A-128399.2 
                 UCCUCACAAUACCACAGAGUA 
                 488 
                 A-128464.1 
                 UACUCUGUGGUAUUGUGAGGAUU 
                 923 
                 226_248 
               
               
                   
               
               
                 AD-64336.1 
                 A-128413.2 
                 CUUGUUGACAAAAAUCCUCAA 
                 489 
                 A-128472.1 
                 UUGAGGAUUUUUGUCAACAAGAA 
                 924 
                 212_234 
               
               
                   
               
               
                 AD-64337.1 
                 A-127955.16 
                 GUGGUGGACUUCUCUCAAUUU 
                 490 
                 A-127958.2 
                 AAAUUGAGAGAAGUCCACCACGA 
                 925 
                 254_276 
               
               
                   
               
               
                 AD-64338.1 
                 A-128439.2 
                 GCAACUUUUUCACCUCUGCCU 
                 491 
                 A-128486.1 
                 AGGCAGAGGUGAAAAAGUUGCAU 
                 926 
                 1814_1836 
               
               
                   
               
               
                 AD-64339.1 
                 A-128369.2 
                 GGGAACAAGAGCUACAGCAUA 
                 492 
                 A-128449.1 
                 UAUGCUGUAGCUCUUGUUCCCAA 
                 927 
                 2828_2850 
               
               
                   
               
               
                 AD-64341.1 
                 A-128401.2 
                 UCAUCUUCUUGUUGGUUCUUA 
                 493 
                 A-128465.1 
                 UAAGAACCAACAAGAAGAUGAGG 
                 928 
                 424_446 
               
               
                   
               
               
                 AD-64342.1 
                 A-128415.2 
                 CUGCUGCUAUGCCUCAUCUUA 
                 494 
                 A-128473.1 
                 UAAGAUGAGGCAUAGCAGCAGGA 
                 929 
                 411_433 
               
               
                   
               
               
                 AD-64343.1 
                 A-128427.2 
                 GUUGGAUGUGUCUGCGGCGUU 
                 495 
                 A-128479.1 
                 AACGCCGCAGACACAUCCAACGA 
                 930 
                 370_392 
               
               
                   
               
               
                 AD-64344.1 
                 A-128441.2 
                 UUCAUCCUGCUGCUAUGCCUA 
                 496 
                 A-128487.1 
                 UAGGCAUAGCAGCAGGAUGAAGA 
                 931 
                 405_427 
               
               
                   
               
               
                 AD-64345.1 
                 A-128371.2 
                 UUCUUGUUGACAAAAAUCCUA 
                 497 
                 A-128450.1 
                 UAGGAUUUUUGUCAACAAGAAAA 
                 932 
                 210_232 
               
               
                   
               
               
                 AD-64347.1 
                 A-123487.3 
                 GGAUGUGUCUGCGGCGUUUUA 
                 498 
                 A-128466.1 
                 UAAAACGCCGCAGACACAUCCAG 
                 933 
                 373_395 
               
               
                   
               
               
                 AD-64348.1 
                 A-128417.2 
                 UAUAUGGAUGAUGUGGUAUUA 
                 499 
                 A-128474.1 
                 UAAUACCACAUCAUCCAUAUAAC 
                 934 
                 734_756 
               
               
                   
               
               
                 AD-64349.1 
                 A-128429.2 
                 UUCAUCCUGCUGCUAUGCCUC 
                 500 
                 A-128480.1 
                 GAGGCAUAGCAGCAGGAUGAAGA 
                 935 
                 405_427 
               
               
                   
               
               
                 AD-64350.1 
                 A-128443.2 
                 GUGCACUUCGCUUCACCUCUA 
                 501 
                 A-128488.1 
                 UAGAGGUGAAGCGAAGUGCACAC 
                 936 
                 1577_1599 
               
               
                   
               
               
                 AD-64351.1 
                 A-128373.2 
                 UUGACAAAAAUCCUCACAAUA 
                 502 
                 A-128451.1 
                 UAUUGUGAGGAUUUUUGUCAACA 
                 937 
                 216_238 
               
               
                   
               
               
                 AD-64352.1 
                 A-128389.2 
                 CCAAGUGUUUGCUGACGCAAA 
                 503 
                 A-128459.1 
                 UUUGCGUCAGCAAACACUUGGCA 
                 938 
                 1174_1196 
               
               
                   
               
               
                 AD-64352.1 
                 A-128389.2 
                 CCAAGUGUUUGCUGACGCAAA 
                 504 
                 A-128459.1 
                 UUUGCGUCAGCAAACACUUGGCA 
                 939 
                 1174_1196 
               
               
                   
               
               
                 AD-64353.1 
                 A-128403.2 
                 AAGCCUCCAAGCUGUGCCUUA 
                 505 
                 A-128467.1 
                 UAAGGCACAGCUUGGAGGCUUGA 
                 940 
                 1864_1886 
               
               
                   
               
               
                 AD-64354.1 
                 A-128419.2 
                 CCUCUUCAUCCUGCUGCUAUA 
                 506 
                 A-128475.1 
                 UAUAGCAGCAGGAUGAAGAGGAA 
                 941 
                 401_423 
               
               
                   
               
               
                 AD-64355.1 
                 A-128431.2 
                 CCUGCUGCUAUGCCUCAUCUU 
                 507 
                 A-128481.1 
                 AAGAUGAGGCAUAGCAGCAGGAU 
                 942 
                 410_432 
               
               
                   
               
               
                 AD-64356.1 
                 A-128375.2 
                 CAUCUUCUUGUUGGUUCUUCU 
                 508 
                 A-128452.1 
                 AGAAGAACCAACAAGAAGAUGAG 
                 943 
                 425_447 
               
               
                   
               
               
                 AD-64357.1 
                 A-128391.2 
                 CCGUCUGUGCCUUCUCAUCUA 
                 509 
                 A-128460.1 
                 UAGAUGAGAAGGCACAGACGGGG 
                 944 
                 1547_1569 
               
               
                   
               
               
                 AD-64358.1 
                 A-128405.2 
                 CCUCAUCUUCUUGUUGGUUCU 
                 510 
                 A-128468.1 
                 AGAACCAACAAGAAGAUGAGGCA 
                 945 
                 422_444 
               
               
                   
               
               
                 AD-64359.1 
                 A-128421.2 
                 CCACCAAAUGCCCCUAUCUUA 
                 511 
                 A-128476.1 
                 UAAGAUAGGGGCAUUUGGUGGUC 
                 946 
                 2298_2320 
               
               
                   
               
               
                 AD-64360.1 
                 A-128433.2 
                 GCUCCUCUGCCGAUCCAUACU 
                 512 
                 A-128482.1 
                 AGUAUGGAUCGGCAGAGGAGCCA 
                 947 
                 1250_1272 
               
               
                   
               
               
                 AD-64700.1 
                 A-129379.1 
                 ACUCGUGGUGTACUUCUCUCA 
                 513 
                 A-127906.26 
                 UGAGAGAAGUCCACCACGAGUCU 
                 948 
                 250_272 
               
               
                   
               
               
                 AD-64701.1 
                 A-127905.20 
                 ACUCGUGGUGGACUUCUCUCA 
                 514 
                 A-129387.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 949 
                 250_272 
               
               
                   
               
               
                 AD-64702.1 
                 A-127905.28 
                 ACUCGUGGUGGACUUCUCUCA 
                 515 
                 A-129395.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 950 
                 250_272 
               
               
                   
               
               
                 AD-64703.1 
                 A-129376.2 
                 ACUCGUGGUGGACUUCACUCA 
                 516 
                 A-129385.5 
                 UGAGAGAAGTCCACCACGAGUCU 
                 951 
                 250_272 
               
               
                   
               
               
                 AD-64704.1 
                 A-129381.3 
                 ACUCGUGGTGTACUUCACUCA 
                 517 
                 A-129389.6 
                 UGAGAGAAGUCCACCACGAGUCU 
                 952 
                 250_272 
               
               
                   
               
               
                 AD-64705.1 
                 A-129380.1 
                 ACUCGUGGUGTACUUCACUCA 
                 518 
                 A-127906.27 
                 UGAGAGAAGUCCACCACGAGUCU 
                 953 
                 250_272 
               
               
                   
               
               
                 AD-64706.1 
                 A-127905.21 
                 ACUCGUGGUGGACUUCUCUCA 
                 519 
                 A-129388.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 954 
                 250_272 
               
               
                   
               
               
                 AD-64707.1 
                 A-127905.29 
                 ACUCGUGGUGGACUUCUCUCA 
                 520 
                 A-129396.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 955 
                 250_272 
               
               
                   
               
               
                 AD-64708.1 
                 A-129382.2 
                 ACUCGUGGTGGACUUCTCUCA 
                 521 
                 A-129385.6 
                 UGAGAGAAGTCCACCACGAGUCU 
                 956 
                 250_272 
               
               
                   
               
               
                 AD-64709.1 
                 A-129373.4 
                 ACUCGUGGUGGACUUCUCUCA 
                 522 
                 A-129391.2 
                 UGAGAGAAGTCCACCACGAGUCU 
                 957 
                 250_272 
               
               
                   
               
               
                 AD-64710.1 
                 A-129373.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 523 
                 A-127906.20 
                 UGAGAGAAGUCCACCACGAGUCU 
                 958 
                 250_272 
               
               
                   
               
               
                 AD-64711.1 
                 A-129381.1 
                 ACUCGUGGTGTACUUCACUCA 
                 524 
                 A-127906.28 
                 UGAGAGAAGUCCACCACGAGUCU 
                 959 
                 250_272 
               
               
                   
               
               
                 AD-64712.1 
                 A-127905.22 
                 ACUCGUGGUGGACUUCUCUCA 
                 525 
                 A-129389.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 960 
                 250_272 
               
               
                   
               
               
                 AD-64713.1 
                 A-127905.30 
                 ACUCGUGGUGGACUUCUCUCA 
                 526 
                 A-129397.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 961 
                 250_272 
               
               
                   
               
               
                 AD-64714.1 
                 A-129384.2 
                 ACUCGUGGTGGACUUCACUCA 
                 527 
                 A-129385.7 
                 UGAGAGAAGTCCACCACGAGUCU 
                 962 
                 250_272 
               
               
                   
               
               
                 AD-64715.1 
                 A-129376.4 
                 ACUCGUGGUGGACUUCACUCA 
                 528 
                 A-129391.3 
                 UGAGAGAAGTCCACCACGAGUCU 
                 963 
                 250_272 
               
               
                   
               
               
                 AD-64716.1 
                 A-129374.1 
                 ACUCGUGGUGGACUUCUCUCA 
                 529 
                 A-127906.21 
                 UGAGAGAAGUCCACCACGAGUCU 
                 964 
                 250_272 
               
               
                   
               
               
                 AD-64717.1 
                 A-129382.1 
                 ACUCGUGGTGGACUUCTCUCA 
                 530 
                 A-127906.29 
                 UGAGAGAAGUCCACCACGAGUCU 
                 965 
                 250_272 
               
               
                   
               
               
                 AD-64718.1 
                 A-127905.23 
                 ACUCGUGGUGGACUUCUCUCA 
                 531 
                 A-129390.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 966 
                 250_272 
               
               
                   
               
               
                 AD-64719.1 
                 A-127917.5 
                 ACUCGUGGUGGACUUCTCUCA 
                 532 
                 A-129385.2 
                 UGAGAGAAGTCCACCACGAGUCU 
                 967 
                 250_272 
               
               
                   
               
               
                 AD-64720.1 
                 A-129381.2 
                 ACUCGUGGTGTACUUCACUCA 
                 533 
                 A-129385.8 
                 UGAGAGAAGTCCACCACGAGUCU 
                 968 
                 250_272 
               
               
                   
               
               
                 AD-64721.1 
                 A-129382.4 
                 ACUCGUGGTGGACUUCTCUCA 
                 534 
                 A-129391.4 
                 UGAGAGAAGTCCACCACGAGUCU 
                 969 
                 250_272 
               
               
                   
               
               
                 AD-64722.1 
                 A-129375.1 
                 ACUCGUGGUGGACUUCCUCA 
                 535 
                 A-127906.22 
                 UGAGAGAAGUCCACCACGAGUCU 
                 970 
                 250_272 
               
               
                   
               
               
                 AD-64723.1 
                 A-129383.1 
                 ACUCGUGGUGGACUUCTCUCA 
                 536 
                 A-127906.30 
                 UGAGAGAAGUCCACCACGAGUCU 
                 971 
                 250_272 
               
               
                   
               
               
                 AD-64725.1 
                 A-127917.6 
                 ACUCGUGGUGGACUUCTCUCA 
                 537 
                 A-129398.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 972 
                 250_272 
               
               
                   
               
               
                 AD-64726.1 
                 A-129373.3 
                 ACUCGUGGUGGACUUCUCUCA 
                 538 
                 A-129389.2 
                 UGAGAGAAGUCCACCACGAGUCU 
                 973 
                 250_272 
               
               
                   
               
               
                 AD-64727.1 
                 A-129384.4 
                 ACUCGUGGTGGACUUCACUCA 
                 539 
                 A-129391.5 
                 UGAGAGAAGTCCACCACGAGUCU 
                 974 
                 250_272 
               
               
                   
               
               
                 AD-64728.1 
                 A-129376.1 
                 ACUCGUGGUGGACUUCACUCA 
                 540 
                 A-127906.23 
                 UGAGAGAAGUCCACCACGAGUCU 
                 975 
                 250_272 
               
               
                   
               
               
                 AD-64729.1 
                 A-129384.1 
                 ACUCGUGGTGGACUUCACUCA 
                 541 
                 A-127906.31 
                 UGAGAGAAGUCCACCACGAGUCU 
                 976 
                 250_272 
               
               
                   
               
               
                 AD-64730.1 
                 A-127905.25 
                 ACUCGUGGUGGACUUCUCUCA 
                 542 
                 A-129392.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 977 
                 250_272 
               
               
                   
               
               
                 AD-64731.1 
                 A-129399.1 
                 ACUCGUGGUGGACUUCTCUCA 
                 543 
                 A-129385.3 
                 UGAGAGAAGTCCACCACGAGUCU 
                 978 
                 250_272 
               
               
                   
               
               
                 AD-64732.1 
                 A-129376.3 
                 ACUCGUGGUGGACUUCACUCA 
                 544 
                 A-129389.3 
                 UGAGAGAAGUCCACCACGAGUCU 
                 979 
                 250_272 
               
               
                   
               
               
                 AD-64733.1 
                 A-129381.4 
                 ACUCGUGGTGTACUUCACUCA 
                 545 
                 A-129391.6 
                 UGAGAGAAGTCCACCACGAGUCU 
                 980 
                 250_272 
               
               
                   
               
               
                 AD-64734.1 
                 A-129377.1 
                 ACUCGUGGUGGACUUCCCUCA 
                 546 
                 A-127906.24 
                 UGAGAGAAGUCCACCACGAGUCU 
                 981 
                 250_272 
               
               
                   
               
               
                 AD-64735.1 
                 A-127905.18 
                 ACUCGUGGUGGACUUCUCUCA 
                 547 
                 A-129385.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 982 
                 250_272 
               
               
                   
               
               
                 AD-64736.1 
                 A-127905.26 
                 ACUCGUGGUGGACUUCUCUCA 
                 548 
                 A-129393.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 983 
                 250_272 
               
               
                   
               
               
                 AD-64737.1 
                 A-129399.2 
                 ACUCGUGGUGGACUUCTCUCA 
                 549 
                 A-129398.2 
                 UGAGAGAAGTCCACCACGAGUCU 
                 984 
                 250_272 
               
               
                   
               
               
                 AD-64738.1 
                 A-129382.3 
                 ACUCGUGGTGGACUUCTCUCA 
                 550 
                 A-129389.4 
                 UGAGAGAAGUCCACCACGAGUCU 
                 985 
                 250_272 
               
               
                   
               
               
                 AD-64739.1 
                 A-129378.1 
                 ACUCGUGGUGGACUUCGCUCA 
                 551 
                 A-127906.25 
                 UGAGAGAAGUCCACCACGAGUCU 
                 986 
                 250_272 
               
               
                   
               
               
                 AD-64740.1 
                 A-127905.19 
                 ACUCGUGGUGGACUUCUCUCA 
                 552 
                 A-129386.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 987 
                 250_272 
               
               
                   
               
               
                 AD-64741.1 
                 A-127905.27 
                 ACUCGUGGUGGACUUCUCUCA 
                 553 
                 A-129394.1 
                 UGAGAGAAGTCCACCACGAGUCU 
                 988 
                 250_272 
               
               
                   
               
               
                 AD-64742.1 
                 A-129373.2 
                 ACUCGUGGUGGACUUCUCUCA 
                 554 
                 A-129385.4 
                 UGAGAGAAGTCCACCACGAGUCU 
                 989 
                 250_272 
               
               
                   
               
               
                 AD-64743.1 
                 A-129384.3 
                 ACUCGUGGTGGACUUCACUCA 
                 555 
                 A-129389.5 
                 UGAGAGAAGUCCACCACGAGUCU 
                 990 
                 250_272 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Modified Sense and Antisense Strand Sequences of HBV dsRNAs 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
                   
                   
                 SEQ 
               
               
                 Duplex 
                 Sense Oligo 
                   
                 ID 
                 Antisense 
                 Antisense Sequence 
                 ID 
               
               
                 Name 
                 Name 
                 Sense Sequence (5′ to 3′) 
                 NO: 
                 Oligo Name 
                 (5′ to 3′) 
                 NO: 
               
               
                   
               
               
                 AD-61522.2 
                 A-123463.2 
                 AfsgsUfuAfuAfuGfGfAfuGfaU 
                  991 
                 A-123464.2 
                 usAfscCfaCfaUfcAfuccAfuA 
                 1210 
               
               
                   
                   
                 fgUfgGfuAfL96 
                   
                   
                 fuAfaCfusgsa 
                   
               
               
                   
               
               
                 AD-61547.2 
                 A-123487.2 
                 GfsgsAfuGfuGfuCfUfGfcGfgC 
                  992 
                 A-123488.2 
                 usAfsaAfaCfgCfcGfcagAfcA 
                 1211 
               
               
                   
                   
                 fgUfuUfuAfL96 
                   
                   
                 fcAfuCfcsasg 
                   
               
               
                   
               
               
                 AD-63938.2 
                 A-127896.1 
                 Y44ACUCGUGGUGGACUUCUCUCA 
                  993 
                 A-127897.1 
                 UGAGAGAAGUCCACCACGAGUCU 
                 1212 
               
               
                   
               
               
                 AD-63939.2 
                 A-127909.1 
                 ascsucGfuGfgUfGfGfaCfuucU 
                  994 
                 A-127906.3 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1213 
               
               
                   
                   
                 fcucaL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63940.2 
                 A-127917.1 
                 ascsucguggugdGacuuc(Tgn)c 
                  995 
                 A-127906.11 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1214 
               
               
                   
                   
                 ucaL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63940.3 
                 A-127917.4 
                 ascsucguggugdGacuuc(Tgn)c 
                  996 
                 A-127906.19 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1215 
               
               
                   
                   
                 ucaL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63941.2 
                 A-127905.8 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                  997 
                 A-127925.1 
                 usGfsaGfagaAfguccaCfcAfc 
                 1216 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 gaGfuscsu 
                   
               
               
                   
               
               
                 AD-63942.2 
                 A-127933.1 
                 uscsGfuGfgUfGfGfaCfuUfcUf 
                  998 
                 A-127934.1 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1217 
               
               
                   
                   
                 cUfcAfL96 
                   
                   
                 fcGfasgsu 
                   
               
               
                   
               
               
                 AD-63943.2 
                 A-127944.2 
                 ascsucGfuGfguGfGfaCfuucuc 
                  999 
                 A-127942.2 
                 usGfsAfgaGfaAfgUfccaCfcA 
                 1218 
               
               
                   
                   
                 ucaL96 
                   
                   
                 fcGfaguscsu 
                   
               
               
                   
               
               
                 AD-63945.2 
                 A-127910.1 
                 ascsucguGfgUfGfGfaCfuucUf 
                 1000 
                 A-127906.4 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1219 
               
               
                   
                   
                 cucaL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63946.2 
                 A-127918.1 
                 ascsucguGfgUfGfGfacuuCfuc 
                 1001 
                 A-127906.12 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1220 
               
               
                   
                   
                 ucaL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63947.2 
                 A-127905.9 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1002 
                 A-127926.1 
                 usGfsaGfagaagUfccaCfcAfc 
                 1221 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 gaGfuscsu 
                   
               
               
                   
               
               
                 AD-63948.2 
                 A-127935.1 
                 gsusGfgUfGfGfaCfuUfcUfcUf 
                 1003 
                 A-127936.1 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1222 
               
               
                   
                   
                 cAfL96 
                   
                   
                 fcsgsa 
                   
               
               
                   
               
               
                 AD-63949.2 
                 A-127944.3 
                 ascsucGfuGfguGfGfaCfuucuc 
                 1004 
                 A-127906.14 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1223 
               
               
                   
                   
                 ucaL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63950.2 
                 A-127900.1 
                 Y44UfcGfuGfgUfgGfaCfuUfcU 
                 1005 
                 A-127901.1 
                 usGfsasGfaGfaAfgUfcCfaCf 
                 1224 
               
               
                   
                   
                 fcUfcAfusuY44 
                   
                   
                 cAfcGfausu 
                   
               
               
                   
               
               
                 AD-63951.2 
                 A-127911.1 
                 ascsucguGfgUfGfGfaCfuucuc 
                 1006 
                 A-127906.5 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1225 
               
               
                   
                   
                 ucaL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63952.2 
                 A-127905.2 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1007 
                 A-127919.1 
                 usGfsaGfaGfaagUfccaCfcAf 
                 1226 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 cGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63953.2 
                 A-127905.10 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1008 
                 A-127927.1 
                 usGfsagagaAfgUfccaCfcAfc 
                 1227 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 gaguscsu 
                   
               
               
                   
               
               
                 AD-63955.2 
                 A-127945.1 
                 ascsucgugguGfGfacuucucuca 
                 1009 
                 A-127940.3 
                 usGfsAfgAfgAfaGfuccaCfCf 
                 1228 
               
               
                   
                   
                 L96 
                   
                   
                 aCfgAfguscsu 
                   
               
               
                   
               
               
                 AD-63956.2 
                 A-127902.1 
                 Y44uscsGfuGfgUfgGfaCfuUfc 
                 1010 
                 A-127903.1 
                 usGfsaGfaGfaAfgUfcCfaCfc 
                 1229 
               
               
                   
                   
                 UfcUfcAfY44 
                   
                   
                 AfcGfasusu 
                   
               
               
                   
               
               
                 AD-63957.2 
                 A-127912.1 
                 ascsucguGfgUfGfGfacuucucu 
                 1011 
                 A-127906.6 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1230 
               
               
                   
                   
                 caL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63958.2 
                 A-127905.3 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1012 
                 A-127920.1 
                 usGfsagaGfaAfgUfccaCfcAf 
                 1231 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 cgaGfuscsu 
                   
               
               
                   
               
               
                 AD-63959.2 
                 A-127905.11 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1013 
                 A-127928.1 
                 usGfsaGfagaAfguccaCfcAfc 
                 1232 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 gaguscsu 
                   
               
               
                   
               
               
                 AD-63960.2 
                 A-126619.2 
                 usasUfuUfCfCfuAfgGfgUfaCf 
                 1014 
                 A-127938.1 
                 PusGfsaGfaGfaAfgUfccaCfc 
                 1233 
               
               
                   
                   
                 aAfL96 
                   
                   
                 Afcsgsa 
                   
               
               
                   
               
               
                 AD-63961.2 
                 A-127945.2 
                 ascsucgugguGfGfacuucucuca 
                 1015 
                 A-127942.3 
                 usGfsAfgaGfaAfgUfccaCfcA 
                 1234 
               
               
                   
                   
                 L96 
                   
                   
                 fcGfaguscsu 
                   
               
               
                   
               
               
                 AD-63962.2 
                 A-127902.2 
                 Y44uscsGfuGfgUfgGfaCfuUfc 
                 1016 
                 A-127904.1 
                 PusGfsaGfaGfaAfgUfcCfaCf 
                 1235 
               
               
                   
                   
                 UfcUfcAfY44 
                   
                   
                 cAfcGfasusu 
                   
               
               
                   
               
               
                 AD-63963.2 
                 A-127913.1 
                 ascsucguggUfgGfacuucucuca 
                 1017 
                 A-127906.7 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1236 
               
               
                   
                   
                 L96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63964.2 
                 A-127905.4 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1018 
                 A-127921.1 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1237 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 fcgaguscsu 
                   
               
               
                   
               
               
                 AD-63965.2 
                 A-127905.12 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1019 
                 A-127929.1 
                 usGfsagaGfaaGfuccaCfcAfc 
                 1238 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 gaguscsu 
                   
               
               
                   
               
               
                 AD-63966.2 
                 A-127939.1 
                 ascsUfcGfugguGfGfaCfuuCfu 
                 1020 
                 A-127940.1 
                 usGfsAfgAfgAfaGfuccaCfCf 
                 1239 
               
               
                   
                   
                 CfucaL96 
                   
                   
                 aCfgAfguscsu 
                   
               
               
                   
               
               
                 AD-63967.2 
                 A-127945.3 
                 ascsucgugguGfGfacuucucuca 
                 1021 
                 A-127906.15 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1240 
               
               
                   
                   
                 L96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63968.2 
                 A-127905.1 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1022 
                 A-127906.1 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1241 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63968.2 
                 A-127905.1 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1023 
                 A-127906.1 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1242 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63968.4 
                 A-127905.15 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1024 
                 A-127906.17 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1243 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63968.5 
                 A-127905.17 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1025 
                 A-127906.18 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1244 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63969.2 
                 A-127914.1 
                 ascsucguggugGfacuucucucaL 
                 1026 
                 A-127906.8 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1245 
               
               
                   
                   
                 96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63970.2 
                 A-127905.5 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1027 
                 A-127922.1 
                 usGfsagaGfaagUfccaCfcAfc 
                 1246 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 gaGfuscsu 
                   
               
               
                   
               
               
                 AD-63971.2 
                 A-127905.13 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1028 
                 A-127930.1 
                 usGfsagaGfaaguccaCfcAfcg 
                 1247 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 aguscsu 
                   
               
               
                   
               
               
                 AD-63972.2 
                 A-127941.1 
                 ascsUfcGfuGfguGfGfaCfuuCf 
                 1029 
                 A-127942.1 
                 usGfsAfgaGfaAfgUfccaCfcA 
                 1248 
               
               
                   
                   
                 uCfucaL96 
                   
                   
                 fcGfaguscsu 
                   
               
               
                   
               
               
                 AD-63973.2 
                 A-127946.1 
                 ascsucguggudGdGacuucucuca 
                 1030 
                 A-127947.1 
                 usdGsaGfaGfaAfgdTccadCcA 
                 1249 
               
               
                   
                   
                 L96 
                   
                   
                 fcGfaguscsu 
                   
               
               
                   
               
               
                 AD-63975.2 
                 A-127915.1 
                 ascsucguggUfgGfacuuc(Tgn) 
                 1031 
                 A-127906.9 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1250 
               
               
                   
                   
                 cucaL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63976.2 
                 A-127905.6 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1032 
                 A-127923.1 
                 usGfsagaGfaAfgUfccaCfcAf 
                 1251 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 cgaguscsu 
                   
               
               
                   
               
               
                 AD-63977.2 
                 A-127917.2 
                 ascsucguggugdGacuuc(Tgn)c 
                 1033 
                 A-127931.1 
                 usdGsagagaaguccadCcacgag 
                 1252 
               
               
                   
                   
                 ucaL96 
                   
                   
                 uscsu 
                   
               
               
                   
               
               
                 AD-63978.2 
                 A-127943.1 
                 ascsUfcGfuGfguGfGfaCfuUfc 
                 1034 
                 A-127906.13 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1253 
               
               
                   
                   
                 UfcUfcaL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63979.2 
                 A-127908.1 
                 ascsucGfuGfgUfGfGfaCfuucU 
                 1035 
                 A-127906.2 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1254 
               
               
                   
                   
                 fcucAfL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63980.2 
                 A-127916.1 
                 ascsucguggugGfacuuc(Tgn)c 
                 1036 
                 A-127906.10 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1255 
               
               
                   
                   
                 ucaL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-63981.2 
                 A-127905.7 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1037 
                 A-127924.1 
                 usGfsaGfagaAfgUfccaCfcAf 
                 1256 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 cgaGfuscsu 
                   
               
               
                   
               
               
                 AD-63982.2 
                 A-127917.3 
                 ascsucguggugdGacuuc(Tgn)c 
                 1038 
                 A-127932.1 
                 PusdGsagagaaguccadCcacga 
                 1257 
               
               
                   
                   
                 ucaL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-63983.2 
                 A-127944.1 
                 ascsucGfuGfguGfGfaCfuucuc 
                 1039 
                 A-127940.2 
                 usGfsAfgAfgAfaGfuccaCfCf 
                 1258 
               
               
                   
                   
                 ucaL96 
                   
                   
                 aCfgAfguscsu 
                   
               
               
                   
               
               
                 AD-63985.2 
                 A-127961.1 
                 gsusggugGfaCfUfUfcUfcucAf 
                 1040 
                 A-127956.4 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1259 
               
               
                   
                   
                 auuuL96 
                   
                   
                 faCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-63986.2 
                 A-127969.1 
                 gsusggugGfaCfUfUfcucuCfaa 
                 1041 
                 A-127956.12 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1260 
               
               
                   
                   
                 uuuL96 
                   
                   
                 faCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-63987.2 
                 A-127955.9 
                 GfsusGfgUfgGfaCfUfUfcUfcU 
                 1042 
                 A-127977.1 
                 asAfsaUfugagaGfaagUfcCfa 
                 1261 
               
               
                   
                   
                 fcAfaUfaUfL96 
                   
                   
                 ccAfcsgsa 
                   
               
               
                   
               
               
                 AD-63988.2 
                 A-127986.1 
                 usgsGfaCfUfUfcUlcUfcAfaUf 
                 1043 
                 A-127987.1 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1262 
               
               
                   
                   
                 aUfL96 
                   
                   
                 fascsc 
                   
               
               
                   
               
               
                 AD-63989.2 
                 A-127996.1 
                 gsusgguggacUfUfcucucaauuu 
                 1044 
                 A-127992.2 
                 asAfsAfUfuGfaGfaGfaagUfc 
                 1263 
               
               
                   
                   
                 L96 
                   
                   
                 CfaCfcacsgsa 
                   
               
               
                   
               
               
                 AD-63990.2 
                 A-127950.1 
                 Y44GfgUfgGfaCfuUfcUfcUfcA 
                 1045 
                 A-127951.1 
                 asAfsasUfuGfaGfaGfaAfgUf 
                 1264 
               
               
                   
                   
                 faUfuUfusuY44 
                   
                   
                 cCfaCfcusu 
                   
               
               
                   
               
               
                 AD-63991.2 
                 A-127962.1 
                 gsusggugGfaCfUfUfcUfcucaa 
                 1046 
                 A-127956.5 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1265 
               
               
                   
                   
                 uuuL96 
                   
                   
                 faCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-63992.2 
                 A-127955.2 
                 GfsusGfgUfgGfaCfUfUfcUfcU 
                 1047 
                 A-127970.1 
                 asAfsaUfuGfagaGfaagUfcCf 
                 1266 
               
               
                   
                   
                 fcAfaUfuUfL96 
                   
                   
                 aCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-63993.2 
                 A-127955.10 
                 GfsusGfgUfgGfaCfUfUfcUfcU 
                 1048 
                 A-127978.1 
                 asAfsauugaGfaGfaagUfcCfa 
                 1267 
               
               
                   
                   
                 fcAfaUfuUfL96 
                   
                   
                 acccsgsa 
                   
               
               
                   
               
               
                 AD-63994.2 
                 A-127984.2 
                 gsgUfgGfaCfUfUfcUfcUfcAfa 
                 1049 
                 A-127988.1 
                 PasAfsaUfuGfaGfaGfaagUfc 
                 1268 
               
               
                   
                   
                 UfuUfL96 
                   
                   
                 CfaCfcsasc 
                   
               
               
                   
               
               
                 AD-63995.2 
                 A-127996.2 
                 gsusgguggacUfUfcucucaauuu 
                 1050 
                 A-127993.2 
                 asAfsAfuuGfaGfaGfaagUfCf 
                 1269 
               
               
                   
                   
                 L96 
                   
                   
                 caCfcacsgsa 
                   
               
               
                   
               
               
                 AD-63996.2 
                 A-127952.1 
                 Y44gsgsUfgGfaCfuUfcUfcUfc 
                 1051 
                 A-127953.1 
                 asAfsaUfuGfaGfaGfaAfgUfc 
                 1270 
               
               
                   
                   
                 AfaUfuUfY44 
                   
                   
                 CfaCfcsusu 
                   
               
               
                   
               
               
                 AD-63997.2 
                 A-127963.1 
                 gsusggugGfaCfUfUfcucucaau 
                 1052 
                 A-127956.6 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1271 
               
               
                   
                   
                 uuL96 
                   
                   
                 faCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-63999.2 
                 A-127955.11 
                 GfsusGfgUfgGfaCfUfUfcUfcU 
                 1053 
                 A-127979.1 
                 asAfsaUfugaGfagaagUfcCfa 
                 1272 
               
               
                   
                   
                 fcAfaUfuUfL96 
                   
                   
                 ccacsgsa 
                   
               
               
                   
               
               
                 AD-64000.2 
                 A-127986.2 
                 usgsGfaCfUfUfcUfcUfcAfaUf 
                 1054 
                 A-127989.1 
                 PasAfsaUfuGfaGfaGfaagUfc 
                 1273 
               
               
                   
                   
                 uUfL96 
                   
                   
                 Cfascsc 
                   
               
               
                   
               
               
                 AD-64001.2 
                 A-127996.3 
                 gsusgguggacUfUfcucucaauuu 
                 1055 
                 A-127994.2 
                 asAfsAfUfuGfaGfaGfaagUfC 
                 1274 
               
               
                   
                   
                 L96 
                   
                   
                 fcaCfcacsgsa 
                   
               
               
                   
               
               
                 AD-64002.2 
                 A-127952.2 
                 Y44gsgsUfgGfaCfuUfcUfcUfc 
                 1056 
                 A-127954.1 
                 PasAfsaUfuGfaGfaGfaAfgUf 
                 1275 
               
               
                   
                   
                 AfaUfuUfY44 
                   
                   
                 cCfaCfcsusu 
                   
               
               
                   
               
               
                 AD-64003.2 
                 A-127964.1 
                 gsusgguggaCfuUfcucucaauuu 
                 1057 
                 A-127956.7 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1276 
               
               
                   
                   
                 L96 
                   
                   
                 faCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-64004.2 
                 A-127955.4 
                 GfsusGfgUfgGfaCfUfUfcUfcU 
                 1058 
                 A-127972.1 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1277 
               
               
                   
                   
                 fcAfaUfuUfL96 
                   
                   
                 faccacsgsa 
                   
               
               
                   
               
               
                 AD-64005.2 
                 A-127955.12 
                 GfsusGfgUfgGfaCfUfUfcUfcU 
                 1059 
                 A-127980.1 
                 asAfsauuGfagAfgaagUfcCfa 
                 1278 
               
               
                   
                   
                 fcAfaUfuUfL96 
                   
                   
                 ccacsgsa 
                   
               
               
                   
               
               
                 AD-64006.2 
                 A-127990.1 
                 gsusGfgugGfaCfUfUfcUfcUfc 
                 1060 
                 A-127991.1 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1279 
               
               
                   
                   
                 AfaUfuuL96 
                   
                   
                 faCfcacsgsa 
                   
               
               
                   
               
               
                 AD-64007.2 
                 A-127996.4 
                 gsusgguggacUfUfcucucaauuu 
                 1061 
                 A-127995.2 
                 asAfsAfUfugaGfaGfaagUfCf 
                 1280 
               
               
                   
                   
                 L96 
                   
                   
                 caCfcacsgsa 
                   
               
               
                   
               
               
                 AD-64008.2 
                 A-127955.1 
                 GfsusGfgUfgGfaCfUfUfcUfcU 
                 1062 
                 A-127956.1 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1281 
               
               
                   
                   
                 fcAfaUfuUfL96 
                   
                   
                 faCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-64008.2 
                 A-127955.1 
                 GfsusGfgUfgGfaCfUfUfcUfcU 
                 1063 
                 A-127956.1 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1282 
               
               
                   
                   
                 fcAfaUfuUfL96 
                   
                   
                 faCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-64008.4 
                 A-127955.15 
                 GfsusGfgUfgGfaCfUfUfcUfcU 
                 1064 
                 A-127956.14 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1283 
               
               
                   
                   
                 fcAfaUfuUfL96 
                   
                   
                 faCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-64009.2 
                 A-127965.1 
                 gsusgguggacuUfcucucaauuuL 
                 1065 
                 A-127956.8 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1284 
               
               
                   
                   
                 96 
                   
                   
                 faCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-64010.2 
                 A-127955.5 
                 GfsusGfgUfgGfaCfUfUfcUfcU 
                 1066 
                 A-127973.1 
                 asAfsauuGfagaGfaagUfcCfa 
                 1285 
               
               
                   
                   
                 fcAfaUfuUTL96 
                   
                   
                 ccAfcsgsa 
                   
               
               
                   
               
               
                 AD-64011.2 
                 A-127955.13 
                 GfsusGfgUfgGfaCfUfUfcUfcU 
                 1067 
                 A-127981.1 
                 asAfsauuGfagagaagUfcCfac 
                 1286 
               
               
                   
                   
                 fcAfaUfuUTL96 
                   
                   
                 cacsgsa 
                   
               
               
                   
               
               
                 AD-64012.2 
                 A-127990.2 
                 gsusGfgugGfaCfUfUfcUfcUfc 
                 1068 
                 A-127992.1 
                 asAfsAfUfuGfaGfaGfaagUfc 
                 1287 
               
               
                   
                   
                 AfaUfuuL96 
                   
                   
                 CfaCfcacsgsa 
                   
               
               
                   
               
               
                 AD-64013.2 
                 A-127997.1 
                 gsusgguggacdTdTcucucaauuu 
                 1069 
                 A-127998.1 
                 asdAsAfuugaGfaGfaagdTdCc 
                 1288 
               
               
                   
                   
                 L96 
                   
                   
                 aCfcacsgsa 
                   
               
               
                   
               
               
                 AD-64014.2 
                 A-127957.1 
                 Y44GfsusGfgUfgGfaCfUfUfcU 
                 1070 
                 A-127958.1 
                 PasAfsaUfuGfaGfaGfaagUfc 
                 1289 
               
               
                   
                   
                 fcUfcAfaUfuUfL96 
                   
                   
                 CfaCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-64015.2 
                 A-127966.1 
                 gsusgguggaCfuUfcucuc(Agn) 
                 1071 
                 A-127956.9 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1290 
               
               
                   
                   
                 auuuL96 
                   
                   
                 faCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-64016.2 
                 A-127955.6 
                 GfsusGfgUfgGfaCfUfLfcUfcU 
                 1072 
                 A-127974.1 
                 asAfsauuGfaGfaGfaagUfcCf 
                 1291 
               
               
                   
                   
                 fcAfaUfuUfL96 
                   
                   
                 accacsgsa 
                   
               
               
                   
               
               
                 AD-64017.2 
                 A-127968.2 
                 gsusgguggacudTcucuc(Agn)a 
                 1073 
                 A-127982.1 
                 asdAsauugagagaagdTccacca 
                 1292 
               
               
                   
                   
                 uuuL96 
                   
                   
                 csgsa 
                   
               
               
                   
               
               
                 AD-64018.2 
                 A-127990.3 
                 gsusGfgugGfaCfUfLfcUfcUfc 
                 1074 
                 A-127993.1 
                 asAfsAfuuGfaGfaGfaagUfCf 
                 1293 
               
               
                   
                   
                 AfaUfuuL96 
                   
                   
                 caCfcacsgsa 
                   
               
               
                   
               
               
                 AD-64019.2 
                 A-127959.1 
                 gsusggUfgGfaCfUfLfcUfcucA 
                 1075 
                 A-127956.2 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1294 
               
               
                   
                   
                 fauuUfL96 
                   
                   
                 faCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-64020.2 
                 A-127967.1 
                 gsusgguggacuUfcucuc(Agn)a 
                 1076 
                 A-127956.10 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1295 
               
               
                   
                   
                 uuuL96 
                   
                   
                 faCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-64021.2 
                 A-127955.7 
                 GfsusGfgUfgGfaCfUfUfcUfcU 
                 1077 
                 A-127975.1 
                 asAfsaUfugaGfaGfaagUfcCf 
                 1296 
               
               
                   
                   
                 fcAfaUfuUfL96 
                   
                   
                 accAfcsgsa 
                   
               
               
                   
               
               
                 AD-64022.2 
                 A-127968.3 
                 gsusgguggacudTcucuc(Agn)a 
                 1078 
                 A-127983.1 
                 PasdAsauugagagaagdTccacc 
                 1297 
               
               
                   
                   
                 uuuL96 
                   
                   
                 acsgsa 
                   
               
               
                   
               
               
                 AD-64023.2 
                 A-127990.4 
                 gsusGfgugGfaCfUfUfcUfcUfc 
                 1079 
                 A-127994.1 
                 asAfsAfUfuGfaGfaGfaagUfC 
                 1298 
               
               
                   
                   
                 AfaUfuuL96 
                   
                   
                 fcaCfcacsgsa 
                   
               
               
                   
               
               
                 AD-64024.2 
                 A-127960.1 
                 gsusggUfgGfaCfUfUfcUfcucA 
                 1080 
                 A-127956.3 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1299 
               
               
                   
                   
                 fauuuL96 
                   
                   
                 faCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-64025.2 
                 A-127968.1 
                 gsusgguggacudTcucuc(Agn)a 
                 1081 
                 A-127956.11 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1300 
               
               
                   
                   
                 uuuL96 
                   
                   
                 faCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-64026.2 
                 A-127955.8 
                 GfsusGfgUfgGfaCfUfUfcUfcU 
                 1082 
                 A-127976.1 
                 asAfsaUfugaGfagaagUfcCfa 
                 1301 
               
               
                   
                   
                 fcAfaUfuUfL96 
                   
                   
                 ccAfcsgsa 
                   
               
               
                   
               
               
                 AD-64027.2 
                 A-127984.1 
                 gsgUfgGfaCfUfUfcUfcUfcAfa 
                 1083 
                 A-127985.1 
                 asAfsaUfuGfaGfaGfaagUfcC 
                 1302 
               
               
                   
                   
                 UfuUfL96 
                   
                   
                 faCfcsasc 
                   
               
               
                   
               
               
                 AD-64028.2 
                 A-127990.5 
                 gsusGfgugGfaCfUfUfcUfcUfc 
                 1084 
                 A-127995.1 
                 asAfsAfUfugaGfaGfaagUfCf 
                 1303 
               
               
                   
                   
                 AfaUfuuL96 
                   
                   
                 caCfcacsgsa 
                   
               
               
                   
               
               
                 AD-64272.2 
                 A-128001.2 
                 GfsusGfcAfcUfuCfGfCfuUfcA 
                 1085 
                 A-128002.2 
                 csAfsgAfgGfuGfaAfgcgAfaG 
                 1304 
               
               
                   
                   
                 fcCfuCfuGfL96 
                   
                   
                 fuGfcAfcsasc 
                   
               
               
                   
               
               
                 AD-64274.1 
                 A-128363.1 
                 GfsusUfgAfcAfaAfAfAfuCfcU 
                 1086 
                 A-128364.1 
                 asUfsuGfuGfaGfgAfuuuUfuG 
                 1305 
               
               
                   
                   
                 fcAfcAfaUfL96 
                   
                   
                 fuCfaAfcsasa 
                   
               
               
                   
               
               
                 AD-64275.1 
                 A-128377.1 
                 UfsgsUfuGfaCfaAfAfAfaUfcC 
                 1087 
                 A-128378.1 
                 usUfsgUfgAfgGfaUfuuuUfgU 
                 1306 
               
               
                   
                   
                 fuCfaCfaAfL96 
                   
                   
                 fcAfaCfasasg 
                   
               
               
                   
               
               
                 AD-64276.1 
                 A-128393.1 
                 GfsgsUfgGfaCfuUfCfUfcUfcA 
                 1088 
                 A-128394.1 
                 usAfsaAfaUfuGfaGfagaAfgU 
                 1307 
               
               
                   
                   
                 faUfuUfuAfL96 
                   
                   
                 fcCfaCfcsasc 
                   
               
               
                   
               
               
                 AD-64277.1 
                 A-128407.1 
                 UfscsUfuUfuGfgAfGfUfgUfgG 
                 1089 
                 A-128408.1 
                 usCfsgAfaUfcCfaCfacuCfcA 
                 1308 
               
               
                   
                   
                 faUfuCfgAfL96 
                   
                   
                 faAfaGfascsa 
                   
               
               
                   
               
               
                 AD-64277.1 
                 A-128407.1 
                 UfscsUfuUfuGfgAfGfUfgUfgG 
                 1090 
                 A-128408.1 
                 usCfsgAfaUfcCfaCfacuCfcA 
                 1309 
               
               
                   
                   
                 faUfuCfgAfL96 
                   
                   
                 faAfaGfascsa 
                   
               
               
                   
               
               
                 AD-64278.1 
                 A-128423.1 
                 AfscsUfgUfuCfaAfGfCfcUfcC 
                 1091 
                 A-128424.1 
                 usAfsgCfuUfgGfaGfgcuUfgA 
                 1310 
               
               
                   
                   
                 faAfgCfuAfL96 
                   
                   
                 faCfaAfgsasc 
                   
               
               
                   
               
               
                 AD-64279.1 
                 A-128435.1 
                 UfscsUfgCfcGfaUfCfCfaUfaC 
                 1092 
                 A-128436.1 
                 usCfscGfcAfgUfaUfggaUfcG 
                 1311 
               
               
                   
                   
                 fuGfcGfgAfL96 
                   
                   
                 fgCfaGfasgsg 
                   
               
               
                   
               
               
                 AD-64280.1 
                 A-128379.1 
                 AfsusGfuGfuCfuGfCfGfgCfgU 
                 1093 
                 A-128380.1 
                 usAfsuAfaAfaCfgCfcgcAfgA 
                 1312 
               
               
                   
                   
                 fuUfuAfuAfL96 
                   
                   
                 fcAfcAfuscsc 
                   
               
               
                   
               
               
                 AD-64281.1 
                 A-128395.1 
                 CfscsCfcGfuCfuGfUfGfcCfuU 
                 1094 
                 A-128396.1 
                 usAfsuGfaGfaAfgGfcacAfgA 
                 1313 
               
               
                   
                   
                 fcUfcAfuAfL96 
                   
                   
                 fcGfgGfgsasg 
                   
               
               
                   
               
               
                 AD-64282.1 
                 A-128409.1 
                 GfscsCfuAfaUfcAfUfCfuCfuU 
                 1095 
                 A-128410.1 
                 asUfsgAfaCfaAfgAfgauGfaU 
                 1314 
               
               
                   
                   
                 fgUfuCfaUfL96 
                   
                   
                 fuAfgCfgsasg 
                   
               
               
                   
               
               
                 AD-64283.1 
                 A-128425.1 
                 UfscsUfaGfaCfuCfGfUfgGfuG 
                 1096 
                 A-128426.1 
                 gsAfsaGfuCfcAfcCfacgAfgU 
                 1315 
               
               
                   
                   
                 fgAfcUfuCfL96 
                   
                   
                 fcUfaGfascsu 
                   
               
               
                   
               
               
                 AD-64284.1 
                 A-128437.1 
                 CfsusGfcCfgAfuCfCfAfuAfcU 
                 1097 
                 A-128438.1 
                 usUfscCfgCfaGfuAfuggAfuC 
                 1316 
               
               
                   
                   
                 fgCfgGfaAfL96 
                   
                   
                 fgGfcAfgsasg 
                   
               
               
                   
               
               
                 AD-64285.1 
                 A-128365.1 
                 UfsusUfuUfcUfuGfUfUfgAfcA 
                 1098 
                 A-128366.1 
                 usAfsuUfuUfuGfuCfaacAfaG 
                 1317 
               
               
                   
                   
                 faAfaAfuAfL96 
                   
                   
                 faAfaAfascsc 
                   
               
               
                   
               
               
                 AD-64286.1 
                 A-128381.1 
                 AfsusCfuUfcUfuGfUfUfgGfuU 
                 1099 
                 A-128382.1 
                 usAfsgAfaGfaAfcCfaacAfaG 
                 1318 
               
               
                   
                   
                 fcUfuCfuAfL96 
                   
                   
                 faAfgAfusgsa 
                   
               
               
                   
               
               
                 AD-64289.1 
                 A-128367.1 
                 GfsusUfuUfuCfuUfGfUfuGfaC 
                 1100 
                 A-128368.1 
                 asUfsuUfuUfgUfcAfacaAfgA 
                 1319 
               
               
                   
                   
                 faAfaAfaUfL96 
                   
                   
                 faAfaAfcscsc 
                   
               
               
                   
               
               
                 AD-64290.1 
                 A-128383.1 
                 CfsusGfcCfuAfaUfCfAfuCfuC 
                 1101 
                 A-128384.1 
                 usAfsaCfaAfgAfgAfugaUfuA 
                 1320 
               
               
                   
                   
                 fuUfgUfuAfL96 
                   
                   
                 fgGfcAfgsasg 
                   
               
               
                   
               
               
                 AD-64291.1 
                 A-128399.1 
                 UfscsCfuCfaCfaAfUfAfcCfaC 
                 1102 
                 A-128400.1 
                 usAfscUfcUfgUfgGfuauUfgU 
                 1321 
               
               
                   
                   
                 faGfaGfuAfL96 
                   
                   
                 fgAfgGfasusu 
                   
               
               
                   
               
               
                 AD-64292.1 
                 A-128413.1 
                 CfsusUfgUfuGfaCfAfAfaAfaU 
                 1103 
                 A-128414.1 
                 usUfsgAfgGfaUfuUfuugUfcA 
                 1322 
               
               
                   
                   
                 fcCfuCfaAfL96 
                   
                   
                 faCfaAfgsasa 
                   
               
               
                   
               
               
                 AD-64293.1 
                 A-128439.1 
                 GfscsAfaCfuUfuUfUTCfaCfcU 
                 1104 
                 A-128440.1 
                 asGfsgCfaGfaGfgUfgaaAfaA 
                 1323 
               
               
                   
                   
                 fcUfgCfcUfL96 
                   
                   
                 fgUfuGfcsasu 
                   
               
               
                   
               
               
                 AD-64294.1 
                 A-128369.1 
                 GfsgsGfaAfcAfaGfAfGfcUfaC 
                 1105 
                 A-128370.1 
                 usAfsuGfcUfgUfaGfcucUfuG 
                 1324 
               
               
                   
                   
                 faGfcAfuAfL96 
                   
                   
                 fuUfcCfcsasa 
                   
               
               
                   
               
               
                 AD-64295.1 
                 A-128385.1 
                 CfsgsUfgGfuGfgAfCfUfuCfuC 
                 1106 
                 A-128386.1 
                 asAfsuUfgAfgAfgAfaguCfcA 
                 1325 
               
               
                   
                   
                 fuCfaAfuUfL96 
                   
                   
                 fcCfaGfcsasg 
                   
               
               
                   
               
               
                 AD-64297.1 
                 A-128415.1 
                 CfsusGfcUfgCfuAfUfGfcCfuC 
                 1107 
                 A-128416.1 
                 usAfsaGfaUfgAfgGfcauAfgC 
                 1326 
               
               
                   
                   
                 faUfcUfuAfL96 
                   
                   
                 faGfcAfgsgsa 
                   
               
               
                   
               
               
                 AD-64298.1 
                 A-128427.1 
                 GfsusUfgGfaUfgUfGfUfcUfgC 
                 1108 
                 A-128428.1 
                 asAfscGfcCfgCfaGfacaCfaU 
                 1327 
               
               
                   
                   
                 fgGfcGfuUfL96 
                   
                   
                 fcCfaAfcsgsa 
                   
               
               
                   
               
               
                 AD-64299.1 
                 A-128441.1 
                 UfsusCfaUfcCfuGfCfUfgCfuA 
                 1109 
                 A-128442.1 
                 usAfsgGfcAfuAfgCfagcAfgG 
                 1328 
               
               
                   
                   
                 fuGfcCfuAfL96 
                   
                   
                 faUfgAfasgsa 
                   
               
               
                   
               
               
                 AD-64300.1 
                 A-128371.1 
                 UfsusCfuUfgUfuGfAfCfaAfaA 
                 1110 
                 A-128372.1 
                 usAfsgGfaUfuUfuUfgucAfaC 
                 1329 
               
               
                   
                   
                 faUfcCfuAfL96 
                   
                   
                 faAfgAfasasa 
                   
               
               
                   
               
               
                 AD-64302.1 
                 A-128417.1 
                 UfsasUfaUfgGfaUfGfAfuGfuG 
                 1111 
                 A-128418.1 
                 usAfsaUfaCfcAfcAfucaUfcC 
                 1330 
               
               
                   
                   
                 fgUfaUfuAfL96 
                   
                   
                 faUfaUfasasc 
                   
               
               
                   
               
               
                 AD-64303.1 
                 A-128429.1 
                 UfsusCfaUfcCfuGfCfUfgCfuA 
                 1112 
                 A-128430.1 
                 gsAfsgGfcAfuAfgCfagcAfgG 
                 1331 
               
               
                   
                   
                 fuGfcCfuCfL96 
                   
                   
                 faUfgAfasgsa 
                   
               
               
                   
               
               
                 AD-64304.1 
                 A-128443.1 
                 GfsusGfcAfcUfuCfGfCfuUfcA 
                 1113 
                 A-128444.1 
                 usAfsgAfgGfuGfaAfgcgAfaG 
                 1332 
               
               
                   
                   
                 fcCfuCfuAfL96 
                   
                   
                 fuGfcAfcsasc 
                   
               
               
                   
               
               
                 AD-64305.1 
                 A-128373.1 
                 UfsusGfaCfaAfaAfAfUfcCfuC 
                 1114 
                 A-128374.1 
                 usAfsuUfgUfgAfgGfauuUfuU 
                 1333 
               
               
                   
                   
                 faCfaAfuAfL96 
                   
                   
                 fgUfcAfascsa 
                   
               
               
                   
               
               
                 AD-64307.1 
                 A-128403.1 
                 AfsasGfcCfuCfcAfAfGfcUfgU 
                 1115 
                 A-128404.1 
                 usAfsaGfgCfaCfaGfcuuGfgA 
                 1334 
               
               
                   
                   
                 fgCfcUfuAfL96 
                   
                   
                 fgGfcUfusgsa 
                   
               
               
                   
               
               
                 AD-64308.1 
                 A-128419.1 
                 CfscsUfcUfuCfaUfCfCfuGfcU 
                 1116 
                 A-128420.1 
                 usAfsuAfgCfaGfcAfggaUfgA 
                 1335 
               
               
                   
                   
                 fgCfuAfuAfL96 
                   
                   
                 faGfaGfgsasa 
                   
               
               
                   
               
               
                 AD-64309.1 
                 A-128431.1 
                 CfscsUfgCfuGfcUfAfUfgCfcU 
                 1117 
                 A-128432.1 
                 asAfsgAfuGfaGfgCfauaGfcA 
                 1336 
               
               
                   
                   
                 fcAfuCfuUfL96 
                   
                   
                 fgCfaGfgsasu 
                   
               
               
                   
               
               
                 AD-64310.1 
                 A-128375.1 
                 CfsasUfcUfuCfuUfGfUfuGfgU 
                 1118 
                 A-128376.1 
                 asGfsaAfgAfaCfcAfacaAfgA 
                 1337 
               
               
                   
                   
                 fuCfuUfcUfL96 
                   
                   
                 faGfaUfgsasg 
                   
               
               
                   
               
               
                 AD-64311.1 
                 A-128391.1 
                 CfscsGfuCfuGfuGfCfCfuUfcU 
                 1119 
                 A-128392.1 
                 usAfsgAfuGfaGfaAfggcAfcA 
                 1338 
               
               
                   
                   
                 fcAfuCfuAfL96 
                   
                   
                 fgAfcGfgsgsg 
                   
               
               
                   
               
               
                 AD-64312.1 
                 A-128405.1 
                 CfscsUfcAfuCfuUfCfUfuGfuU 
                 1120 
                 A-128406.1 
                 asGfsaAfcCfaAfcAfagaAfgA 
                 1339 
               
               
                   
                   
                 fgGfuUfcUfL96 
                   
                   
                 fuGfaGfgscsa 
                   
               
               
                   
               
               
                 AD-64313.1 
                 A-128421.1 
                 CfscsAfcCfaAfaUfGfCfcCfcU 
                 1121 
                 A-128422.1 
                 usAfsaGfaUfaGfgGfgcaUfuU 
                 1340 
               
               
                   
                   
                 faUfcUfuAfL96 
                   
                   
                 fgGfuGfgsusc 
                   
               
               
                   
               
               
                 AD-64314.1 
                 A-128433.1 
                 GfscsUfcCfuCfuGfCfCfgAfuC 
                 1122 
                 A-128434.1 
                 asGfsuAfuGfgAfuCfggcAfgA 
                 1341 
               
               
                   
                   
                 fcAfuAfcUfL96 
                   
                   
                 fgGfaGfcscsa 
                   
               
               
                   
               
               
                 AD-64315.1 
                 A-128363.2 
                 GfsusUfgAfcAfaAfAfAfuCfcU 
                 1123 
                 A-128445.1 
                 PasUfsuGfuGfaGfgAfuuuUfu 
                 1342 
               
               
                   
                   
                 fcAfcAfaUfL96 
                   
                   
                 GfuCfaAfcsasa 
                   
               
               
                   
               
               
                 AD-64316.1 
                 A-128377.2 
                 UfsgsUfuGfaCfaAfAfAfaUfcC 
                 1124 
                 A-128453.1 
                 PusUfsgUfgAfgGfaUfuuuUfg 
                 1343 
               
               
                   
                   
                 fuCfaCfaAfL96 
                   
                   
                 UfcAfaCfasasg 
                   
               
               
                   
               
               
                 AD-64317.1 
                 A-128393.2 
                 GfsgsUfgGfaCfuUfCfUfcUfcA 
                 1125 
                 A-128461.1 
                 PusAfsaAfaUfuGfaGfagaAfg 
                 1344 
               
               
                   
                   
                 faUfuUfuAfL96 
                   
                   
                 UfcCfaCfcsasc 
                   
               
               
                   
               
               
                 AD-64318.1 
                 A-128407.2 
                 UfscsUfuUfuGfgAfGfUfgUfgG 
                 1126 
                 A-128469.1 
                 PusCfsgAfaUfcCfaCfacuCfc 
                 1345 
               
               
                   
                   
                 faUfuCfgAfL96 
                   
                   
                 AfaAfaGfascsa 
                   
               
               
                   
               
               
                 AD-64318.1 
                 A-128407.2 
                 UfscsUfuUfuGfgAfGfUfgUfgG 
                 1127 
                 A-128469.1 
                 PusCfsgAfaUfcCfaCfacuCfc 
                 1346 
               
               
                   
                   
                 faUfuCfgAfL96 
                   
                   
                 AfaAfaGfascsa 
                   
               
               
                   
               
               
                 AD-64319.1 
                 A-128423.2 
                 AfscsUfgUfuCfaAfGfCfcUfcC 
                 1128 
                 A-128477.1 
                 PusAfsgCfuUfgGfaGfgcuUfg 
                 1347 
               
               
                   
                   
                 faAfgCfuAfL96 
                   
                   
                 AfaCfaAfgsasc 
                   
               
               
                   
               
               
                 AD-64320.1 
                 A-128435.2 
                 UfscsUfgCfcGfaUfCfCfaUfaC 
                 1129 
                 A-128483.1 
                 PusCfscGfcAfgUfaUfggaUfc 
                 1348 
               
               
                   
                   
                 fuGfcGfgAfL96 
                   
                   
                 GfgCfaGfasgsg 
                   
               
               
                   
               
               
                 AD-64321.1 
                 A-123463.3 
                 AfsgsUfuAfuAfuGfGfAfuGfaU 
                 1130 
                 A-128446.1 
                 PusAfscCfaCfaUfcAfuccAfu 
                 1349 
               
               
                   
                   
                 fgUfgGfuAfL96 
                   
                   
                 AfuAfaCfusgsa 
                   
               
               
                   
               
               
                 AD-64322.1 
                 A-128379.2 
                 AfsusGfuGfuCfuGfCfGfgCfgU 
                 1131 
                 A-128454.1 
                 PusAfsuAfaAfaCfgCfcgcAfg 
                 1350 
               
               
                   
                   
                 fuUfuAfuAfL96 
                   
                   
                 AfcAfcAfuscsc 
                   
               
               
                   
               
               
                 AD-64323.1 
                 A-128395.2 
                 CfscsCfcGfuCfuGfUfGfcCfuU 
                 1132 
                 A-128462.1 
                 PusAfsuGfaGfaAfgGfcacAfg 
                 1351 
               
               
                   
                   
                 fcUfcAfuAfL96 
                   
                   
                 AfcGfgGfgsasg 
                   
               
               
                   
               
               
                 AD-64324.1 
                 A-128409.2 
                 GfscsCfuAfaUfcAfUfCfuCfuU 
                 1133 
                 A-128470.1 
                 PasUfsgAfaCfaAfgAfgauGfa 
                 1352 
               
               
                   
                   
                 fgUfuCfaUfL96 
                   
                   
                 UfuAfgCfgsasg 
                   
               
               
                   
               
               
                 AD-64325.1 
                 A-128425.2 
                 UfscsUfaGfaCfuCfGfUfgGfuG 
                 1134 
                 A-128478.1 
                 PgsAfsaGfuCfcAfcCfacgAfg 
                 1353 
               
               
                   
                   
                 fgAfcUfuCfL96 
                   
                   
                 UfcUfaGfascsu 
                   
               
               
                   
               
               
                 AD-64326.1 
                 A-128437.2 
                 CfsusGfcCfgAfuCfCfAfuAfcU 
                 1135 
                 A-128484.1 
                 PusUfscCfgCfaGfuAfuggAfu 
                 1354 
               
               
                   
                   
                 fgCfgGfaAfL96 
                   
                   
                 CfgGfcAfgsasg 
                   
               
               
                   
               
               
                 AD-64328.1 
                 A-128381.2 
                 AfsusCfuUfcUfuGfUfUfgGfuU 
                 1136 
                 A-128455.1 
                 PusAfsgAfaGfaAfcCfaacAfa 
                 1355 
               
               
                   
                   
                 fcUfuCfuAfL96 
                   
                   
                 GfaAfgAfusgsa 
                   
               
               
                   
               
               
                 AD-64330.1 
                 A-128411.2 
                 UfsusCfuCfuCfaAfUfUfuUfcU 
                 1137 
                 A-128471.1 
                 PusCfscCfcUfaGfaAfaauUfg 
                 1356 
               
               
                   
                   
                 faGfgGfgAfL96 
                   
                   
                 AfgAfgAfasgsu 
                   
               
               
                   
               
               
                 AD-64331.1 
                 A-127905.16 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1138 
                 A-127907.2 
                 PusGfsaGfaGfaAfgUfccaCfc 
                 1357 
               
               
                   
                   
                 cfUfcUfcAfL96 
                   
                   
                 AfcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-64332.1 
                 A-128001.3 
                 GfsusGfcAfcUfuCfGfCfuUfcA 
                 1139 
                 A-128485.1 
                 PcsAfsgAfgGfuGfaAfgcgAfa 
                 1358 
               
               
                   
                   
                 fcCfuCfuGfL96 
                   
                   
                 GfuGfcAfcsasc 
                   
               
               
                   
               
               
                 AD-64333.1 
                 A-128367.2 
                 GfsusUfuUfuCfuUfGfUfuGfaC 
                 1140 
                 A-128448.1 
                 PasUfsuUfuUfgUfcAfacaAfg 
                 1359 
               
               
                   
                   
                 faAfaAfaUfL96 
                   
                   
                 AfaAfaAfcscsc 
                   
               
               
                   
               
               
                 AD-64334.1 
                 A-128383.2 
                 CfsusGfcCfuAfaUfCfAfuCfuC 
                 1141 
                 A-128456.1 
                 PusAfsaCfaAfgAfgAfugaUfu 
                 1360 
               
               
                   
                   
                 fuUfgUfuAfL96 
                   
                   
                 AfgGfcAfgsasg 
                   
               
               
                   
               
               
                 AD-64335.1 
                 A-128399.2 
                 UfscsCfuCfaCfaAfUfAfcCfaC 
                 1142 
                 A-128464.1 
                 PusAfscUfcUfgUfgGfuauUfg 
                 1361 
               
               
                   
                   
                 faGfaGfuAfL96 
                   
                   
                 UfgAfgGfasusu 
                   
               
               
                   
               
               
                 AD-64336.1 
                 A-128413.2 
                 CfsusUfgUfuGfaCfAfAfaAfaU 
                 1143 
                 A-128472.1 
                 PusUfsgAfgGfaUfuUfuugUfc 
                 1362 
               
               
                   
                   
                 fcCfuCfaAfL96 
                   
                   
                 AfaCfaAfgsasa 
                   
               
               
                   
               
               
                 AD-64337.1 
                 A-127955.16 
                 GfsusGfgUfgGfaCfUfUfcUfcU 
                 1144 
                 A-127958.2 
                 PasAfsaUfuGfaGfaGfaagUfc 
                 1363 
               
               
                   
                   
                 fcAfaUfuUfL96 
                   
                   
                 CfaCfcAfcsgsa 
                   
               
               
                   
               
               
                 AD-64338.1 
                 A-128439.2 
                 GfscsAfaCfuUfuUfUfCfaCfcU 
                 1145 
                 A-128486.1 
                 PasGfsgCfaGfaGfgUfgaaAfa 
                 1364 
               
               
                   
                   
                 fcUfgCfcUfL96 
                   
                   
                 AfgUfuGfcsasu 
                   
               
               
                   
               
               
                 AD-64339.1 
                 A-128369.2 
                 GfsgsGfaAfcAfaGfAfGfcUfaC 
                 1146 
                 A-128449.1 
                 PusAfsuGfcUfgUfaGfcucUfu 
                 1365 
               
               
                   
                   
                 faGfcAfuAfL96 
                   
                   
                 GfuUfcCfcsasa 
                   
               
               
                   
               
               
                 AD-64341.1 
                 A-128401.2 
                 UfscsAfuCfuUfcUfUfGfuUfgG 
                 1147 
                 A-128465.1 
                 PusAfsaGfaAfcCfaAfcaaGfa 
                 1366 
               
               
                   
                   
                 fuUfcUfuAfL96 
                   
                   
                 AfgAfuGfasgsg 
                   
               
               
                   
               
               
                 AD-64342.1 
                 A-128415.2 
                 CfsusGfcUfgCfuAfUfGfcCfuC 
                 1148 
                 A-128473.1 
                 PusAfsaGfaUfgAfgGfcauAfg 
                 1367 
               
               
                   
                   
                 faUfcUfuAfL96 
                   
                   
                 CfaGfcAfgsgsa 
                   
               
               
                   
               
               
                 AD-64343.1 
                 A-128427.2 
                 GfsusUfgGfaUfgUfGfUfcUfgC 
                 1149 
                 A-128479.1 
                 PasAfscGfcCfgCfaGfacaCfa 
                 1368 
               
               
                   
                   
                 fgGfcGfuUfL96 
                   
                   
                 UfcCfaAfcsgsa 
                   
               
               
                   
               
               
                 AD-64344.1 
                 A-128441.2 
                 UfsusCfaUfcCfuGfCfUfgCfuA 
                 1150 
                 A-128487.1 
                 PusAfsgGfcAfuAfgCfagcAfg 
                 1369 
               
               
                   
                   
                 fuGfcCfuAfL96 
                   
                   
                 GfaUfgAfasgsa 
                   
               
               
                   
               
               
                 AD-64345.1 
                 A-128371.2 
                 UfsusCfuUfgUfuGfAfCfaAfaA 
                 1151 
                 A-128450.1 
                 PusAfsgGfaUfuUfuUfgucAfa 
                 1370 
               
               
                   
                   
                 faUfcCfuAfL96 
                   
                   
                 CfaAfgAfasasa 
                   
               
               
                   
               
               
                 AD-64347.1 
                 A-123487.3 
                 GfsgsAfuGfuGfuCfUfGfcGfgC 
                 1152 
                 A-128466.1 
                 PusAfsaAfaCfgCfcGfcagAfc 
                 1371 
               
               
                   
                   
                 fgUfuUfuAfL96 
                   
                   
                 AfcAfuCfcsasg 
                   
               
               
                   
               
               
                 AD-64348.1 
                 A-128417.2 
                 UfsasUfaUfgGfaUfGfAfuGfuG 
                 1153 
                 A-128474.1 
                 PusAfsaUfaCfcAfcAfucaUfc 
                 1372 
               
               
                   
                   
                 fgUfaUfuAfL96 
                   
                   
                 CfaUfaUfasasc 
                   
               
               
                   
               
               
                 AD-64349.1 
                 A-128429.2 
                 UfsusCfaUfcCfuGfCfUfgCfuA 
                 1154 
                 A-128480.1 
                 PgsAfsgGfcAfuAfgCfagcAfg 
                 1373 
               
               
                   
                   
                 fuGfcCfuCfL96 
                   
                   
                 GfaUfgAfasgsa 
                   
               
               
                   
               
               
                 AD-64350.1 
                 A-128443.2 
                 GfsusGfcAfcUfuCfGfCfuUfcA 
                 1155 
                 A-128488.1 
                 PusAfsgAfgGfuGfaAfgcgAfa 
                 1374 
               
               
                   
                   
                 fcCfuCfuAfL96 
                   
                   
                 GfuGfcAfcsasc 
                   
               
               
                   
               
               
                 AD-64351.1 
                 A-128373.2 
                 UfsusGfaCfaAfaAfAfUfcCfuC 
                 1156 
                 A-128451.1 
                 PusAfsuUfgUfgAfgGfauuUfu 
                 1375 
               
               
                   
                   
                 faCfaAfuAfL96 
                   
                   
                 UfgUfcAfascsa 
                   
               
               
                   
               
               
                 AD-64352.1 
                 A-128389.2 
                 CfscsAfaGfuGfuUfUfGfcUfgA 
                 1157 
                 A-128459.1 
                 PusUfsuGfcGfuCfaGfcaaAfc 
                 1376 
               
               
                   
                   
                 fcGfcAfaAfL96 
                   
                   
                 AfcUfuGfgscsa 
                   
               
               
                   
               
               
                 AD-64352.1 
                 A-128389.2 
                 CfscsAfaGfuGfuUfUfGfcUfgA 
                 1158 
                 A-128459.1 
                 PusUfsuGfcGfuCfaGfcaaAfc 
                 1377 
               
               
                   
                   
                 fcGfcAfaAfL96 
                   
                   
                 AfcUfuGfgscsa 
                   
               
               
                   
               
               
                 AD-64353.1 
                 A-128403.2 
                 AfsasGfcCfuCfcAfAfGfcUfgU 
                 1159 
                 A-128467.1 
                 PusAfsaGfgCfaCfaGfcuuGfg 
                 1378 
               
               
                   
                   
                 fgCfcUfuAfL96 
                   
                   
                 AfgGfcUfusgsa 
                   
               
               
                   
               
               
                 AD-64354.1 
                 A-128419.2 
                 CfscsUfcUfuCfaUfCfCfuGfcU 
                 1160 
                 A-128475.1 
                 PusAfsuAfgCfaGfcAfggaUfg 
                 1379 
               
               
                   
                   
                 fgCfuAfuAfL96 
                   
                   
                 AfaGfaGfgsasa 
                   
               
               
                   
               
               
                 AD-64355.1 
                 A-128431.2 
                 CfscsUfgCfuGfcUfAfUfgCfcU 
                 1161 
                 A-128481.1 
                 PasAfsgAfuGfaGfgCfauaGfc 
                 1380 
               
               
                   
                   
                 fcAfuCfuUfL96 
                   
                   
                 AfgCfaGfgsasu 
                   
               
               
                   
               
               
                 AD-64356.1 
                 A-128375.2 
                 CfsasUfcUfuCfuUfGfUfuGfgU 
                 1162 
                 A-128452.1 
                 PasGfsaAfgAfaCfcAfacaAfg 
                 1381 
               
               
                   
                   
                 fuCfuUfcUfL96 
                   
                   
                 AfaGfaUfgsasg 
                   
               
               
                   
               
               
                 AD-64357.1 
                 A-128391.2 
                 CfscsGfuCfuGfuGfCfCfuUfcU 
                 1163 
                 A-128460.1 
                 PusAfsgAfuGfaGfaAfggcAfc 
                 1382 
               
               
                   
                   
                 fcAfuCfuAfL96 
                   
                   
                 AfgAfcGfgsgsg 
                   
               
               
                   
               
               
                 AD-64358.1 
                 A-128405.2 
                 CfscsUfcAfuCfuUTCfUfuGfuU 
                 1164 
                 A-128468.1 
                 PasGfsaAfcCfaAfcAfagaAfg 
                 1383 
               
               
                   
                   
                 fgGfuUfcUfL96 
                   
                   
                 AfuGfaGfgscsa 
                   
               
               
                   
               
               
                 AD-64359.1 
                 A-128421.2 
                 CfscsAfcCfaAfaUfGfCfcCfcU 
                 1165 
                 A-128476.1 
                 PusAfsaGfaUfaGfgGfgcaUfu 
                 1384 
               
               
                   
                   
                 faUfcUfuAfL96 
                   
                   
                 UfgGfuGfgsusc 
                   
               
               
                   
               
               
                 AD-64360.1 
                 A-128433.2 
                 GfscsUfcCfuCfuGfCfCfgAfuC 
                 1166 
                 A-128482.1 
                 PasGfsuAfuGfgAfuCfggcAfg 
                 1385 
               
               
                   
                   
                 fcAfuAfcUfL96 
                   
                   
                 AfgGfaGfcscsa 
                   
               
               
                   
               
               
                 AD-64700.1 
                 A-129379.1 
                 ascsucguggugdTacuu(Cgn)uc 
                 1167 
                 A-127906.26 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1386 
               
               
                   
                   
                 ucaL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-64701.1 
                 A-127905.20 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1168 
                 A-129387.1 
                 PusgsagagaagdTccadCcacga 
                 1387 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64702.1 
                 A-127905.28 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1169 
                 A-129395.1 
                 usGsagadGaaguccaCcacgagu 
                 1388 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 scsu 
                   
               
               
                   
               
               
                 AD-64703.1 
                 A-129376.2 
                 ascsucguggugdGacuucdAcuca 
                 1170 
                 A-129385.5 
                 usdGsagagaagdTccadCcacga 
                 1389 
               
               
                   
                   
                 L96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64704.1 
                 A-129381.3 
                 ascsucguggdTgdTacuucdAcuc 
                 1171 
                 A-129389.6 
                 usdGsagadGaaguccadCcacga 
                 1390 
               
               
                   
                   
                 aL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64705.1 
                 A-129380.1 
                 ascsucguggugdTacuucdAcuca 
                 1172 
                 A-127906.27 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1391 
               
               
                   
                   
                 L96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-64706.1 
                 A-127905.21 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1173 
                 A-129388.1 
                 usdGsadGagaaguccadCcacga 
                 1392 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64707.1 
                 A-127905.29 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1174 
                 A-129396.1 
                 usgsagadGaagdTccadCcacga 
                 1393 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64708.1 
                 A-129382.2 
                 ascsucguggdTgdGacuuc(Tgn) 
                 1175 
                 A-129385.6 
                 usdGsagagaagdTccadCcacga 
                 1394 
               
               
                   
                   
                 cucaL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64709.1 
                 A-129373.4 
                 ascsucguggugdGacuu(Cgn)uc 
                 1176 
                 A-129391.2 
                 usdGsagadGaagdTccadCcacg 
                 1395 
               
               
                   
                   
                 ucaL96 
                   
                   
                 aguscsu 
                   
               
               
                   
               
               
                 AD-64710.1 
                 A-129373.1 
                 ascsucguggugdGacuu(Cgn)uc 
                 1177 
                 A-127906.20 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1396 
               
               
                   
                   
                 ucaL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-64711.1 
                 A-129381.1 
                 ascsucguggdTgdTacuucdAcuc 
                 1178 
                 A-127906.28 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1397 
               
               
                   
                   
                 aL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-64712.1 
                 A-127905.22 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1179 
                 A-129389.1 
                 usdGsagadGaaguccadCcacga 
                 1398 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64713.1 
                 A-127905.30 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1180 
                 A-129397.1 
                 PusgsagadGaagdTccadCcacg 
                 1399 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 aguscsu 
                   
               
               
                   
               
               
                 AD-64714.1 
                 A-129384.2 
                 ascsucguggdTgdGacuucdAcuc 
                 1181 
                 A-129385.7 
                 usdGsagagaagdTccadCcacga 
                 1400 
               
               
                   
                   
                 aL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64715.1 
                 A-129376.4 
                 ascsucguggugdGacuucdAcuca 
                 1182 
                 A-129391.3 
                 usdGsagadGaagdTccadCcacg 
                 1401 
               
               
                   
                   
                 L96 
                   
                   
                 aguscsu 
                   
               
               
                   
               
               
                 AD-64716.1 
                 A-129374.1 
                 ascsucguggugdGacuucu(Cgn) 
                 1183 
                 A-127906.21 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1402 
               
               
                   
                   
                 ucaL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-64717.1 
                 A-129382.1 
                 ascsucguggdTgdGacuuc(Tgn) 
                 1184 
                 A-127906.29 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1403 
               
               
                   
                   
                 cucaL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-64718.1 
                 A-127905.23 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1185 
                 A-129390.1 
                 usdGsagagadAguccadCcacga 
                 1404 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64719.1 
                 A-127917.5 
                 ascsucguggugdGacuuc(Tgn)c 
                 1186 
                 A-129385.2 
                 usdGsagagaagdTccadCcacga 
                 1405 
               
               
                   
                   
                 ucaL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64720.1 
                 A-129381.2 
                 ascsucguggdTgdTacuucdAcuc 
                 1187 
                 A-129385.8 
                 usdGsagagaagdTccadCcacga 
                 1406 
               
               
                   
                   
                 aL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64721.1 
                 A-129382.4 
                 ascsucguggdTgdGacuuc(Tgn) 
                 1188 
                 A-129391.4 
                 usdGsagadGaagdTccadCcacg 
                 1407 
               
               
                   
                   
                 cucaL96 
                   
                   
                 aguscsu 
                   
               
               
                   
               
               
                 AD-64722.1 
                 A-129375.1 
                 ascsucguggugdGacuucY34cuc 
                 1189 
                 A-127906.22 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1408 
               
               
                   
                   
                 aL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-64723.1 
                 A-129383.1 
                 ascsucguggugdGdAcuuc(Tgn) 
                 1190 
                 A-127906.30 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1409 
               
               
                   
                   
                 cucaL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-64725.1 
                 A-127917.6 
                 ascsucguggugdGacuuc(Tgn)c 
                 1191 
                 A-129398.1 
                 PusdGsagagaagdTccadCcacg 
                 1410 
               
               
                   
                   
                 ucaL96 
                   
                   
                 aguscsu 
                   
               
               
                   
               
               
                 AD-64726.1 
                 A-129373.3 
                 ascsucguggugdGacuu(Cgn)uc 
                 1192 
                 A-129389.2 
                 usdGsagadGaaguccadCcacga 
                 1411 
               
               
                   
                   
                 ucaL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64727.1 
                 A-129384.4 
                 ascsucguggdTgdGacuucdAcuc 
                 1193 
                 A-129391.5 
                 usdGsagadGaagdTccadCcacg 
                 1412 
               
               
                   
                   
                 aL96 
                   
                   
                 aguscsu 
                   
               
               
                   
               
               
                 AD-64728.1 
                 A-129376.1 
                 ascsucguggugdGacuucdAcuca 
                 1194 
                 A-127906.23 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1413 
               
               
                   
                   
                 L96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-64729.1 
                 A-129384.1 
                 ascsucguggdTgdGacuucdAcuc 
                 1195 
                 A-127906.31 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1414 
               
               
                   
                   
                 aL96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-64730.1 
                 A-127905.25 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1196 
                 A-129392.1 
                 usGsagagaagdTccadCcacgag 
                 1415 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 uscsu 
                   
               
               
                   
               
               
                 AD-64731.1 
                 A-129399.1 
                 Y34ascsucguggugdGacuuc 
                 1197 
                 A-129385.3 
                 usdGsagagaagdTccadCcacga 
                 1416 
               
               
                   
                   
                 (Tgn)cucaL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64732.1 
                 A-129376.3 
                 ascsucguggugdGacuucdAcuca 
                 1198 
                 A-129389.3 
                 usdGsagadGaaguccadCcacga 
                 1417 
               
               
                   
                   
                 L96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64733.1 
                 A-129381.4 
                 ascsucguggdTgdTacuucdAcuc 
                 1199 
                 A-129391.6 
                 usdGsagadGaagdTccadCcacg 
                 1418 
               
               
                   
                   
                 aL96 
                   
                   
                 aguscsu 
                   
               
               
                   
               
               
                 AD-64734.1 
                 A-129377.1 
                 ascsucguggugdGacuucdCcuca 
                 1200 
                 A-127906.24 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1419 
               
               
                   
                   
                 L96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-64735.1 
                 A-127905.18 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1201 
                 A-129385.1 
                 usdGsagagaagdTccadCcacga 
                 1420 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64736.1 
                 A-127905.26 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1202 
                 A-129393.1 
                 usdGsagagaagdTccaCcacgag 
                 1421 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 uscsu 
                   
               
               
                   
               
               
                 AD-64737.1 
                 A-129399.2 
                 Y34ascsucguggugdGacuuc 
                 1203 
                 A-129398.2 
                 PusdGsagagaagdTccadCcacg 
                 1422 
               
               
                   
                   
                 (Tgn)cucaL96 
                   
                   
                 aguscsu 
                   
               
               
                   
               
               
                 AD-64738.1 
                 A-129382.3 
                 ascsucguggdTgdGacuuc(Tgn) 
                 1204 
                 A-129389.4 
                 usdGsagadGaaguccadCcacga 
                 1423 
               
               
                   
                   
                 cucaL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64739.1 
                 A-129378.1 
                 ascsucguggugdGacuucdGcuca 
                 1205 
                 A-127906.25 
                 usGfsaGfaGfaAfgUfccaCfcA 
                 1424 
               
               
                   
                   
                 L96 
                   
                   
                 fcGfaGfuscsu 
                   
               
               
                   
               
               
                 AD-64740.1 
                 A-127905.19 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1206 
                 A-129386.1 
                 usgsagagaagdTccadCcacgag 
                 1425 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 uscsu 
                   
               
               
                   
               
               
                 AD-64741.1 
                 A-127905.27 
                 AfscsUfcGfuGfgUfGfGfaCfuU 
                 1207 
                 A-129394.1 
                 usGsagagaagdTccaCcacgagu 
                 1426 
               
               
                   
                   
                 fcUfcUfcAfL96 
                   
                   
                 scsu 
                   
               
               
                   
               
               
                 AD-64742.1 
                 A-129373.2 
                 ascsucguggugdGacuu(Cgn)uc 
                 1208 
                 A-129385.4 
                 usdGsagagaagdTccadCcacga 
                 1427 
               
               
                   
                   
                 ucaL96 
                   
                   
                 guscsu 
                   
               
               
                   
               
               
                 AD-64743.1 
                 A-129384.3 
                 ascsucguggdTgdGacuucdAcuc 
                 1209 
                 A-129389.5 
                 usdGsagadGaaguccadCcacga 
                 1428 
               
               
                   
                   
                 aL96 
                   
                   
                 guscsu 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 HBV single dose screen using Dual-Glo Luciferase ® Assay 
               
            
           
           
               
               
               
               
               
            
               
                 Duplex ID 
                 10 nM Avg 
                 0.1 nM Avg 
                 10 nM SD 
                 0.1 nM_SD 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 AD-63938.2 
                 0.12 
                 ND 
                 0.01 
                 ND 
               
               
                 AD-63950.2 
                 0.38 
                 ND 
                 0.04 
                 ND 
               
               
                 AD-63956.2 
                 0.31 
                 ND 
                 0.02 
                 ND 
               
               
                 AD-63962.2 
                 0.16 
                 ND 
                 0.03 
                 ND 
               
               
                 AD-63968.2 
                 0.56 
                 ND 
                 0.10 
                 ND 
               
               
                 AD-63968.2 
                 0.79 
                 ND 
                 0.09 
                 ND 
               
               
                 AD-63979.2 
                 0.54 
                 ND 
                 0.02 
                 ND 
               
               
                 AD-63939.2 
                 0.51 
                 ND 
                 0.01 
                 ND 
               
               
                 AD-63945.2 
                 0.54 
                 ND 
                 0.08 
                 ND 
               
               
                 AD-63951.2 
                 0.60 
                 ND 
                 0.03 
                 ND 
               
               
                 AD-63957.2 
                 0.57 
                 ND 
                 0.02 
                 ND 
               
               
                 AD-63963.2 
                 0.91 
                 ND 
                 0.06 
                 ND 
               
               
                 AD-63969.2 
                 0.92 
                 ND 
                 0.02 
                 ND 
               
               
                 AD-63975.2 
                 0.83 
                 ND 
                 0.01 
                 ND 
               
               
                 AD-63980.2 
                 0.77 
                 ND 
                 0.01 
                 ND 
               
               
                 AD-63940.2 
                 0.77 
                 ND 
                 0.06 
                 ND 
               
               
                 AD-63946.2 
                 0.60 
                 ND 
                 0.10 
                 ND 
               
               
                 AD-63952.2 
                 0.48 
                 ND 
                 0.04 
                 ND 
               
               
                 AD-63958.2 
                 0.51 
                 ND 
                 0.01 
                 ND 
               
               
                 AD-63964.2 
                 0.58 
                 ND 
                 0.04 
                 ND 
               
               
                 AD-63970.2 
                 0.69 
                 ND 
                 0.07 
                 ND 
               
               
                 AD-63976.2 
                 0.63 
                 ND 
                 0.04 
                 ND 
               
               
                 AD-63981.2 
                 0.60 
                 ND 
                 0.04 
                 ND 
               
               
                 AD-63941.2 
                 0.56 
                 ND 
                 0.09 
                 ND 
               
               
                 AD-63947.2 
                 0.55 
                 ND 
                 0.08 
                 ND 
               
               
                 AD-63953.2 
                 0.56 
                 ND 
                 0.06 
                 ND 
               
               
                 AD-63959.2 
                 0.51 
                 ND 
                 0.03 
                 ND 
               
               
                 AD-63965.2 
                 0.55 
                 ND 
                 0.03 
                 ND 
               
               
                 AD-63971.2 
                 0.65 
                 ND 
                 0.02 
                 ND 
               
               
                 AD-63977.2 
                 0.88 
                 ND 
                 0.01 
                 ND 
               
               
                 AD-63982.2 
                 0.73 
                 ND 
                 0.07 
                 ND 
               
               
                 AD-63942.2 
                 0.32 
                 ND 
                 0.09 
                 ND 
               
               
                 AD-63948.2 
                 0.57 
                 ND 
                 0.09 
                 ND 
               
               
                 AD-63960.2 
                 0.92 
                 ND 
                 0.05 
                 ND 
               
               
                 AD-63966.2 
                 0.85 
                 ND 
                 0.06 
                 ND 
               
               
                 AD-63972.2 
                 0.82 
                 ND 
                 0.06 
                 ND 
               
               
                 AD-63978.2 
                 0.83 
                 ND 
                 0.02 
                 ND 
               
               
                 AD-63983.2 
                 0.89 
                 ND 
                 0.02 
                 ND 
               
               
                 AD-63943.2 
                 0.86 
                 ND 
                 0.04 
                 ND 
               
               
                 AD-63949.2 
                 0.76 
                 ND 
                 0.02 
                 ND 
               
               
                 AD-63955.2 
                 0.82 
                 ND 
                 0.02 
                 ND 
               
               
                 AD-63961.2 
                 0.83 
                 ND 
                 0.07 
                 ND 
               
               
                 AD-63967.2 
                 0.86 
                 ND 
                 0.03 
                 ND 
               
               
                 AD-63973.2 
                 0.86 
                 ND 
                 0.03 
                 ND 
               
               
                 AD-63990.2 
                 0.27 
                 ND 
                 0.07 
                 ND 
               
               
                 AD-63996.2 
                 0.29 
                 ND 
                 0.06 
                 ND 
               
               
                 AD-64002.2 
                 0.30 
                 ND 
                 0.11 
                 ND 
               
               
                 AD-64008.2 
                 0.28 
                 ND 
                 0.05 
                 ND 
               
               
                 AD-64008.2 
                 0.34 
                 ND 
                 0.07 
                 ND 
               
               
                 AD-64014.2 
                 0.30 
                 ND 
                 0.03 
                 ND 
               
               
                 AD-64019.2 
                 0.36 
                 ND 
                 0.04 
                 ND 
               
               
                 AD-64024.2 
                 0.27 
                 ND 
                 0.03 
                 ND 
               
               
                 AD-63985.2 
                 0.28 
                 ND 
                 0.06 
                 ND 
               
               
                 AD-63991.2 
                 0.33 
                 ND 
                 0.02 
                 ND 
               
               
                 AD-63997.2 
                 0.47 
                 ND 
                 0.07 
                 ND 
               
               
                 AD-64003.2 
                 0.69 
                 ND 
                 0.06 
                 ND 
               
               
                 AD-64009.2 
                 0.91 
                 ND 
                 0.03 
                 ND 
               
               
                 AD-64015.2 
                 0.69 
                 ND 
                 0.09 
                 ND 
               
               
                 AD-64020.2 
                 0.81 
                 ND 
                 0.06 
                 ND 
               
               
                 AD-64025.2 
                 0.77 
                 ND 
                 0.06 
                 ND 
               
               
                 AD-63986.2 
                 0.28 
                 ND 
                 0.05 
                 ND 
               
               
                 AD-63992.2 
                 0.44 
                 ND 
                 0.04 
                 ND 
               
               
                 AD-64004.2 
                 0.45 
                 ND 
                 0.04 
                 ND 
               
               
                 AD-64010.2 
                 0.37 
                 ND 
                 0.05 
                 ND 
               
               
                 AD-64016.2 
                 0.48 
                 ND 
                 0.05 
                 ND 
               
               
                 AD-64021.2 
                 0.39 
                 ND 
                 0.03 
                 ND 
               
               
                 AD-64026.2 
                 0.30 
                 ND 
                 0.02 
                 ND 
               
               
                 AD-63987.2 
                 0.20 
                 ND 
                 0.02 
                 ND 
               
               
                 AD-63993.2 
                 0.33 
                 ND 
                 0.02 
                 ND 
               
               
                 AD-63999.2 
                 0.36 
                 ND 
                 0.05 
                 ND 
               
               
                 AD-64005.2 
                 0.45 
                 ND 
                 0.11 
                 ND 
               
               
                 AD-64011.2 
                 0.39 
                 ND 
                 0.08 
                 ND 
               
               
                 AD-64017.2 
                 0.84 
                 ND 
                 0.06 
                 ND 
               
               
                 AD-64022.2 
                 0.81 
                 ND 
                 0.03 
                 ND 
               
               
                 AD-64027.2 
                 0.38 
                 ND 
                 0.05 
                 ND 
               
               
                 AD-63988.2 
                 0.37 
                 ND 
                 0.04 
                 ND 
               
               
                 AD-63994.2 
                 0.23 
                 ND 
                 0.01 
                 ND 
               
               
                 AD-64000.2 
                 0.29 
                 ND 
                 0.00 
                 ND 
               
               
                 AD-64006.2 
                 0.40 
                 ND 
                 0.04 
                 ND 
               
               
                 AD-64012.2 
                 0.45 
                 ND 
                 0.17 
                 ND 
               
               
                 AD-64018.2 
                 0.65 
                 ND 
                 0.07 
                 ND 
               
               
                 AD-64023.2 
                 0.53 
                 ND 
                 0.07 
                 ND 
               
               
                 AD-64028.2 
                 0.52 
                 ND 
                 0.07 
                 ND 
               
               
                 AD-63989.2 
                 0.47 
                 ND 
                 0.04 
                 ND 
               
               
                 AD-63995.2 
                 0.81 
                 ND 
                 0.03 
                 ND 
               
               
                 AD-64001.2 
                 0.83 
                 ND 
                 0.04 
                 ND 
               
               
                 AD-64007.2 
                 0.87 
                 ND 
                 0.04 
                 ND 
               
               
                 AD-64013.2 
                 0.88 
                 ND 
                 0.03 
                 ND 
               
               
                 AD-64289.1 
                 0.276 
                 ND 
                 0.009 
                 ND 
               
               
                 AD-64333.1 
                 0.208 
                 ND 
                 0.015 
                 ND 
               
               
                 AD-64285.1 
                 0.324 
                 ND 
                 0.034 
                 ND 
               
               
                 AD-64300.1 
                 0.225 
                 ND 
                 0.005 
                 ND 
               
               
                 AD-64345.1 
                 0.102 
                 ND 
                 0.090 
                 ND 
               
               
                 AD-64292.1 
                 0.288 
                 ND 
                 0.232 
                 ND 
               
               
                 AD-64336.1 
                 0.199 
                 ND 
                 0.056 
                 ND 
               
               
                 AD-64275.1 
                 0.287 
                 ND 
                 0.185 
                 ND 
               
               
                 AD-64316.1 
                 0.297 
                 ND 
                 0.024 
                 ND 
               
               
                 AD-64274.1 
                 0.209 
                 ND 
                 0.033 
                 ND 
               
               
                 AD-64315.1 
                 0.199 
                 ND 
                 0.002 
                 ND 
               
               
                 AD-64305.1 
                 0.360 
                 ND 
                 0.035 
                 ND 
               
               
                 AD-64351.1 
                 0.281 
                 ND 
                 0.014 
                 ND 
               
               
                 AD-64291.1 
                 0.725 
                 ND 
                 0.005 
                 ND 
               
               
                 AD-64335.1 
                 0.478 
                 ND 
                 0.020 
                 ND 
               
               
                 AD-64283.1 
                 0.917 
                 ND 
                 0.018 
                 ND 
               
               
                 AD-64304.1 
                 0.937 
                 ND 
                 0.050 
                 ND 
               
               
                 AD-64325.1 
                 0.446 
                 ND 
                 0.223 
                 ND 
               
               
                 AD-64350.1 
                 0.934 
                 ND 
                 0.055 
                 ND 
               
               
                 AD-63968.4 
                 0.748 
                 ND 
                 0.008 
                 ND 
               
               
                 AD-64331.1 
                 0.294 
                 ND 
                 0.038 
                 ND 
               
               
                 AD-64008.4 
                 0.416 
                 ND 
                 0.028 
                 ND 
               
               
                 AD-64337.1 
                 0.318 
                 ND 
                 0.049 
                 ND 
               
               
                 AD-64295.1 
                 0.415 
                 ND 
                 0.034 
                 ND 
               
               
                 AD-64276.1 
                 0.453 
                 ND 
                 0.073 
                 ND 
               
               
                 AD-64317.1 
                 0.203 
                 ND 
                 0.040 
                 ND 
               
               
                 AD-64330.1 
                 0.313 
                 ND 
                 0.030 
                 ND 
               
               
                 AD-64298.1 
                 0.797 
                 ND 
                 0.007 
                 ND 
               
               
                 AD-64343.1 
                 0.667 
                 ND 
                 0.020 
                 ND 
               
               
                 AD-61547.2 
                 0.637 
                 ND 
                 0.019 
                 ND 
               
               
                 AD-64347.1 
                 0.418 
                 ND 
                 0.066 
                 ND 
               
               
                 AD-64280.1 
                 0.754 
                 ND 
                 0.092 
                 ND 
               
               
                 AD-64322.1 
                 0.407 
                 ND 
                 0.013 
                 ND 
               
               
                 AD-64308.1 
                 0.720 
                 ND 
                 0.055 
                 ND 
               
               
                 AD-64354.1 
                 0.315 
                 ND 
                 0.034 
                 ND 
               
               
                 AD-64303.1 
                 0.815 
                 ND 
                 0.150 
                 ND 
               
               
                 AD-64349.1 
                 0.447 
                 ND 
                 0.030 
                 ND 
               
               
                 AD-64299.1 
                 0.831 
                 ND 
                 0.007 
                 ND 
               
               
                 AD-64344.1 
                 0.404 
                 ND 
                 0.009 
                 ND 
               
               
                 AD-64309.1 
                 0.856 
                 ND 
                 0.005 
                 ND 
               
               
                 AD-64355.1 
                 0.498 
                 ND 
                 0.040 
                 ND 
               
               
                 AD-64297.1 
                 0.895 
                 ND 
                 0.024 
                 ND 
               
               
                 AD-64342.1 
                 0.508 
                 ND 
                 0.006 
                 ND 
               
               
                 AD-64312.1 
                 0.590 
                 ND 
                 0.034 
                 ND 
               
               
                 AD-64358.1 
                 0.425 
                 ND 
                 0.044 
                 ND 
               
               
                 AD-64341.1 
                 0.223 
                 ND 
                 0.119 
                 ND 
               
               
                 AD-64310.1 
                 0.301 
                 ND 
                 0.064 
                 ND 
               
               
                 AD-64356.1 
                 0.336 
                 ND 
                 0.024 
                 ND 
               
               
                 AD-64286.1 
                 0.611 
                 ND 
                 0.012 
                 ND 
               
               
                 AD-64328.1 
                 0.317 
                 ND 
                 0.043 
                 ND 
               
               
                 AD-61522.2 
                 0.447 
                 ND 
                 0.008 
                 ND 
               
               
                 AD-64321.1 
                 0.237 
                 ND 
                 0.009 
                 ND 
               
               
                 AD-64302.1 
                 0.523 
                 ND 
                 0.020 
                 ND 
               
               
                 AD-64348.1 
                 0.208 
                 ND 
                 0.003 
                 ND 
               
               
                 AD-64352.1 
                 0.343 
                 ND 
                 0.224 
                 ND 
               
               
                 AD-64352.1 
                 0.567 
                 ND 
                 0.015 
                 ND 
               
               
                 AD-64314.1 
                 0.920 
                 ND 
                 0.044 
                 ND 
               
               
                 AD-64360.1 
                 0.778 
                 ND 
                 0.029 
                 ND 
               
               
                 AD-64279.1 
                 0.882 
                 ND 
                 0.034 
                 ND 
               
               
                 AD-64320.1 
                 0.589 
                 ND 
                 0.017 
                 ND 
               
               
                 AD-64284.1 
                 0.696 
                 ND 
                 0.119 
                 ND 
               
               
                 AD-64326.1 
                 0.552 
                 ND 
                 0.009 
                 ND 
               
               
                 AD-64281.1 
                 0.921 
                 ND 
                 0.019 
                 ND 
               
               
                 AD-64323.1 
                 0.715 
                 ND 
                 0.097 
                 ND 
               
               
                 AD-64311.1 
                 0.815 
                 ND 
                 0.030 
                 ND 
               
               
                 AD-64357.1 
                 0.549 
                 ND 
                 0.001 
                 ND 
               
               
                 AD-64272.2 
                 0.965 
                 ND 
                 0.024 
                 ND 
               
               
                 AD-64332.1 
                 0.548 
                 ND 
                 0.013 
                 ND 
               
               
                 AD-64293.1 
                 0.837 
                 ND 
                 0.013 
                 ND 
               
               
                 AD-64338.1 
                 0.597 
                 ND 
                 0.031 
                 ND 
               
               
                 AD-64290.1 
                 0.489 
                 ND 
                 0.026 
                 ND 
               
               
                 AD-64334.1 
                 0.368 
                 ND 
                 0.003 
                 ND 
               
               
                 AD-64282.1 
                 0.767 
                 ND 
                 0.009 
                 ND 
               
               
                 AD-64324.1 
                 0.726 
                 ND 
                 0.077 
                 ND 
               
               
                 AD-64278.1 
                 0.951 
                 ND 
                 0.077 
                 ND 
               
               
                 AD-64319.1 
                 0.895 
                 ND 
                 0.029 
                 ND 
               
               
                 AD-64307.1 
                 0.890 
                 ND 
                 0.065 
                 ND 
               
               
                 AD-64353.1 
                 0.567 
                 ND 
                 0.500 
                 ND 
               
               
                 AD-64277.1 
                 0.416 
                 ND 
                 0.019 
                 ND 
               
               
                 AD-64277.1 
                 0.839 
                 ND 
                 0.058 
                 ND 
               
               
                 AD-64318.1 
                 0.613 
                 ND 
                 0.042 
                 ND 
               
               
                 AD-64318.1 
                 0.768 
                 ND 
                 0.042 
                 ND 
               
               
                 AD-64313.1 
                 0.698 
                 ND 
                 0.062 
                 ND 
               
               
                 AD-64359.1 
                 0.441 
                 ND 
                 0.081 
                 ND 
               
               
                 AD-64294.1 
                 0.563 
                 ND 
                 0.066 
                 ND 
               
               
                 AD-64339.1 
                 0.486 
                 ND 
                 0.044 
                 ND 
               
               
                 AD-63968.5 
                 0.57 
                 0.72 
                 0.07 
                 0.03 
               
               
                 AD-63940.3 
                 0.81 
                 0.83 
                 0.11 
                 0.03 
               
               
                 AD-64710.1 
                 0.79 
                 0.85 
                 0.12 
                 0.04 
               
               
                 AD-64716.1 
                 0.73 
                 0.85 
                 0.08 
                 0.01 
               
               
                 AD-64722.1 
                 0.67 
                 0.80 
                 0.06 
                 0.02 
               
               
                 AD-64728.1 
                 0.74 
                 0.87 
                 0.06 
                 0.05 
               
               
                 AD-64734.1 
                 0.78 
                 0.83 
                 0.08 
                 0.05 
               
               
                 AD-64739.1 
                 0.73 
                 0.85 
                 0.07 
                 0.02 
               
               
                 AD-64700.1 
                 0.54 
                 0.75 
                 0.13 
                 0.02 
               
               
                 AD-64705.1 
                 0.67 
                 0.79 
                 0.15 
                 0.04 
               
               
                 AD-64711.1 
                 0.57 
                 0.83 
                 0.13 
                 0.04 
               
               
                 AD-64717.1 
                 0.72 
                 0.83 
                 0.13 
                 0.02 
               
               
                 AD-64723.1 
                 0.83 
                 0.87 
                 0.12 
                 0.01 
               
               
                 AD-64729.1 
                 0.74 
                 0.87 
                 0.08 
                 0.07 
               
               
                 AD-64735.1 
                 0.73 
                 0.89 
                 0.05 
                 0.04 
               
               
                 AD-64740.1 
                 0.89 
                 0.88 
                 0.05 
                 0.07 
               
               
                 AD-64701.1 
                 0.88 
                 0.84 
                 0.07 
                 0.05 
               
               
                 AD-64706.1 
                 0.71 
                 0.88 
                 0.12 
                 0.05 
               
               
                 AD-64712.1 
                 0.81 
                 0.86 
                 0.13 
                 0.07 
               
               
                 AD-64718.1 
                 0.84 
                 0.89 
                 0.16 
                 0.01 
               
               
                 AD-64730.1 
                 0.88 
                 0.89 
                 0.02 
                 0.04 
               
               
                 AD-64736.1 
                 0.80 
                 0.88 
                 0.10 
                 0.05 
               
               
                 AD-64741.1 
                 0.85 
                 0.83 
                 0.06 
                 0.05 
               
               
                 AD-64702.1 
                 0.87 
                 0.93 
                 0.02 
                 0.06 
               
               
                 AD-64707.1 
                 0.95 
                 0.88 
                 0.05 
                 0.08 
               
               
                 AD-64713.1 
                 0.90 
                 0.85 
                 0.08 
                 0.03 
               
               
                 AD-64719.1 
                 0.80 
                 0.89 
                 0.09 
                 0.09 
               
               
                 AD-64725.1 
                 0.70 
                 0.84 
                 0.09 
                 0.03 
               
               
                 AD-64731.1 
                 0.82 
                 0.87 
                 0.04 
                 0.08 
               
               
                 AD-64737.1 
                 0.76 
                 0.84 
                 0.09 
                 0.08 
               
               
                 AD-64742.1 
                 0.76 
                 0.85 
                 0.09 
                 0.03 
               
               
                 AD-64703.1 
                 0.79 
                 0.88 
                 0.05 
                 0.02 
               
               
                 AD-64708.1 
                 0.83 
                 0.82 
                 0.08 
                 0.06 
               
               
                 AD-64714.1 
                 0.75 
                 0.85 
                 0.12 
                 0.03 
               
               
                 AD-64720.1 
                 0.61 
                 0.81 
                 0.17 
                 0.04 
               
               
                 AD-64726.1 
                 0.75 
                 0.83 
                 0.07 
                 0.02 
               
               
                 AD-64732.1 
                 0.86 
                 0.84 
                 0.14 
                 0.10 
               
               
                 AD-64738.1 
                 0.80 
                 0.90 
                 0.04 
                 0.02 
               
               
                 AD-64743.1 
                 0.75 
                 0.85 
                 0.12 
                 0.04 
               
               
                 AD-64704.1 
                 0.67 
                 0.78 
                 0.16 
                 0.02 
               
               
                 AD-64709.1 
                 0.83 
                 0.86 
                 0.16 
                 0.03 
               
               
                 AD-64715.1 
                 0.87 
                 0.88 
                 0.09 
                 0.04 
               
               
                 AD-64721.1 
                 0.77 
                 0.82 
                 0.12 
                 0.06 
               
               
                 AD-64727.1 
                 0.75 
                 0.85 
                 0.14 
                 0.02 
               
               
                 AD-64733.1 
                 0.67 
                 0.81 
                 0.14 
                 0.03 
               
               
                   
               
            
           
         
       
     
     Example 3. Synthesis and In Vitro Screening of Additional iRNA Duplexes 
     Additional iRNA molecules targeting the HBV genome were synthesized as described above. A detailed list of the additional modified HBV sense and antisense strand sequences is shown in Table 6. 
     A single dose screen of these duplexes was performed by transfecting the duplexes into HepG2.215 and Hep3B cells and measuring Firefly (transfection control) and Rinella (fused to HBV target sequence) luciferase, as described above. The results of the assays in HepG2.2.15 cells are shown in Table 7 and the results of the assays in Hep3B cells are provided in Table 8. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Modified Sense and Antisense Strand Sequences of HBV dsRNAs 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                   
                 SEQ 
               
               
                   
                   
                 ID 
                   
                 ID 
               
               
                 DuplexID 
                 Sense Sequence (5′ to 3′) 
                 NO: 
                 Antisense Sequence (5′ to 3′) 
                 NO: 
               
               
                   
               
               
                 AD-65369 
                 uscsguGfgUfGfGfacuuCfUfcucaL96 
                 1429 
                 PusGfsagaGfaAfGfuccaCfcAfcgasusu 
                 1458 
               
               
                   
               
               
                 AD-65381 
                 uscsguGfgUfGfGfacuucucucaL96 
                 1430 
                 PusGfsagaGfaAfGfuccaCfcAfcgasusu 
                 1459 
               
               
                   
               
               
                 AD-63962 
                 Y44uscsGfuGfgUfgGfaCfuUfcUfcUfcAfY44 
                 1431 
                 PusGfsaGfaGfaAfgUfcCfaCfcAfcGfasusu 
                 1460 
               
               
                   
               
               
                 AD-63938 
                 Y44ACUCGUGGUGGACUUCUCUCA 
                 1432 
                 UGAGAGAAGUCCACCACGAGUCU 
                 1461 
               
               
                   
               
               
                 AD-65561 
                 uscsguGfgUfGfGfacuuCfUfcucaL96 
                 1433 
                 UfsGfsagaGfaAfGfuccaCfcAfcgasusu 
                 1462 
               
               
                   
               
               
                 AD-65566 
                 uscsguGfgUfGfGfacuucucucaL96 
                 1434 
                 UfsGfsagaGfaAfGfuccaCfcAfcgasusu 
                 1463 
               
               
                   
               
               
                 AD-63944 
                 Y44ucGuGGuGGAcuucucucAusuY44 
                 1435 
                 UfGfagAfgAfAfGUfccaCfCAfcgAusu 
                 1464 
               
               
                   
               
               
                 AD-63968 
                 AfscsUfcGfuGfgUfGfGfaCfuUfcUfcUfcAfL96 
                 1436 
                 usGfsaGfaGfaAfgUfccaCfcAfcGfaGfuscsu 
                 1465 
               
               
                   
               
               
                 AD-65406 
                 uscsguGfgUfGfGfacuuCfUfcucaL96 
                 1437 
                 usGfsagaGfaAfGfuccaCfcAfcgasusu 
                 1466 
               
               
                   
               
               
                 AD-65396 
                 ascsucguGfgUfGfGfacuucucucaL96 
                 1438 
                 usGfsagaGfaaguccaCfcAfcgagususu 
                 1467 
               
               
                   
               
               
                 AD-65427 
                 gsusgcacUfuCfGfCfuucaccucuaL96 
                 1439 
                 PusAfsgagGfugaagcgAfaGfugcacsusu 
                 1468 
               
               
                   
               
               
                 AD-65573 
                 gsusgcacUfuCfGfCfuucaCfCfucuaL96 
                 1440 
                 UfsAfsgagGfuGfAfagcgAfaGfugcacsasc 
                 1469 
               
               
                   
               
               
                 AD-65432 
                 gscsacUfucGfCfuucacCfucuaL96 
                 1441 
                 PusAfsgagGfuGfAfagcgAfaGfugcsasc 
                 1470 
               
               
                   
               
               
                 AD-64332 
                 GfsusGfcAfcUfuCfGfCfuUfcAfcCfuCfuGfL96 
                 1442 
                 PcsAfsgAfgGfuGfaAfgcgAfaGfuGfcAfcsasc 
                 1471 
               
               
                   
               
               
                 AD-64322 
                 AfsusGfuGfuCfuGfCfGfgCfgUfuUfuAfuAfL96 
                 1443 
                 PusAfsuAfaAfaCfgCfcgcAfgAfcAfcAfuscsc 
                 1472 
               
               
                   
               
               
                 AD-64272 
                 GfsusGfcAfcUfuCfGfCfuUfcAfcCfuCfuGfL96 
                 1444 
                 csAfsgAfgGfuGfaAfgcgAfaGfuGfcAfcsasc 
                 1473 
               
               
                   
               
               
                 AD-65583 
                 gscsacuucgdCuucac(Cgn)ucuaL96 
                 1445 
                 usdAsgagdGugaagcgdAagugcsusu 
                 1474 
               
               
                   
               
               
                 AD-63994 
                 gsgsUfgGfaCfUfUfcUfcUfcAfaUfuUTL96 
                 1446 
                 PasAfsaUfuGfaGfaGfaagUfcCfaCfcsasc 
                 1475 
               
               
                   
               
               
                 AD-65370 
                 csgsugguGfgAfCfUfucucUfCfaauuL96 
                 1447 
                 asAfsuugAfgAfGfaaguCfcAfccagcsasg 
                 1476 
               
               
                   
               
               
                 AD-65265 
                 gsusggugGfaCfUfUfcUfcucaauuuL96 
                 1448 
                 asAfsaUfugagaGfaagUfcCfaccAfcsgsa 
                 1477 
               
               
                   
               
               
                 AD-65407 
                 csgsugguGfgAfCfUfucucUfCfaauuL96 
                 1449 
                 asAfsuugAfgAfgAfaguCfcAfccagcsasg 
                 1478 
               
               
                   
               
               
                 AD-64027 
                 gsgsUfgGfaCfUfUfcUfcUfcAfaUfuUTL96 
                 1450 
                 asAfsaUfuGfaGfaGfaagUfcCfaCfcsasc 
                 1479 
               
               
                   
               
               
                 AD-65266 
                 gsusggugGfaCfUfUfcucuCfaauuuL96 
                 1451 
                 asAfsaUfugagaGfaagUfcCfaccAfcsgsa 
                 1480 
               
               
                   
               
               
                 AD-65389 
                 usgsgudGgucdTucucuaaauuL96 
                 1452 
                 asdAsuugagagdAagudCcaccasusu 
                 1481 
               
               
                   
               
               
                 AD-64008 
                 GfsusGfgUfgGfaCfUfUfcUfcUfcAfaUfuUTL96 
                 1453 
                 asAfsaUfuGfaGfaGfaagUfcCfaCfcAfcsgsa 
                 1482 
               
               
                   
               
               
                 AD-65377 
                 csgsuggudGgucdTucucuaaauuL96 
                 1454 
                 asdAsuugagagdAagudCcaccagcsusu 
                 1483 
               
               
                   
               
               
                 AD-65409 
                 gsgsuggaCfuUTCfUfcucaAfUfuuuaL96 
                 1455 
                 PusAfsaaaUfuGfAfgagaAfgUfccaccsasc 
                 1484 
               
               
                   
               
               
                 AD-65403 
                 gsgsuggaCfuUTCfUfcucaAfUfuuuaL96 
                 1456 
                 usAfsaaaUfuGfAfgagaAfgUfccaccsasc 
                 1485 
               
               
                   
               
               
                 AD-65385 
                 usgsgacuacdTcucaaauuuaL96 
                 1457 
                 usdAsaaauugadGagadAguccasusu 
                 1486 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 HBV single dose screen In HepG2.2.15  
               
               
                 cells using Dual-Glo Luciferase ® Assay 
               
            
           
           
               
               
               
               
               
            
               
                 Duplex ID 
                 PORF-1_A 
                 PORF-1_B 
                 SORF-2_A 
                 SORF-2_B 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 AD-65369 
                 0.1875 
                 0.042 
                 0.0446 
                 0.3018 
               
               
                 AD-65381 
                 0.086 
                 0.249 
                 0.1008 
                 0.553 
               
               
                 AD-63962 
                 0.4838 
                 0.3475 
                 0.2237 
                 0.5258 
               
               
                 AD-63938 
                 0.3587 
                 2.1213 
                 0.0501 
                 1.1434 
               
               
                 AD-65561 
                 0.1076 
                 0.3801 
                 0.0718 
                 0.6897 
               
               
                 AD-65566 
                 0.4127 
                 0.3211 
                 0.185 
                 11.1161 
               
               
                 AD-63944 
                 0.9489 
                 0.7098 
                 0.393 
                 0.2771 
               
               
                 AD-63968 
                 NoIC50 
                 NoIC50 
                 1.8788 
                 NoIC50 
               
               
                 AD-65406 
                 3.3749 
                 18.8396 
                 3.8204 
                 2.2662 
               
               
                 AD-65396 
                 NoIC50 
                 6.8758 
                 3.7382 
                 4.2157 
               
               
                 AD-65427 
                 0.0089 
                 0.0181 
                 0.0066 
                 0.015 
               
               
                 AD-65573 
                 0.0174 
                 0.0332 
                 0.0029 
                 0.0227 
               
               
                 AD-65432 
                 0.0211 
                 0.0593 
                 0.0112 
                 0.0366 
               
               
                 AD-64332 
                 0.0268 
                 0.0329 
                 0.0624 
                 0.0217 
               
               
                 AD-64322 
                 0.0963 
                 0.1077 
                 0.0992 
                 0.0963 
               
               
                 AD-64272 
                 0.0773 
                 0.1199 
                 0.0763 
                 0.093 
               
               
                 AD-65583 
                 0.1624 
                 0.2228 
                 0.1568 
                 0.1496 
               
               
                 AD-63994 
                 0.7019 
                 0.1467 
                 0.0832 
                 0.0385 
               
               
                 AD-65370 
                 0.2404 
                 0.7916 
                 0.3952 
                 0.1964 
               
               
                 AD-65265 
                 0.2255 
                 0.5008 
                 0.2893 
                 0.318 
               
               
                 AD-65407 
                 0.9533 
                 0.261 
                 0.4254 
                 0.1121 
               
               
                 AD-64027 
                 0.7692 
                 0.5887 
                 0.5208 
                 0.5697 
               
               
                 AD-65266 
                 3.4109 
                 0.5055 
                 0.8532 
                 0.3658 
               
               
                 AD-65389 
                 0.9172 
                 0.6514 
                 0.4915 
                 0.2872 
               
               
                 AD-64008 
                 1.2738 
                 0.7865 
                 1.9519 
                 0.808 
               
               
                 AD-65377 
                 0.6052 
                 1.6 
                 24.9403 
                 0.6065 
               
               
                 AD-65409 
                 1.8304 
                 1.6479 
                 0.104 
                 0.0557 
               
               
                 AD-65403 
                 12.1516 
                 0.667 
                 1.006 
                 0.233 
               
               
                 AD-65385 
                 NoIC50 
                 NoIC50 
                 NoIC50 
                 NoIC50 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 HBV single dose screen In Hep3B cells  
               
               
                 using Dual-Glo Luciferase  ® Assay 
               
            
           
           
               
               
               
            
               
                 Duplex ID 
                 PORF-1_A 
                 PORF-1_B 
               
               
                   
               
            
           
           
               
               
               
            
               
                 AD-65369 
                 0.0982 
                 0.0508 
               
               
                 AD-65381 
                 0.2392 
                 0.1097 
               
               
                 AD-63962 
                 0.0769 
                 0.0706 
               
               
                 AD-63938 
                 0.039 
                 0.0111 
               
               
                 AD-65561 
                 0.6316 
                 0.6931 
               
               
                 AD-65566 
                 0.2747 
                 0.5331 
               
               
                 AD-63944 
                 0.1317 
                 0.0566 
               
               
                 AD-63968 
                 0.4374 
                 0.8811 
               
               
                 AD-65406 
                 1.4961 
                 1.2573 
               
               
                 AD-65396 
                 1.9971 
                 0.9952 
               
               
                 AD-65427 
                 0.0234 
                 0.006 
               
               
                 AD-65573 
                 0.0346 
                 0.0334 
               
               
                 AD-65432 
                 0.0352 
                 0.2664 
               
               
                 AD-64332 
                 0.0221 
                 0.4541 
               
               
                 AD-64322 
                 0.1743 
                 0.1616 
               
               
                 AD-64272 
                 0.1885 
                 0.6699 
               
               
                 AD-65583 
                 0.1241 
                 8.1611 
               
               
                 AD-63994 
                 3.3623 
                 5.2897 
               
               
                 AD-65370 
                 0.2281 
                 NoIC50 
               
               
                 AD-65265 
                 NoIC50 
                 7.3426 
               
               
                 AD-65407 
                 0.1404 
                 1.3833 
               
               
                 AD-64027 
                 27.1417 
                 1.1832 
               
               
                 AD-65266 
                 NoIC50 
                 NoIC50 
               
               
                 AD-65389 
                 NoIC50 
                 NoIC50 
               
               
                 AD-64008 
                 NoIC50 
                 NoIC50 
               
               
                 AD-65377 
                 NoIC50 
                 NoIC50 
               
               
                 AD-65409 
                 1.8065 
                 3.436 
               
               
                 AD-65403 
                 0.5113 
                 18.0359 
               
               
                 AD-65385 
                 NoIC50 
                 NoIC50 
               
               
                   
               
            
           
         
       
     
     A subset of these duplexes were also assayed for in vitro stability using two assays, a tritosome stability assay and a cytosol stability assay. 
     For the tritosome stability assays, rat liver tritosomes (Xenotech custom product PR14044) were thawed to room temperature and diluted to 0.5 units/mL Acid Phosphatase in 20 mM Sodium Citrate pH 5.0 Buffer. Twenty-four hour samples were prepared by mixing 100 μL of 0.5 units/mL Acid Phosphatase Tritosomes with 25 μL of 0.4 mg/mL siRNA sample in a microcentrifuge tube and incubating for twenty-four hours in an eppendorf Thermomixer set to 37° C. and 300 rpm. After twenty-four hours of incubation 300 μL of Phenomenex Lysis Loading Buffer (Cat. # ALO-8498) and 12.5 μL of a 0.4 mg/mL internal standard siRNA were added to each sample. Time 0 hour samples were prepared by by mixing 100 μL of 0.5 units/mL Acid Phosphatase Tritosomes with 25 μL of 0.4 mg/mL siRNA sample, 300 μL of Phenomenex Lysis Loading Buffer, and 12.5 μL of a 0.4 mg/mL internal standard siRNA. siRNA was extracted from twenty-four hour samples and 0 hour samples using a Phenomenex Clarity OTX Starter Kit (Cat. # KSO-8494). After the samples were extracted they were transferred to a microcentrifuge tube and dried down using a Labconco CentriVap Concentrator (Cat. #7810010). The samples were then resuspended with 500 μL of nuclease free water. Fifty μL of each sample was run on an Agilent Technologies 1260 Infinity Binary LC with Agilent Technologies 6130 Quadrupole LC/MS. The Quaternary pump method was run for 12.20 minutes at 0.400 mL/min with the following timetable: 
                                 Time Function   Parameter                  0.20   5% Buffer A(16 mM TEA 200 mM HFIP),            95% Buffer B (100% Methanol)       2.50   5% Buffer A(16 mM TEA 200 mM HFIP),            95% Buffer B (100% Methanol)       3.00   100% Buffer A(16 mM TEA 200 mM HFIP)                    
The Binary Pump method was run for 12.20 min at 0.700 mL/min with the following timetable:
 
                                 Time Function   Parameter                                        0.00   100% Buffer A(16 mM TEA 200 mM HFIP)       0.40   100% Buffer A(16 mM TEA 200 mM HFIP)       10.00   60% Buffer A(16 mM TEA 200 mM HFIP),            40% Buffer B (100% ACN)       10.10   100% Buffer A(16 mM TEA 200 mM HFIP)       12.20   100% Buffer A(16 mM TEA 200 mM HFIP)                    
Both the left and right column was set at 75.00° C. The UV signal was measured at 260 nm wavelength. The percent remaining of each strand was calculated using the following equation:
 
       % Strand remaining=100*(Peak Areas Strand 24 h /Peak Area Strand 0 h *(Peak Area Standard 24 h /Peak Area Standard 0 h )). 
     For the cytosol stability assay, female rat liver cytosol (Xenotech Cat. # R1500.C) were thawed to room temperature and diluted to 1 mg/mL in 50 mM Tris buffer: HCl pH 7.4, 5 mM MgCl2. 24 hour samples were prepared by mixing 100 uL of 1 mg/mL Cytosol with 25 uL of 0.4 mg/mL siRNA sample in a microcentrifuge tube and incubating for 24 hours in an eppendorf Thermomixer set to 37° C. and 300 rpm. After 24 hours of incubation 300 uL of Phenomenex Lysis Loading Buffer (Cat. # ALO-8498) and 12.5 uL of a 0.4 mg/mL internal standard siRNA were added to each sample. 0 hour samples were prepared by by mixing 100 uL of 1 mg/mL Cytosol with 25 uL of 0.4 mg/mL siRNA sample, 300 uL of Phenomenex Lysis Loading Buffer, and 12.5 uL of a 0.4 mg/mL internal standard siRNA. siRNA was extracted from 24 hour samples and 0 hour samples using a Phenomenex Clarity OTX Starter Kit (Cat. # KSO-8494). After the samples were extracted they were transferred to a microcentrifuge tube and dried down using a Labconco CentriVap Concentrator (Cat. #7810010). The samples were then resuspended with 500 uL of nuclease free water. 50 uL of each sample was run on an Agilent Technologies 1260 Infinity Binary LC with Agilent Technologies 6130 Quadrupole LC/MS. The Quaternary pump method was run for 12.20 minutes at 0.400 mL/min with the following timetable: 
                                 Time Function   Parameter                  0.20   5% Buffer A(16 mM TEA 200 mM HFIP),            95% Buffer B (100% Methanol)       2.50   5% Buffer A(16 mM TEA 200 mM HFIP),            95% Buffer B (100% Methanol)       3.00   100% Buffer A(16 mM TEA 200 mM HFIP)                    
The Binary Pump method was run for 12.20 min at 0.700 mL/min with the following timetable:
 
     Time FunctionParameter 
       
                                 Time Function   Parameter                                        0.00   100% Buffer A(16 mM TEA 200 mM HFIP)       0.40   100% Buffer A(16 mM TEA 200 mM HFIP)       10.00   60% Buffer A(16 mM TEA 200 mM HFIP),            40% Buffer B (100% ACN)       10.10   100% Buffer A(16 mM TEA 200 mM HFIP)       12.20   100% Buffer A(16 mM TEA 200 mM HFIP)                    
Both the left and right column was set at 75.00° C. The UV signal was measured at 260 nm wavelength. The percent remaining of each strand was calculated using the following equation:
 
       % Strand remaining=100*(Peak Area Strand 24 h /Peak Area Strand 0 h *(Peak Area Standard 24 h /Peak Area Standard 0 h )). 
     The results of the twenty-four hour tritosome stability assays are provided in Table 9 and the results of the twenty-four hour cytosol stability assays are provided in Table 10. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Twenty-four hour tritosome stability assays. 
               
            
           
           
               
               
               
               
            
               
                   
                 % Antisense 
                   
                   
               
               
                   
                 Remaining 
                 % Sense Remaining 
                 DuplexID 
               
               
                   
                   
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 AD-65369 
               
               
                   
                 87.59 
                 72.43 
                 AD-65381 
               
               
                   
                   
                   
                 AD-63962 
               
               
                   
                   
                   
                 AD-63938 
               
               
                   
                   
                   
                 AD-65561 
               
               
                   
                 67.59 
                 82.48 
                 AD-65566 
               
               
                   
                   
                   
                 AD-63944 
               
               
                   
                 30.52 
                 34.98 
                 AD-63968 
               
               
                   
                   
                   
                 AD-65406 
               
               
                   
                   
                   
                 AD-65396 
               
               
                   
                 115.17 
                 79.61 
                 AD-65427 
               
               
                   
                 43.00 
                 76.84 
                 AD-65573 
               
               
                   
                   
                   
                 AD-65432 
               
               
                   
                   
                   
                 AD-64332 
               
               
                   
                   
                   
                 AD-64322 
               
               
                   
                 129.69 
                 128.59 
                 AD-64272 
               
               
                   
                   
                   
                 AD-65583 
               
               
                   
                   
                   
                 AD-63994 
               
               
                   
                   
                   
                 AD-65370 
               
               
                   
                   
                   
                 AD-65265 
               
               
                   
                 100.30 
                 119.85 
                 AD-65407 
               
               
                   
                   
                   
                 AD-64027 
               
               
                   
                   
                   
                 AD-65266 
               
               
                   
                   
                   
                 AD-65389 
               
               
                   
                 94.06 
                 110.90 
                 AD-64008 
               
               
                   
                 98.63 
                 127.48 
                 AD-65377 
               
               
                   
                 105.06 
                 119.88 
                 AD-65409 
               
               
                   
                 117.55 
                 104.30 
                 AD-65403 
               
               
                   
                   
                   
                 AD-65385 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Twenty-four hour cytosol stability assays. 
               
            
           
           
               
               
               
            
               
                 % Antisense 
                   
                   
               
               
                 Remaining 
                 % Sense Remaining 
                 DuplexID 
               
               
                   
               
               
                   
                   
                 AD-65369 
               
               
                 67.78 
                 22.42 
                 AD-65381 
               
               
                   
                   
                 AD-63962 
               
               
                   
                   
                 AD-63938 
               
               
                   
                   
                 AD-65561 
               
               
                 55.89 
                 15.26 
                 AD-65566 
               
               
                   
                   
                 AD-63944 
               
               
                 88.39 
                 46.94 
                 AD-63968 
               
               
                   
                   
                 AD-65406 
               
               
                   
                   
                 AD-65396 
               
               
                 89.50 
                 66.35 
                 AD-65427 
               
               
                 69.01 
                 41.47 
                 AD-65573 
               
               
                   
                   
                 AD-65432 
               
               
                   
                   
                 AD-64332 
               
               
                   
                   
                 AD-64322 
               
               
                 96.77 
                 78.00 
                 AD-64272 
               
               
                   
                   
                 AD-65583 
               
               
                   
                   
                 AD-63994 
               
               
                   
                   
                 AD-65370 
               
               
                   
                   
                 AD-65265 
               
               
                 64.46 
                 24.10 
                 AD-65407 
               
               
                   
                   
                 AD-64027 
               
               
                   
                   
                 AD-65266 
               
               
                   
                   
                 AD-65389 
               
               
                 35.39 
                 26.39 
                 AD-64008 
               
               
                 79.98 
                 66.50 
                 AD-65377 
               
               
                 86.24 
                 74.25 
                 AD-65409 
               
               
                 60.45 
                 62.41 
                 AD-65403 
               
               
                   
                   
                 AD-65385 
               
               
                   
               
            
           
         
       
     
     Example 4. Synthesis and In Vitro Screening of iRNA Duplexes Targeting HDV 
     The selection of iRNA designs targeting HDV was driven by two primary factors: a) potency and b), the desire to employ iRNA with near-perfect matches with greater than 90% fractional coverage of the large number of public HDV sequences of all known clades (I-VIII or 1-8). However, due to the low level of conservation between members of the various HDV clades and the small genome, selection of sequences that effectively target multiple HDV clades was difficult. Exemplary sequences for the various HDV clades 1-8 are provided in SEQ ID NOs: 29, 31, 33, 35, 37, 39, 41, and 43. Their reverse complements are provided in SEQ ID NOs: 30, 32, 34, 36, 38, 40, 42, and 44. 
     iRNA molecules targeting the HDV genome were synthesized as described above. A detailed list of the unmodified HDV sense and antisense strand sequences is shown in Table 11 and a detailed list of the modified HDV sense and antisense strand sequences is shown in Table 12. The results of a single dose screen of these agents using the Dual-Glo Luciferase® Assay described above are shown in Table 13. 
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Unmodified Sense and Antisense Strand Sequences of HDV dsRNAs 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 SEQ ID NO 
               
               
                 Duplex 
                 Sense 
                 Antisense 
                   
                   
                   
                 Sense/ 
               
               
                 Name 
                 Strand 
                 Strand 
                 Clade 
                 Sense Seq 
                 Antisense Seq 
                 Antisense 
               
               
                   
               
               
                 AD-45013.1 
                 A-94349.1 
                 A-94350.1 
                 HDV1 
                 ACGAAGGAAGGCCCUCGAGdTdT 
                 CUCGAGGGCCUUCCUUCGUdTdT 
                  45/46 
               
               
                   
               
               
                 AD-45019.1 
                 A-94351.1 
                 A-94352.1 
                 HDV1 
                 CGAAGGAAGGCCCUCGAGAdTdT 
                 UCUCGAGGGCCUUCCUUCGdTdT 
                  47/48 
               
               
                   
               
               
                 AD-45025.1 
                 A-94353.1 
                 A-94354.1 
                 HDV1 
                 GAAGGAAGGCCCUCGAGAAdTdT 
                 UUCUCGAGGGCCUUCCUUCdTdT 
                  49/50 
               
               
                   
               
               
                 AD-45036.1 
                 A-94357.1 
                 A-94358.1 
                 HDV1 
                 AGGAAGGCCCUCGAGAACAdTdT 
                 UGUUCUCGAGGGCCUUCCUdTdT 
                  51/52 
               
               
                   
               
               
                 AD-45041.1 
                 A-94359.1 
                 A-94360.1 
                 HDV1 
                 GGAAGGCCCUCGAGAACAAdTdT 
                 UUGUUCUCGAGGGCCUUCCdTdT 
                  53/54 
               
               
                   
               
               
                 AD-45046.1 
                 A-94361.1 
                 A-94362.1 
                 HDV1 
                 GAAGGCCCUCGAGAACAAGdTdT 
                 CUUGUUCUCGAGGGCCUUCdTdT 
                  55/56 
               
               
                   
               
               
                 AD-45051.1 
                 A-94363.1 
                 A-94364.1 
                 HDV1 
                 GGGGUGUGAACCCCCUCGAdTdT 
                 UCGAGGGGGUUCACACCCCdTdT 
                  57/58 
               
               
                   
               
               
                 AD-45014.1 
                 A-94365.1 
                 A-94366.1 
                 HDV1 
                 GGGUGUGAACCCCCUCGAAdTdT 
                 UUCGAGGGGGUUCACACCCdTdT 
                  59/60 
               
               
                   
               
               
                 AD-45020.1 
                 A-94367.1 
                 A-94368.1 
                 HDV1 
                 GGUGUGAACCCCCUCGAAGdTdT 
                 CUUCGAGGGGGUUCACACCdTdT 
                  61/62 
               
               
                   
               
               
                 AD-45026.1 
                 A-94369.1 
                 A-94370.1 
                 HDV1 
                 UGUGAACCCCCUCGAAGGUdTdT 
                 ACCUUCGAGGGGGUUCACAdTdT 
                  63/64 
               
               
                   
               
               
                 AD-45032.1 
                 A-94371.1 
                 A-94372.1 
                 HDV2 
                 AAAAUCCCUGGCUGGGGAAdTdT 
                 UUCCCCAGCCAGGGAUUUUdTdT 
                  65/66 
               
               
                   
               
               
                 AD-45042.1 
                 A-94375.1 
                 A-94376.1 
                 HDV2 
                 AAUCCCUGGCUGGGGAACAdTdT 
                 UGUUCCCCAGCCAGGGAUUdTdT 
                  67/68 
               
               
                   
               
               
                 AD-45047.1 
                 A-94377.1 
                 A-94378.1 
                 HDV2 
                 AUCCCUGGCUGGGGAACAUdTdT 
                 AUGUUCCCCAGCCAGGGAUdTdT 
                  69/70 
               
               
                   
               
               
                 AD-45015.1 
                 A-94381.1 
                 A-94382.1 
                 HDV2 
                 AAGAGCGGGUUCACCGACAdTdT 
                 UGUCGGUGAACCCGCUCUUdTdT 
                  71/72 
               
               
                   
               
               
                 AD-45021.1 
                 A-94383.1 
                 A-94384.1 
                 HDV2 
                 AGAGCGGGUUCACCGACAAdTdT 
                 UUGUCGGUGAACCCGCUCUdTdT 
                  73/74 
               
               
                   
               
               
                 AD-45027.1 
                 A-94385.1 
                 A-94386.1 
                 HDV2 
                 GAGCGGGUUCACCGACAAGdTdT 
                 CUUGUCGGUGAACCCGCUCdTdT 
                  75/76 
               
               
                   
               
               
                 AD-45033.1 
                 A-94387.1 
                 A-94388.1 
                 HDV2 
                 GCGGGUUCACCGACAAGGAdTdT 
                 UCCUUGUCGGUGAACCCGCdTdT 
                  77/78 
               
               
                   
               
               
                 AD-45038.1 
                 A-94389.1 
                 A-94390.1 
                 HDV2 
                 CGGGUUCACCGACAAGGAGdTdT 
                 CUCCUUGUCGGUGAACCCGdTdT 
                  79/80 
               
               
                   
               
               
                 AD-45043.1 
                 A-94391.1 
                 A-94392.1 
                 HDV2 
                 GGGUUCACCGACAAGGAGAdTdT 
                 UCUCCUUGUCGGUGAACCCdTdT 
                  81/82 
               
               
                   
               
               
                 AD-45048.1 
                 A-94393.1 
                 A-94394.1 
                 HDV2 
                 GGUUCACCGACAAGGAGAGdTdT 
                 CUCUCCUUGUCGGUGAACCdTdT 
                  83/84 
               
               
                   
               
               
                 AD-45053.1 
                 A-94395.1 
                 A-94396.1 
                 HDV2 
                 GGGAGGGACUGGACAUCAGdTdT 
                 CUGAUGUCCAGUCCCUCCCdTdT 
                  85/86 
               
               
                   
               
               
                 AD-45016.1 
                 A-94397.1 
                 A-94398.1 
                 HDV3 
                 GGGUAGAGGAAAGGAAGAAdTdT 
                 UUCUUCCUUUCCUCUACCCdTdT 
                  87/88 
               
               
                   
               
               
                 AD-45022.1 
                 A-94399.1 
                 A-94400.1 
                 HDV3 
                 GAGGCGGGACCACAGAAGAdTdT 
                 UCUUCUGUGGUCCCGCCUCdTdT 
                  89/90 
               
               
                   
               
               
                 AD-45028.1 
                 A-94401.1 
                 A-94402.1 
                 HDV3 
                 ACAGAAGAAGGAAGGCCCUdTdT 
                 AGGGCCUUCCUUCUUCUGUdTdT 
                  91/92 
               
               
                   
               
               
                 AD-45034.1 
                 A-94403.1 
                 A-94404.1 
                 HDV3 
                 GAAGAAGAGGAACUCCGGAdTdT 
                 UCCGGAGUUCCUCUUCUUCdTdT 
                  93/94 
               
               
                   
               
               
                 AD-45039.1 
                 A-94405.1 
                 A-94406.1 
                 HDV3 
                 CAGGGAUGACGACGAAAGAdTdT 
                 UCUUUCGUCGUCAUCCCUGdTdT 
                  95/96 
               
               
                   
               
               
                 AD-45044.1 
                 A-94407.1 
                 A-94408.1 
                 HDV3 
                 GGGAUGACGACGAAAGAGAdTdT 
                 UCUCUUUCGUCGUCAUCCCdTdT 
                  97/98 
               
               
                   
               
               
                 AD-45049.1 
                 A-94409.1 
                 A-94410.1 
                 HDV3 
                 GGAUGACGACGAAAGAGAAdTdT 
                 UUCUCUUUCGUCGUCAUCCdTdT 
                  99/100 
               
               
                   
               
               
                 AD-45054.1 
                 A-94411.1 
                 A-94412.1 
                 HDV3 
                 CCUGGGGGUGUGAACCCAAdTdT 
                 UUGGGUUCACACCCCCAGGdTdT 
                 101/102 
               
               
                   
               
               
                 AD-45017.1 
                 A-94413.1 
                 A-94414.1 
                 HDV3 
                 CUGGGGGUGUGAACCCAAUdTdT 
                 AUUGGGUUCACACCCCCAGdTdT 
                 103/104 
               
               
                   
               
               
                 AD-45023.1 
                 A-94415.1 
                 A-94416.1 
                 HDV3 
                 CCUUUUCCCGAACGGGAGAdTdT 
                 UCUCCCGUUCGGGAAAAGGdTdT 
                 105/106 
               
               
                   
               
               
                 AD-45035.1 
                 A-94419.1 
                 A-94420.1 
                 HDV3 
                 GAACGGGAGAGGGGAUCGAdTdT 
                 UCGAUCCCCUCUCCCGUUCdTdT 
                 107/108 
               
               
                   
               
               
                 AD-45040.1 
                 A-94421.1 
                 A-94422.1 
                 HDV3 
                 ACGGGAGAGGGGAUCGACAdTdT 
                 UGUCGAUCCCCUCUCCCGUdTdT 
                 109/110 
               
               
                   
               
               
                 AD-45050.1 
                 A-94425.1 
                 A-94426.1 
                 HDV3 
                 AGAGGGGAUCGACAUCCGAdTdT 
                 UCGGAUGUCGAUCCCCUCUdTdT 
                 111/112 
               
               
                   
               
               
                 AD-45055.1 
                 A-94427.1 
                 A-94428.1 
                 HDV3 
                 GGGGAUCGACAUCCGAGGAdTdT 
                 UCCUCGGAUGUCGAUCCCCdTdT 
                 113/114 
               
               
                   
               
               
                 AD-45018.1 
                 A-94429.1 
                 A-94430.1 
                 HDV3 
                 GGGAUCGACAUCCGAGGAAdTdT 
                 UUCCUCGGAUGUCGAUCCCdTdT 
                 115/116 
               
               
                   
               
               
                 AD-45024.1 
                 A-94431.1 
                 A-94432.1 
                 HDV3 
                 ACAUCCGAGGAACCCAGCAdTdT 
                 UGCUGGGUUCCUCGGAUGUdTdT 
                 117/118 
               
               
                   
               
               
                 AD-45030.1 
                 A-94433.1 
                 A-94434.1 
                 HDV3 
                 GGAACCCAGCAGUUCCCAUdTdT 
                 AUGGGAACUGCUGGGUUCCdTdT 
                 119/120 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Modified Sense and Antisense Strand Sequences of HDV dsRNAs 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                 Anti- 
                   
                   
                 SEQ 
                   
                 SEQ 
               
               
                 Duplex 
                 Sense 
                 sense 
                   
                 Sense Sequence 
                 ID 
                 Antisense Sequence 
                 ID 
               
               
                 Name 
                 Strand 
                 Strand 
                 Clade 
                 (5′ to 3′) 
                 NO: 
                 (5′ to 3′) 
                 NO: 
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV1 
                 AcGAAGGAAGGcccucGAGdTsdT 
                 1487 
                 CUCGAGGGCCUUCCUUCGUdTsdT 
                 1525 
               
               
                 45013.1 
                 94349.1 
                 94350.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV1 
                 cGAAGGAAGGcccucGAGAdTsdT 
                 1488 
                 UCUCGAGGGCCUUCCUUCGdTsdT 
                 1526 
               
               
                 45019.1 
                 94351.1 
                 94352.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV1 
                 GAAGGAAGGcccucGAGAAdTsdT 
                 1489 
                 UUCUCGAGGGCCUUCCUUCdTsdT 
                 1527 
               
               
                 45025.1 
                 94353.1 
                 94354.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV1 
                 AGGAAGGcccucGAGAAcAdTsdT 
                 1490 
                 UGUUCUCGAGGGCCUUCCUdTsdT 
                 1528 
               
               
                 45036.1 
                 94357.1 
                 94358.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV1 
                 GGAAGGcccucGAGAAcAAdTsdT 
                 1491 
                 UUGUUCUCGAGGGCCUUCCdTsdT 
                 1529 
               
               
                 45041.1 
                 94359.1 
                 94360.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV1 
                 GAAGGcccucGAGAAcAAGdTsdT 
                 1492 
                 CUUGUUCUCGAGGGCCUUCdTsdT 
                 1530 
               
               
                 45046.1 
                 94361.1 
                 94362.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV1 
                 GGGGuGuGAAcccccucGAdTsdT 
                 1493 
                 UCGAGGGGGUUcAcACCCCdTsdT 
                 1531 
               
               
                 45051.1 
                 94363.1 
                 94364.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV1 
                 GGGuGuGAAcccccucGAAdTsdT 
                 1494 
                 UUCGAGGGGGUUcAcACCCdTsdT 
                 1532 
               
               
                 45014.1 
                 94365.1 
                 94366.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV1 
                 GGuGuGAAcccccucGAAGdTsdT 
                 1495 
                 CUUCGAGGGGGUUcAcACCdTsdT 
                 1533 
               
               
                 45020.1 
                 94367.1 
                 94368.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV1 
                 uGuGAAcccccucGAAGGudTsdT 
                 1496 
                 ACCUUCGAGGGGGUUcAcAdTsdT 
                 1534 
               
               
                 45026.1 
                 94369.1 
                 94370.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV2 
                 AAAAucccuGGcuGGGGAAdTsdT 
                 1497 
                 UUCCCcAGCcAGGGAUUUUdTsdT 
                 1535 
               
               
                 45032.1 
                 94371.1 
                 94372.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV2 
                 AAucccuGGcuGGGGAAcAdTsdT 
                 1498 
                 UGUUCCCcAGCcAGGGAUUdTsdT 
                 1536 
               
               
                 45042.1 
                 94375.1 
                 94376.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV2 
                 AucccuGGcuGGGGAAcAudTsdT 
                 1499 
                 AUGUUCCCcAGCcAGGGAUdTsdT 
                 1537 
               
               
                 45047.1 
                 94377.1 
                 94378.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV2 
                 AAGAGcGGGuucAccGAcAdTsdT 
                 1500 
                 UGUCGGUGAACCCGCUCUUdTsdT 
                 1538 
               
               
                 45015.1 
                 94381.1 
                 94382.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV2 
                 AGAGcGGGuucAccGAcAAdTsdT 
                 1501 
                 UUGUCGGUGAACCCGCUCUdTsdT 
                 1539 
               
               
                 45021.1 
                 94383.1 
                 94384.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV2 
                 GAGcGGGuucAccGAcAAGdTsdT 
                 1502 
                 CUUGUCGGUGAACCCGCUCdTsdT 
                 1540 
               
               
                 45027.1 
                 94385.1 
                 94386.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV2 
                 GcGGGuucAccGAcAAGGAdTsdT 
                 1503 
                 UCCUUGUCGGUGAACCCGCdTsdT 
                 1541 
               
               
                 45033.1 
                 94387.1 
                 94388.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV2 
                 cGGGuucAccGAcAAGGAGdTsdT 
                 1504 
                 CUCCUUGUCGGUGAACCCGdTsdT 
                 1542 
               
               
                 45038.1 
                 94389.1 
                 94390.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV2 
                 GGGuucAccGAcAAGGAGAdTsdT 
                 1505 
                 UCUCCUUGUCGGUGAACCCdTsdT 
                 1543 
               
               
                 45043.1 
                 94391.1 
                 94392.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV2 
                 GGuucAccGAcAAGGAGAGdTsdT 
                 1506 
                 CUCUCCUUGUCGGUGAACCdTsdT 
                 1544 
               
               
                 45048.1 
                 94393.1 
                 94394.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV2 
                 GGGAGGGAcuGGAcAucAGdTsdT 
                 1507 
                 CUGAUGUCcAGUCCCUCCCdTsdT 
                 1545 
               
               
                 45053.1 
                 94395.1 
                 94396.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 GGGuAGAGGAAAGGAAGAAdTsdT 
                 1508 
                 UUCUUCCUUUCCUCuACCCdTsdT 
                 1546 
               
               
                 45016.1 
                 94397.1 
                 94398.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 GAGGcGGGAccAcAGAAGAdTsdT 
                 1509 
                 UCUUCUGUGGUCCCGCCUCdTsdT 
                 1547 
               
               
                 45022.1 
                 94399.1 
                 94400.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 AcAGAAGAAGGAAGGcccudTsdT 
                 1510 
                 AGGGCCUUCCUUCUUCUGUdTsdT 
                 1548 
               
               
                 45028.1 
                 94401.1 
                 94402.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 GAAGAAGAGGAAcuccGGAdTsdT 
                 1511 
                 UCCGGAGUUCCUCUUCUUCdTsdT 
                 1549 
               
               
                 45034.1 
                 94403.1 
                 94404.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 cAGGGAuGAcGAcGAAAGAdTsdT 
                 1512 
                 UCUUUCGUCGUcAUCCCUGdTsdT 
                 1550 
               
               
                 45039.1 
                 94405.1 
                 94406.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 GGGAuGAcGAcGAAAGAGAdTsdT 
                 1513 
                 UCUCUUUCGUCGUcAUCCCdTsdT 
                 1551 
               
               
                 45044.1 
                 94407.1 
                 94408.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 GGAuGAcGAcGAAAGAGAAdTsdT 
                 1514 
                 UUCUCUUUCGUCGUcAUCCdTsdT 
                 1552 
               
               
                 45049.1 
                 94409.1 
                 94410.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 ccuGGGGGuGuGAAcccAAdTsdT 
                 1515 
                 UUGGGUUcAcACCCCcAGGdTsdT 
                 1553 
               
               
                 45054.1 
                 94411.1 
                 94412.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 cuGGGGGuGuGAAcccAAudTsdT 
                 1516 
                 AUUGGGUUcAcACCCCcAGdTsdT 
                 1554 
               
               
                 45017.1 
                 94413.1 
                 94414.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 ccuuuucccGAAcGGGAGAdTsdT 
                 1517 
                 UCUCCCGUUCGGGAAAAGGdTsdT 
                 1555 
               
               
                 45023.1 
                 94415.1 
                 94416.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 GAAcGGGAGAGGGGAucGAdTsdT 
                 1518 
                 UCGAUCCCCUCUCCCGUUCdTsdT 
                 1556 
               
               
                 45035.1 
                 94419.1 
                 94420.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 AcGGGAGAGGGGAucGAcAdTsdT 
                 1519 
                 UGUCGAUCCCCUCUCCCGUdTsdT 
                 1557 
               
               
                 45040.1 
                 94421.1 
                 94422.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 AGAGGGGAucGAcAuccGAdTsdT 
                 1520 
                 UCGGAUGUCGAUCCCCUCUdTsdT 
                 1558 
               
               
                 45050.1 
                 94425.1 
                 94426.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 GGGGAucGAcAuccGAGGAdTsdT 
                 1521 
                 UCCUCGGAUGUCGAUCCCCdTsdT 
                 1559 
               
               
                 45055.1 
                 94427.1 
                 94428.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 GGGAucGAcAuccGAGGAAdTsdT 
                 1522 
                 UUCCUCGGAUGUCGAUCCCdTsdT 
                 1560 
               
               
                 45018.1 
                 94429.1 
                 94430.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 AcAuccGAGGAAcccAGcAdTsdT 
                 1523 
                 UGCUGGGUUCCUCGGAUGUdTsdT 
                 1561 
               
               
                 45024.1 
                 94431.1 
                 94432.1 
                   
                   
                   
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 A- 
                 HDV3 
                 GGAAcccAGcAGuucccAudTsdT 
                 1524 
                 AUGGGAACUGCUGGGUUCCdTsdT 
                 1562 
               
               
                 45030.1 
                 94433.1 
                 94434.1 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 HDV single dose screen using Dual-Glo Luciferase ® Assay 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 10 nM  
                 0.1 nM  
                   
                   
                   
               
               
                 Duplex 
                 mean 
                 mean  
                 Sense 
                 Antisense 
                   
               
               
                 Name 
                 KD 
                 KD 
                 Strand 
                 Strand 
                 Clade 
               
               
                   
               
               
                 AD-45013.1 
                 0.564 
                 0.885 
                 A-94349.1 
                 A-94350.1 
                 HDV1 
               
               
                 AD-45019.1 
                 0.238 
                 0.749 
                 A-94351.1 
                 A-94352.1 
                 HDV1 
               
               
                 AD-45025.1 
                 0.203 
                 0.747 
                 A-94353.1 
                 A-94354.1 
                 HDV1 
               
               
                 AD-45036.1 
                 0.557 
                 0.865 
                 A-94357.1 
                 A-94358.1 
                 HDV1 
               
               
                 AD-45041.1 
                 0.710 
                 0.865 
                 A-94359.1 
                 A-94360.1 
                 HDV1 
               
               
                 AD-45046.1 
                 0.849 
                 0.937 
                 A-94361.1 
                 A-94362.1 
                 HDV1 
               
               
                 AD-45051.1 
                 0.863 
                 0.909 
                 A-94363.1 
                 A-94364.1 
                 HDV1 
               
               
                 AD-45014.1 
                 0.556 
                 0.883 
                 A-94365.1 
                 A-94366.1 
                 HDV1 
               
               
                 AD-45020.1 
                 0.860 
                 0.949 
                 A-94367.1 
                 A-94368.1 
                 HDV1 
               
               
                 AD-45026.1 
                 0.793 
                 0.847 
                 A-94369.1 
                 A-94370.1 
                 HDV1 
               
               
                 AD-45032.1 
                 0.569 
                 0.878 
                 A-94371.1 
                 A-94372.1 
                 HDV2 
               
               
                 AD-45042.1 
                 0.913 
                 0.928 
                 A-94375.1 
                 A-94376.1 
                 HDV2 
               
               
                 AD-45047.1 
                 0.593 
                 0.858 
                 A-94377.1 
                 A-94378.1 
                 HDV2 
               
               
                 AD-45015.1 
                 0.615 
                 0.948 
                 A-94381.1 
                 A-94382.1 
                 HDV2 
               
               
                 AD-45021.1 
                 0.856 
                 0.903 
                 A-94383.1 
                 A-94384.1 
                 HDV2 
               
               
                 AD-45027.1 
                 1.001 
                 0.934 
                 A-94385.1 
                 A-94386.1 
                 HDV2 
               
               
                 AD-45033.1 
                 0.926 
                 0.939 
                 A-94387.1 
                 A-94388.1 
                 HDV2 
               
               
                 AD-45038.1 
                 0.838 
                 0.876 
                 A-94389.1 
                 A-94390.1 
                 HDV2 
               
               
                 AD-45043.1 
                 0.721 
                 0.949 
                 A-94391.1 
                 A-94392.1 
                 HDV2 
               
               
                 AD-45048.1 
                 0.873 
                 0.927 
                 A-94393.1 
                 A-94394.1 
                 HDV2 
               
               
                 AD-45053.1 
                 0.415 
                 0.826 
                 A-94395.1 
                 A-94396.1 
                 HDV2 
               
               
                 AD-45016.1 
                 0.634 
                 0.917 
                 A-94397.1 
                 A-94398.1 
                 HDV3 
               
               
                 AD-45022.1 
                 0.943 
                 0.900 
                 A-94399.1 
                 A-94400.1 
                 HDV3 
               
               
                 AD-45028.1 
                 0.817 
                 0.914 
                 A-94401.1 
                 A-94402.1 
                 HDV3 
               
               
                 AD-45034.1 
                 0.601 
                 0.890 
                 A-94403.1 
                 A-94404.1 
                 HDV3 
               
               
                 AD-45039.1 
                 0.931 
                 0.888 
                 A-94405.1 
                 A-94406.1 
                 HDV3 
               
               
                 AD-45044.1 
                 0.912 
                 0.905 
                 A-94407.1 
                 A-94408.1 
                 HDV3 
               
               
                 AD-45049.1 
                 0.976 
                 0.980 
                 A-94409.1 
                 A-94410.1 
                 HDV3 
               
               
                 AD-45054.1 
                 0.929 
                 0.896 
                 A-94411.1 
                 A-94412.1 
                 HDV3 
               
               
                 AD-45017.1 
                 0.977 
                 0.974 
                 A-94413.1 
                 A-94414.1 
                 HDV3 
               
               
                 AD-45023.1 
                 0.887 
                 0.878 
                 A-94415.1 
                 A-94416.1 
                 HDV3 
               
               
                 AD-45035.1 
                 0.915 
                 0.928 
                 A-94419.1 
                 A-94420.1 
                 HDV3 
               
               
                 AD-45040.1 
                 1.671 
                 0.934 
                 A-94421.1 
                 A-94422.1 
                 HDV3 
               
               
                 AD-45050.1 
                 0.878 
                 0.963 
                 A-94425.1 
                 A-94426.1 
                 HDV3 
               
               
                 AD-45055.1 
                 0.926 
                 0.873 
                 A-94427.1 
                 A-94428.1 
                 HDV3 
               
               
                 AD-45018.1 
                 0.912 
                 0.976 
                 A-94429.1 
                 A-94430.1 
                 HDV3 
               
               
                 AD-45024.1 
                 0.873 
                 0.884 
                 A-94431.1 
                 A-94432.1 
                 HDV3 
               
               
                 AD-45030.1 
                 0.909 
                 0.937 
                 A-94433.1 
                 A-94434.1 
                 HDV3 
               
               
                   
               
            
           
         
       
     
     Example 5. Synthesis and Screening of Additional siRNA Duplexes Targeted to HBV 
     Additional iRNA molecules targeting the HBV genome were designed and synthesized as described above. A detailed list of the additional unmodified HBV sense and antisense strand sequences is shown in Table 14 and a detailed list of the modified HBV sense and antisense strand sequences is shown in Table 15. 
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 Unmodified Sense and Antisense Strand Sequences of HBV dsRNAs 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
                   
                   
                 SEQ 
               
               
                 Duplex 
                   
                 Sense Sequence 
                 ID 
                 Antisense 
                 Antisense Sequence 
                 ID 
               
               
                 ID 
                 Sense ID 
                 (5′ to 3′) 
                 NO: 
                 ID 
                 (5′ to 3′) 
                 NO: 
               
               
                   
               
               
                 AD-65381 
                 A-130366.9 
                 UCGUGGUGGACUUCUCUCA 
                 1563 
                 A-131904.1 
                 UGAGAGAAGUCCACCACGAUU 
                 1574 
               
               
                   
               
               
                 AD-66019 
                 A-130366.9 
                 UCGUGGUGGACUUCUCUCA 
                 1564 
                 A-131904.1 
                 UGAGAGAAGUCCACCACGAUU 
                 1575 
               
               
                   
               
               
                 AD-65375 
                 A-130366.9 
                 UCGUGGUGGACUUCUCUCA 
                 1565 
                 A-130364.7 
                 UGAGAGAAGUCCACCACGAUU 
                 1576 
               
               
                   
               
               
                 AD-65427 
                 A-130441.7 
                 GUGCACUUCGCUUCACCUCUA 
                 1566 
                 A-131905.1 
                 UAGAGGUGAAGCGAAGUGCACUU 
                 1577 
               
               
                   
               
               
                 AD-66110 
                 A-130441.7 
                 GUGCACUUCGCUUCACCUCUA 
                 1567 
                 A-131905.1 
                 UAGAGGUGAAGCGAAGUGCACUU 
                 1578 
               
               
                   
               
               
                 AD-65421 
                 A-130441.7 
                 GUGCACUUCGCUUCACCUCUA 
                 1568 
                 A-130442.6 
                 UAGAGGUGAAGCGAAGUGCACUU 
                 1579 
               
               
                   
               
               
                 AD-65407 
                 A-130371.12 
                 CGUGGUGGACUUCUCUCAAUU 
                 1569 
                 A-130372.5 
                 AAUUGAGAGAAGUCCACCAGCAG 
                 1580 
               
               
                   
               
               
                 AD-65377 
                 A-130384.4 
                 CGUGGUGGUCTUCUCUAAAUU 
                 1570 
                 A-130748.3 
                 AAUUGAGAGAAGUCCACCAGCUU 
                 1581 
               
               
                   
               
               
                 AD-65409 
                 A-130388.15 
                 GGUGGACUUCUCUCAAUUUUA 
                 1571 
                 A-131906.1 
                 UAAAAUUGAGAGAAGUCCACCAC 
                 1582 
               
               
                   
               
               
                 AD-66111 
                 A-130388.15 
                 GGUGGACUUCUCUCAAUUUUA 
                 1572 
                 A-131906.1 
                 UAAAAUUGAGAGAAGUCCACCAC 
                 1583 
               
               
                   
               
               
                 AD-65403 
                 A-130388.15 
                 GGUGGACUUCUCUCAAUUUUA 
                 1573 
                 A-130389.4 
                 UAAAAUUGAGAGAAGUCCACCAC 
                 1584 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 Modified Sense and Antisense Strand Sequences of HBV dsRNAs 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 SEQ 
                 Anti- 
                   
                 SEQ 
               
               
                 Duplex 
                   
                   
                 ID 
                 sense 
                   
                 ID 
               
               
                 ID 
                 Sense ID 
                 Sense Sequence (5′ to 3′) 
                 NO: 
                 ID 
                 Antisense Sequence (5′ to 3′) 
                 NO: 
               
               
                   
               
               
                 AD- 
                 A- 
                 uscsguGfgUfGfGfacuucucucaL96 
                 1585 
                 A- 
                     P   usGfsagaGfaAfGfuccaCfcAfcgasusu 
                 1596 
               
               
                 65381 
                 130366.9 
                   
                   
                 131904.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 uscsguGfgUfGfGfacuucucucaL96 
                 1586 
                 A- 
                     VP   usGfsagaGfaAfGfuccaCfcAfcgasusu 
                 1597 
               
               
                 66019 
                 130366.9 
                   
                   
                 131904.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 uscsguGfgUfGfGfacuucucucaL96 
                 1587 
                 A- 
                 usGfsagaGfaAfGfuccaCfcAfcgasusu 
                 1598 
               
               
                 65375 
                 130366.9 
                   
                   
                 130364.7 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsusgcacUfuCfGfCfuucaccucuaL96 
                 1588 
                 A- 
                     P   usAfsgagGfugaagcgAfaGfugcacsusu 
                 1599 
               
               
                 65427 
                 130441.7 
                   
                   
                 131905.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsusgcacUfuCfGfCfuucaccucuaL96 
                 1589 
                 A- 
                     VP   usAfsgagGfugaagcgAfaGfugcacsusu 
                 1600 
               
               
                 66110 
                 130441.7 
                   
                   
                 131905.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsusgcacUfuCfGfCfuucaccucuaL96 
                 1590 
                 A- 
                 usAfsgagGfugaagcgAfaGfugcacsusu 
                 1601 
               
               
                 65421 
                 130441.7 
                   
                   
                 130442.6 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csgsugguGfgAfCfUfucucUfCfaauuL96 
                 1591 
                 A- 
                 asAfsuugAfgAfgAfaguCfcAfccagcsasg 
                 1602 
               
               
                 65407 
                 130371.12 
                   
                   
                 130372.5 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csgsuggudGgucdTucucuaaauuL96 
                 1592 
                 A- 
                 asdAsuugagagdAagudCcaccagcsusu 
                 1603 
               
               
                 65377 
                 130384.4 
                   
                   
                 130748.3 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsgsuggaCfuUTCfUfcucaAfUfuuuaL96 
                 1593 
                 A- 
                     P   usAfsaaaUfuGfAfgagaAfgUfccaccsasc 
                 1604 
               
               
                 65409 
                 130388.15 
                   
                   
                 131906.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsgsuggaCfuUTCfUfcucaAfUfuuuaL96 
                 1594 
                 A- 
                     VP   usAfsaaaUfuGfAfgagaAfgUfccaccsasc 
                 1605 
               
               
                 66111 
                 130388.15 
                   
                   
                 131906.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsgsuggaCfuUTCfUfcucaAfUfuuuaL96 
                 1595 
                 A- 
                 usAfsaaaUfuGfAfgagaAfgUfccaccsasc 
                 1606 
               
               
                 65403 
                 130388.15 
                   
                   
                 130389.4 
               
               
                   
               
            
           
         
       
     
     A primary single dose screen of these iRNA duplexes was performed using the Dual-Glo® Luciferase assay, as described above. The results of this screen in Cos7 cells transfected with the indicated HBV iRNAs are shown in Table 16. Data are expressed as percent of mRNA remaining relative to negative control at 24 hours. 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 HBV single dose primary screen In Cos7 cells using Dual-Glo  
               
               
                 Luciferase ® Assay 
               
            
           
           
               
               
            
               
                   
                 Dual luciferase primary screen 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 DRC 
               
            
           
           
               
               
               
            
               
                   
                 % Message remaining at 24 hr 
                 ED50 
               
            
           
           
               
               
               
               
               
               
            
               
                 Duplex ID 
                 at 50 nM 
                 STDEV 
                 at 1 nM 
                 STDEV 
                 (nM) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 AD-65381 
                 9.3 
                 0.24 
                 15.6 
                 0.77 
                 0.019 
               
               
                 AD-66019 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 AD-65375 
                 24.2 
                 0.36 
                 71.4 
                 0.69 
                 No ED50 
               
               
                 AD-65427 
                 28.8 
                 1.60 
                 41.0 
                 1.73 
                 0.117 
               
               
                 AD-66110 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 AD-65421 
                 47.6 
                 3.49 
                 85.5 
                 4.76 
                 No ED50 
               
               
                 AD-65407 
                 14.3 
                 0.52 
                 25.3 
                 2.11 
                 0.038 
               
               
                 AD-65377 
                 21.8 
                 0.31 
                 37.9 
                 1.12 
                 0.130 
               
               
                 AD-65409 
                 9.5 
                 0.41 
                 13.2 
                 0.71 
                 0.013 
               
               
                 AD-66111 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 AD-65403 
                 12.6 
                 0.50 
                 37.2 
                 2.31 
                 0.069 
               
               
                   
               
               
                 ND—not done 
               
            
           
         
       
     
     These duplexes were also assayed for dose response for silencing viral RNA using the Dual-Glo® Luciferase assay, as described above. The doses of the duplexes used for these assays were 50 nM, 8.333333333 nM, 1.388888889 nM, 0.231481481 nM, 0.038580247 nM, 0.006430041 nM, 0.001071674 nM, 0.000178612 nM, 2.97687×10 −5  nM, 4.96145×10 −6  nM, 8.26909×10 −7  nM, and 1.37818E×10 −7  nM, which represent a 1 to 6 dilution of the duplexes starting at 50 nM over 12 doses. The results of this screen in Cos7 cells transfected with the indicated HBV iRNAs are shown in Table 17. Data are expressed as percent of mRNA remaining relative to negative control at 24 hours. 
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 Dose response screen In Cos7 cells using Dual-Glo Luciferase ® Assay 
               
               
                 Dual luciferase HBV reporter cells 
               
               
                 IC50 (nM) at 24 hr 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Duplex ID 
                 Assay 1 
                 Assay 2 
                 Assay 3 
                 Assay 4 
                 Assay 5 
                 Assay 6 
                 Assay 7 
                 Average 1   
                 Stdev 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 AD-65381 
                 0.019 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.019 
                   
               
               
                 AD-66019 
                 ND 
                 0.021 
                 0.021 
                 0.016 
                 0.026 
                 0.019 
                 0.031 
                 0.022 
                 0.005 
               
               
                 AD-65375 
                 UD 
                 0.215 
                 0.149 
                 0.081 
                 0.246 
                 0.138 
                 0.276 
                 0.184 
                 0.074 
               
               
                 AD-65407 
                 0.038 
                 0.045 
                 0.051 
                 0.021 
                 0.050 
                 0.056 
                 0.068 
                 0.047 
                 0.015 
               
               
                 AD-65377 
                 0.130 
                 0.029 
                 0.046 
                 0.087 
                 0.096 
                 0.146 
                 0.090 
                 0.089 
                 0.042 
               
               
                 AD-65409 
                 0.013 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.013 
               
               
                 AD-66111 
                 ND 
                 0.018 
                 0.013 
                 0.012 
                 0.018 
                 0.021 
                 0.033 
                 0.019 
                 0.007 
               
               
                 AD-65403 
                 0.069 
                 0.044 
                 0.033 
                 0.039 
                 0.042 
                 0.046 
                 0.062 
                 0.048 
                 0.013 
               
               
                 AD-65427 
                 0.017 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.117 
               
               
                 AD-66110 
                 ND 
                 0.238 
                 0.296 
                 0.145 
                 0.157 
                 0.161 
                 ND 
                 0.199 
                 0.065 
               
               
                 AD-65421 
                 UD 
                 1.219 
                 1.385 
                 2.254 
                 0.799 
                 2.906 
                 ND 
                 1.713 
                 0.852 
               
               
                   
               
               
                   1 Averages from 5-7 biological replicates run in triplicate 
               
               
                 ND—not done 
               
            
           
         
       
     
     The in vitro efficacy and potency of these duplexes were also assayed. In particular, the dose response of the duplexes for silencing viral RNA in transfected HepG2.2.15 and Hep3B cell lysates and for silencing HBsAg in HepG2.2.15 cell supernatants were determined. Cells were transfected with 12 separate doses of the duplexes ranging from 50 nM to 1×10 −7  nM and at seventy-two hours after transfection, the level of viral RNA was determined using primer/probe pairs to detect the P ORF and/or the S ORF. The level of HBsAg was determined using an ELISA assay. 
     The results of the P ORF viral RNA silencing in HepG2.2.15 cells using the indicated duplexes are provided in Table 18. The results of the S ORF viral RNA silencing in HepG2.2.15 cells using the indicated duplexes are provided in Table 19. The results of HBsAg silencing in HepG2.2.15 cells are provided in Table 20. 
     The results of the P ORF viral RNA silencing in Hep3B cells using the indicated duplexes are provided in Table 21. 
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 Dose response screen In HepG2.2.15 cells 
               
               
                 Viral RNA silencing in HepG2.2.15 cells 
               
               
                 P-ORF primer/probe set 
               
               
                 IC50 (nM) at 72 hr 
               
            
           
           
               
               
            
               
                   
                 Optimized Assay 
               
            
           
           
               
               
               
               
               
            
               
                 Duplex ID 
                 Assay Development 
                 Assay 1 
                 Assay 2 
                 Assay 3 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 AD-65381 
                 0.079 
                 0.208 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 AD-66019 
                 ND 
                 ND 
                 0.265 
                 0.010 
                 0.022 
                 0.032 
                 0.023 
               
               
                 AD-65375 
                 12.3   
                 UD 
                 UD 
                 UD 
                 0.172 
                 0.257 
                 0.672 
               
               
                 AD-65407 
                 0.247 
                 1.0  
                 0.365 
                 0.109 
                 0.069 
                 0.103 
                 0.095 
               
               
                 AD-65377 
                 1.3  
                 UD 
                 4.9  
                 UD 
                 0.842 
                 0.838 
                 0.615 
               
               
                 AD-65409 
                 0.436 
                 1.0  
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 AD-66111 
                 ND 
                 ND 
                 0.456 
                 0.030 
                 50 
                 0.294 
                 ND 
               
               
                 AD-65403 
                 9.2  
                 10.4   
                 3.4  
                 UD 
                 0.114 
                 0.384 
                 1.0  
               
               
                 AD-65427 
                 0.007 
                 0.018 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 AD-66110 
                 ND 
                 ND 
                 0.012 
                 0.053 
                 0.016 
                 0.010 
                 0.021 
               
               
                 AD-65421 
                 0.069 
                 0.091 
                 0.034 
                 0.006 
                 0.002 
                 0.003 
                 0.007 
               
               
                   
               
               
                 ND—not done 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 Dose response screen In HepG2.2.15 cells 
               
               
                 Viral RNA silencing in HepG2.2.15 cells 
               
               
                 S-ORF primer/probe set 
               
               
                 IC50 (nM) at 72 hr 
               
            
           
           
               
               
            
               
                   
                 Optimized Assay 
               
            
           
           
               
               
               
               
               
            
               
                 Duplex ID 
                 Assay Development 
                 Assay 1 
                 Assay 2 
                 Assay 3 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 AD-65381 
                 0.252 
                 0.215 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 AD-66019 
                 ND 
                 ND 
                 0.245 
                 0.011 
                 0.009 
                 0.016 
                 0.005 
               
               
                 AD-65375 
                 45    
                 UD 
                 UD 
                 UD 
                 0.124 
                 0.048 
                 0.056 
               
               
                 AD-65407 
                 0.232 
                 0.645 
                 0.577 
                 0.015 
                 0.021 
                 0.023 
                 0.016 
               
               
                 AD-65377 
                 1.4  
                 8.6  
                 UD 
                 UD 
                 0.575 
                 0.483 
                 0.117 
               
               
                 AD-65409 
                 0.433 
                 0.242 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 AD-66111 
                 ND 
                 ND 
                 2.1  
                 0.455 
                 ND 
                 0.416 
                 ND 
               
               
                 AD-65403 
                 0.997 
                 0.670 
                 0.668 
                 UD 
                 0.074 
                 0.270 
                 1.1  
               
               
                 AD-65427 
                 0.008 
                 0.018 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 AD-66110 
                 ND 
                 ND 
                 0.022 
                 0.050 
                 0.035 
                 0.038 
                 0.020 
               
               
                 AD-65421 
                 0.083 
                 0.097 
                 0.046 
                 0.003 
                 0.003 
                 0.005 
                 0.001 
               
               
                   
               
               
                 ND—not done 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 Dose response screen In HepG2.2.15 cells 
               
               
                 HBsAg ELISA 
               
               
                 IC50 (nM) 
               
            
           
           
               
               
               
            
               
                   
                 Duplex 
                   
               
               
                   
                 ID 
                 Assay 1 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 AD-65381 
                 ND 
               
               
                   
                 AD-66019 
                 0.105 
               
               
                   
                 AD-65375 
                 1.2 
               
               
                   
                 AD-65407 
                 0.102 
               
               
                   
                 AD-65377 
                 2.9 
               
               
                   
                 AD-65409 
                 ND 
               
               
                   
                 AD-66111 
                 0.018 
               
               
                   
                 AD-65403 
                 0.064 
               
               
                   
                 AD-65427 
                 ND 
               
               
                   
                 AD-66110 
                 0.002 
               
               
                   
                 AD-65421 
                 0.008 
               
               
                   
                   
               
               
                   
                 ND—not done 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 21 
               
             
            
               
                   
               
               
                 Dose response screen In Hep3B cells 
               
            
           
           
               
               
            
               
                   
                 Hep3B cells screen 
               
               
                   
                 DRC ED50 
               
               
                   
                 P-ORF primer/probe set 
               
            
           
           
               
               
               
               
            
               
                   
                 P-ORF 
                 P-ORF 
                   
               
               
                 Duplex ID 
                 run 1 
                 run 2 
                 Combined 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 AD-65381 
                 0.239 
                 0.110 
                 0.194 
               
               
                 AD-66019 
                 ND 
                 ND 
                 ND 
               
               
                 AD-65375 
                 ND 
                 ND 
                 ND 
               
               
                 AD-65427 
                 0.023 
                 0.006 
                 0.018 
               
               
                 AD-66110 
                 ND 
                 ND 
                 ND 
               
               
                 AD-65421 
                 ND 
                 ND 
                 ND 
               
               
                 AD-65407 
                 0.140 
                 1.383 
                 0.527 
               
               
                 AD-65377 
                 No ED50 
                 No ED50 
                 No ED50 
               
               
                 AD-65409 
                 1.807 
                 3.436 
                 2.905 
               
               
                 AD-66111 
                 ND 
                 ND 
                 ND 
               
               
                 AD-65403 
                 0.511 
                 18.036 
                 5.013 
               
               
                   
               
               
                 ND—not done 
               
            
           
         
       
     
     These duplexes were also assayed for in vitro stability using two assays, a tritosome stability assay and a cytosol stability assay, as described above. The results of these assays are provided in Table 22. 
     
       
         
           
               
             
               
                 TABLE 22 
               
             
            
               
                   
               
               
                 Twenty-four hour tritosome and cytosol stability assays. 
               
            
           
           
               
               
            
               
                   
                 In vitro metabolic stability 
               
               
                   
                 parent remaining at 24 hr  
               
               
                   
                 % incubation 
               
            
           
           
               
               
               
            
               
                   
                 Endo-lysosome 
                 Cytosol 
               
            
           
           
               
               
               
               
               
            
               
                 Duplex ID 
                 % AS 
                 % SS 
                 % AS 
                 % SS 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 AD-65381 
                 88 
                 72 
                 68 
                 22 
               
               
                 AD-66019 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 AD-65375 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 AD-65407 
                 100 
                 120 
                 64 
                 24 
               
               
                 AD-65377 
                 99 
                 127 
                 80 
                 67 
               
               
                 AD-65409 
                 105 
                 120 
                 86 
                 74 
               
               
                 AD-66111 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 AD-65403 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 AD-65427 
                 115 
                 80 
                 89 
                 66 
               
               
                 AD-66110 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 AD-65421 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
               
            
           
         
       
     
     Dose response screens of various combinations of these duplexes were also performed in HepG2.215 cells. The doses of the duplexes used for these assays were 50 nM, 8.333333333 nM, 1.388888889 nM, 0.231481481 nM, 0.038580247 nM, 0.006430041 nM, 0.001071674 nM, 0.000178612 nM, 2.97687×10 −5  nM, 4.96145×10 −6  nM, 8.26909×10 −7  nM, and 1.37818E×10 −7  nM, which represent a 1 to 6 dilution of the duplexes starting at 50 nM over 12 doses. At seventy-two hours after transfection of these duplexes, the level of viral RNA (P ORF and S ORF) and the level of secreted HBsAg were determined, as described above. The results of these assays are provided in Table 23. 
     
       
         
           
               
             
               
                 TABLE 23 
               
             
            
               
                   
               
               
                 Seventy-two hour HBV single dose screen In HepG2.2.15 cells 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 S-ORF2 
                 S-ORF2 
                 S-ORF2 
                 P-ORF1 
                 P-ORF1 
                 P-ORF1 
                 S Ag ELISA 
               
               
                   
                 IC50_A 
                 IC50_B 
                 IC50_Combine 
                 IC50_A 
                 IC50_B 
                 IC50_Combine 
                 ED50 
               
               
                 DuplexID 
                 (nM) 
                 (nM) 
                 (nM) 
                 (nM) 
                 (nM) 
                 (nM) 
                 (nM) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 AD-66019/AD-66110 
                 0.0091 
                 0.0017 
                 0.0038 
                 0.0213 
                 0.002 
                 0.0076 
                 0.007482 
               
               
                 AD-66019/AD-65421 
                 0.0438 
                 0.2371 
                 0.0131 
                 0.0367 
                 0.0106 
                 0.0204 
                 0.026398 
               
               
                 AD-65375/AD-66110 
                 0.0832 
                 1.0896 
                 0.193 
                 0.0377 
                 0.2348 
                 0.2022 
                 0.004174 
               
               
                 AD-65375/AD-65421 
                 0.084 
                 0.0475 
                 0.0708 
                 0.0566 
                 0.0388 
                 0.0371 
                 0.030822 
               
               
                 AD-65407/AD-66110 
                 0.0387 
                 0.001 
                 0.0083 
                 0.0402 
                 0.0018 
                 0.0116 
                 0.010172 
               
               
                 AD-65407/AD-65421 
                 0.0686 
                 0.0062 
                 0.0225 
                 0.0711 
                 0.0177 
                 0.0396 
                 0.066556 
               
               
                 AD-65377/AD-66110 
                 0.0634 
                 0.8267 
                 0.6269 
                 0.0477 
                 0.073 
                 0.0618 
                 0.01435 
               
               
                 AD-65377/AD-65421 
                 0.1461 
                 0.0468 
                 0.1372 
                 0.1207 
                 0.0088 
                 0.0451 
                 0.03419 
               
               
                 AD-66111/AD-66110 
                 0.0382 
                 0.0094 
                 0.0161 
                 0.0292 
                 0.0027 
                 0.0088 
                 0.013155 
               
               
                 AD-66111/AD-65421 
                 0.1628 
                 0.0919 
                 0.1579 
                 0.1297 
                 0.0396 
                 0.0722 
                 0.026889 
               
               
                 AD-65403/AD-66110 
                 0.0499 
                 0.0094 
                 0.0444 
                 0.0383 
                 0.0164 
                 0.0348 
                 0.003783 
               
               
                 AD-65403/AD-65421 
                 0.1011 
                 0.0007 
                 0.0208 
                 0.1118 
                 0.0031 
                 0.0297 
                 0.014569 
               
               
                   
               
            
           
         
       
     
     Example 6. Synthesis and In Vitro Screening of Additional siRNA Duplexes Targeting HBV 
     Additional iRNA molecules targeting the X ORF of the HBV genome were designed and synthesized as described above. A detailed list of the additional unmodified HBV sense and antisense strand sequences is shown in Table 24. A detailed list of the additional modified HBV sense and antisense strand sequences is shown in Table 25. 
     
       
         
           
               
             
               
                 TABLE 24 
               
             
            
               
                   
               
               
                 Unmodified Sense and Antisense Strand Sequences of HBV dsRNAs 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Sense 
                   
                 SEQ 
                 Antisense 
                   
                 SEQ 
               
               
                 Duplex 
                 Oligo 
                 Sence Sequence 
                 ID 
                 Oligo 
                 Antisense Sequence 
                 ID 
               
               
                 ID 
                 Name 
                 (5′ to 3′) 
                 NO: 
                 Name 
                 (5′ to 3′) 
                 NO: 
               
               
                   
               
               
                 AD-65776 
                 A-131859.1 
                 UGUGCACUUCGCUUCACCUCU 
                 1607 
                 A-131860.1 
                 AGAGGUGAAGCGAAGUGCACACG 
                 1653 
               
               
                   
               
               
                 AD-65782 
                 A-131877.1 
                 UGCACUUCGCUUCACCUCUGA 
                 1608 
                 A-131878.1 
                 UCAGAGGUGAAGCGAAGUGCACA 
                 1654 
               
               
                   
               
               
                 AD-65792 
                 A-131865.1 
                 GUGUGCACUUCGCUUCACCUA 
                 1609 
                 A-131866.1 
                 UAGGUGAAGCGAAGUGCACACGG 
                 1655 
               
               
                   
               
               
                 AD-65781 
                 A-131861.1 
                 CGUGUGCACUUCGCUUCACCU 
                 1610 
                 A-131862.1 
                 AGGUGAAGCGAAGUGCACACGGU 
                 1656 
               
               
                   
               
               
                 AD-64304 
                 A-128443.6 
                 GUGCACUUCGCUUCACCUCUA 
                 1611 
                 A-128444.5 
                 UAGAGGUGAAGCGAAGUGCACAC 
                 1657 
               
               
                   
               
               
                 AD-65771 
                 A-131857.1 
                 CCGUGUGCACUUCGCUUCACA 
                 1612 
                 A-131858.1 
                 UGUGAAGCGAAGUGCACACGGUC 
                 1658 
               
               
                   
               
               
                 AD-65758 
                 A-131867.1 
                 CACUUCGCUUCACCUCUGCAA 
                 1613 
                 A-131868.1 
                 UUGCAGAGGUGAAGCGAAGUGCA 
                 1659 
               
               
                   
               
               
                 AD-65777 
                 A-131875.1 
                 ACUUCGCUUCACCUCUGCACA 
                 1614 
                 A-131876.1 
                 UGUGCAGAGGUGAAGCGAAGUGC 
                 1660 
               
               
                   
               
               
                 AD-61567 
                 A-123525.2 
                 GGCUGUAGGCAUAAAUUGGUA 
                 1615 
                 A-123526.2 
                 UACCAAUUUAUGCCUACAGCCUC 
                 1661 
               
               
                   
               
               
                 AD-65772 
                 A-131873.1 
                 UUCGCUUCACCUCUGCACGUA 
                 1616 
                 A-131874.1 
                 UACGUGCAGAGGUGAAGCGAAGU 
                 1662 
               
               
                   
               
               
                 AD-65767 
                 A-131871.1 
                 UCGCUUCACCUCUGCACGUCA 
                 1617 
                 A-131872.1 
                 UGACGUGCAGAGGUGAAGCGAAG 
                 1663 
               
               
                   
               
               
                 AD-65763 
                 A-131869.1 
                 CUUCGCUUCACCUCUGCACGU 
                 1618 
                 A-131870.1 
                 ACGUGCAGAGGUGAAGCGAAGUG 
                 1664 
               
               
                   
               
               
                 AD-64281 
                 A-128395.3 
                 CCCCGUCUGUGCCUUCUCAUA 
                 1619 
                 A-128396.2 
                 UAUGAGAAGGCACAGACGGGGAG 
                 1665 
               
               
                   
               
               
                 AD-64311 
                 A-128391.3 
                 CCGUCUGUGCCUUCUCAUCUA 
                 1620 
                 A-128392.2 
                 UAGAUGAGAAGGCACAGACGGGG 
                 1666 
               
               
                   
               
               
                 AD-65790 
                 A-131837.1 
                 CCAGCACCAUGCAACUUUUUA 
                 1621 
                 A-131838.1 
                 UAAAAAGUUGCAUGGUGCUGGUG 
                 1667 
               
               
                   
               
               
                 AD-65761 
                 A-131841.1 
                 CACCAGCACCAUGCAACUUUU 
                 1622 
                 A-131842.1 
                 AAAAGUUGCAUGGUGCUGGUGCG 
                 1668 
               
               
                   
               
               
                 AD-65786 
                 A-131849.1 
                 CACCAUGCAACUUUUUCACCU 
                 1623 
                 A-131850.1 
                 AGGUGAAAAAGUUGCAUGGUGCU 
                 1669 
               
               
                   
               
               
                 AD-65785 
                 A-131835.1 
                 CAAUGUCAACGACCGACCUUA 
                 1624 
                 A-131836.1 
                 UAAGGUCGGUCGUUGACAUUGCA 
                 1670 
               
               
                   
               
               
                 AD-65787 
                 A-131863.1 
                 CGCUUCACCUCUGCACGUCGA 
                 1625 
                 A-131864.1 
                 UCGACGUGCAGAGGUGAAGCGAA 
                 1671 
               
               
                   
               
               
                 AD-65770 
                 A-131845.1 
                 ACCUUGAGGCAUACUUCAAAG 
                 1626 
                 A-131846.1 
                 CUUUGAAGUAUGCCUCAAGGUCG 
                 1672 
               
               
                   
               
               
                 AD-65766 
                 A-131843.1 
                 CCGACCUUGAGGCAUACUUCA 
                 1627 
                 A-131844.1 
                 UGAAGUAUGCCUCAAGGUCGGUC 
                 1673 
               
               
                   
               
               
                 AD-61555 
                 A-123521.2 
                 GACCUUGAGGCAUACUUCAAA 
                 1628 
                 A-123522.2 
                 UUUGAAGUAUGCCUCAAGGUCGG 
                 1674 
               
               
                   
               
               
                 AD-65762 
                 A-131855.1 
                 ACCGACCUUGAGGCAUACUUA 
                 1629 
                 A-131856.1 
                 UAAGUAUGCCUCAAGGUCGGUCG 
                 1675 
               
               
                   
               
               
                 AD-65755 
                 A-131827.1 
                 UCGCAUGGAGACCACCGUGAA 
                 1630 
                 A-131828.1 
                 UUCACGGUGGUCUCCAUGCGACG 
                 1676 
               
               
                   
               
               
                 AD-65788 
                 A-131811.1 
                 UUACAUAAGAGGACUCUUGGA 
                 1631 
                 A-131812.1 
                 UCCAAGAGUCCUCUUAUGUAAGA 
                 1677 
               
               
                   
               
               
                 AD-65768 
                 A-131803.1 
                 UCUUACAUAAGAGGACUCUUA 
                 1632 
                 A-131804.1 
                 UAAGAGUCCUCUUAUGUAAGACC 
                 1678 
               
               
                   
               
               
                 AD-61561 
                 A-123523.2 
                 ACUUCAAAGACUGUUUGUUUA 
                 1633 
                 A-123524.2 
                 UAAACAAACAGUCUUUGAAGUAU 
                 1679 
               
               
                   
               
               
                 AD-65764 
                 A-131801.1 
                 UACUUCAAAGACUGUUUGUUU 
                 1634 
                 A-131802.1 
                 AAACAAACAGUCUUUGAAGUAUG 
                 1680 
               
               
                   
               
               
                 AD-65753 
                 A-131799.1 
                 AUACUUCAAAGACUGUUUGUU 
                 1635 
                 A-131800.1 
                 AACAAACAGUCUUUGAAGUAUGC 
                 1681 
               
               
                   
               
               
                 AD-65765 
                 A-131817.1 
                 UUGUUUAAAGACUGGGAGGAA 
                 1636 
                 A-131818.1 
                 UUCCUCCCAGUCUUUAAACAAAC 
                 1682 
               
               
                   
               
               
                 AD-65769 
                 A-131819.1 
                 GCAUACUUCAAAGACUGUUUA 
                 1637 
                 A-131820.1 
                 UAAACAGUCUUUGAAGUAUGCCU 
                 1683 
               
               
                   
               
               
                 AD-65759 
                 A-131815.1 
                 CAAAGACUGUUUGUUUAAAGA 
                 1638 
                 A-131816.1 
                 UCUUUAAACAAACAGUCUUUGAA 
                 1684 
               
               
                   
               
               
                 AD-65774 
                 A-131831.1 
                 AGACUGUUUGUUUAAAGACUA 
                 1639 
                 A-131832.1 
                 UAGUCUUUAAACAAACAGUCUUU 
                 1685 
               
               
                   
               
               
                 AD-65778 
                 A-131807.1 
                 GUUUGUUUAAAGACUGGGAGA 
                 1640 
                 A-131808.1 
                 UCUCCCAGUCUUUAAACAAACAG 
                 1686 
               
               
                   
               
               
                 AD-65773 
                 A-131805.1 
                 GGGGGAGGAGAUUAGAUUAAA 
                 1641 
                 A-131806.1 
                 UUUAAUCUAAUCUCCUCCCCCAA 
                 1687 
               
               
                   
               
               
                 AD-65789 
                 A-131825.1 
                 GGGGAGGAGAUUAGAUUAAAG 
                 1642 
                 A-131826.1 
                 CUUUAAUCUAAUCUCCUCCCCCA 
                 1688 
               
               
                   
               
               
                 AD-65783 
                 A-131809.1 
                 GUUGGGGGAGGAGAUUAGAUU 
                 1643 
                 A-131810.1 
                 AAUCUAAUCUCCUCCCCCAACUC 
                 1689 
               
               
                   
               
               
                 AD-65754 
                 A-131813.1 
                 UUGGGGGAGGAGAUUAGAUUA 
                 1644 
                 A-131814.1 
                 UAAUCUAAUCUCCUCCCCCAACU 
                 1690 
               
               
                   
               
               
                 AD-65779 
                 A-131821.1 
                 GGGAGGAGAUUAGAUUAAAGA 
                 1645 
                 A-131822.1 
                 UCUUUAAUCUAAUCUCCUCCCCC 
                 1691 
               
               
                   
               
               
                 AD-65791 
                 A-131851.1 
                 UUAGAUUAAAGGUCUUUGUAA 
                 1646 
                 A-131852.1 
                 UUACAAAGACCUUUAAUCUAAUC 
                 1692 
               
               
                   
               
               
                 AD-65760 
                 A-131829.1 
                 UAGAUUAAAGGUCUUUGUACU 
                 1647 
                 A-131830.1 
                 AGUACAAAGACCUUUAAUCUAAU 
                 1693 
               
               
                   
               
               
                 AD-65784 
                 A-131823.1 
                 AUUAGAUUAAAGGUCUUUGUA 
                 1648 
                 A-131824.1 
                 UACAAAGACCUUUAAUCUAAUCU 
                 1694 
               
               
                   
               
               
                 AD-65757 
                 A-131853.1 
                 GAGGAGAUUAGAUUAAAGGUA 
                 1649 
                 A-131854.1 
                 UACCUUUAAUCUAAUCUCCUCCC 
                 1695 
               
               
                   
               
               
                 AD-65775 
                 A-131847.1 
                 GGACUCUUGGACUCUCUGCAA 
                 1650 
                 A-131848.1 
                 UUGCAGAGAGUCCAAGAGUCCUC 
                 1696 
               
               
                   
               
               
                 AD-65780 
                 A-131833.1 
                 ACUCUUGGACUCUCUGCAAUA 
                 1651 
                 A-131834.1 
                 UAUUGCAGAGAGUCCAAGAGUCC 
                 1697 
               
               
                   
               
               
                 AD-65756 
                 A-131839.1 
                 AGAUUAAAGGUCUUUGUACUA 
                 1652 
                 A-131840.1 
                 UAGUACAAAGACCUUUAAUCUAA 
                 1698 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 25 
               
             
            
               
                   
               
               
                 Modified Sense and Antisense Strand Sequences of HBV dsRNAs 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Anti- 
                   
                   
               
               
                   
                 Sense 
                   
                 SEQ 
                 sense 
                   
                 SEQ 
               
               
                 Duplex 
                 Oligo 
                   
                 ID 
                 Oligo 
                   
                 ID 
               
               
                 ID 
                 Name 
                 Sense Sequence (5′ to 3′) 
                 NO: 
                 Name 
                 Antisense Sequence (5′ to 3′) 
                 NO: 
               
               
                   
               
               
                 AD- 
                 A- 
                 UfsgsUfgCfaCfuUfCfGfcUfuC 
                 1699 
                 A- 
                 asGfsaGfgUfgAfaGfcgaAfgUfgCfa 
                 1745 
               
               
                 65776 
                 131859.1 
                 faCfcUfcUfL96 
                   
                 131860.1 
                 Cfascsg 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 UfsgsCfaCfuUfcGfCfUfuCfaC 
                 1700 
                 A- 
                 usCfsaGfaGfgUfgAfagcGfaAfgUfg 
                 1746 
               
               
                 65782 
                 131877.1 
                 fcUfcUfgAfL96 
                   
                 131878.1 
                 Cfascsa 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 GfsusGfuGfcAfcUfUfCfgCfuU 
                 1701 
                 A- 
                 usAfsgGfuGfaAfgCfgaaGfuGfcAfc 
                 1747 
               
               
                 65792 
                 131865.1 
                 fcAfcCfuAfL96 
                   
                 131866.1 
                 Afcsgsg 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 CfsgsUfgUfgCfaCfUfUfcGfcU 
                 1702 
                 A- 
                 asGfsgUfgAfaGfcGfaagUfgCfaCfa 
                 1748 
               
               
                 65781 
                 131861.1 
                 fuCfaCfcUfL96 
                   
                 131862.1 
                 Cfgsgsu 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 GfsusGfcAfcUfuCfGfCfuUfcA 
                 1703 
                 A- 
                 usAfsgAfgGfuGfaAfgcgAfaGfuGfc 
                 1749 
               
               
                 64304 
                 128443.6 
                 fcCfuCfuAfL96 
                   
                 128444.5 
                 Afcsasc 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 CfscsGfuGfuGfcAfCfUfuCfgC 
                 1704 
                 A- 
                 usGfsuGfaAfgCfgAfaguGfcAfcAfc 
                 1750 
               
               
                 65771 
                 131857.1 
                 fuUfcAfcAfL96 
                   
                 131858.1 
                 Gfgsusc 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 CfsasCfuUfcGfcUfUfCfaCfcU 
                 1705 
                 A- 
                 usUfsgCfaGfaGfgUfgaaGfcGfaAfg 
                 1751 
               
               
                 65758 
                 131867.1 
                 fcUfgCfaAfL96 
                   
                 131868.1 
                 Ufgscsa 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 AfscsUfuCfgCfuUfCfAfcCfuC 
                 1706 
                 A- 
                 usGfsuGfcAfgAfgGfugaAfgCfgAfa 
                 1752 
               
               
                 65777 
                 131875.1 
                 fuGfcAfcAfL96 
                   
                 131876.1 
                 Gfusgsc 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 GfsgsCfuGfuAfgGfCfAfuAfaA 
                 1707 
                 A- 
                 usAfscCfaAfuUfuAfugcCfuAfcAfg 
                 1753 
               
               
                 61567 
                 123525.2 
                 fuUfgGfuAfL96 
                   
                 123526.2 
                 Cfcsusc 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 UfsusCfgCfuUfcAfCfCfuCfuG 
                 1708 
                 A- 
                 usAfscGfuGfcAfgAfgguGfaAfgCfg 
                 1754 
               
               
                 65772 
                 131873.1 
                 fcAfcGfuAfL96 
                   
                 131874.1 
                 Afasgsu 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 UfscsGfcUfuCfaCfCfUfcUfgC 
                 1709 
                 A- 
                 usGfsaCfgUfgCfaGfaggUfgAfaGfc 
                 1755 
               
               
                 65767 
                 131871.1 
                 faCfgUfcAfL96 
                   
                 131872.1 
                 Gfasasg 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 CfsusUfcGfcUfuCfAfCfcUfcU 
                 1710 
                 A- 
                 asCfsgUfgCfaGfaGfgugAfaGfcGfa 
                 1756 
               
               
                 65763 
                 131869.1 
                 fgCfaCfgUfL96 
                   
                 131870.1 
                 Afgsusg 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 CfscsCfcGfuCfuGfUfGfcCfuU 
                 1711 
                 A- 
                 usAfsuGfaGfaAfgGfcacAfgAfcGfg 
                 1757 
               
               
                 64281 
                 128395.3 
                 fcUfcAfuAfL96 
                   
                 128396.2 
                 Gfgsasg 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 CfscsGfuCfuGfuGfCfCfuUfcU 
                 1712 
                 A- 
                 usAfsgAfuGfaGfaAfggcAfcAfgAfc 
                 1758 
               
               
                 64311 
                 128391.3 
                 fcAfuCfuAfL96 
                   
                 128392.2 
                 Gfgsgsg 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 CfscsAfgCfaCfcAfUfGfcAfaC 
                 1713 
                 A- 
                 usAfsaAfaAfgUfuGfcauGfgUfgCfu 
                 1759 
               
               
                 65790 
                 131837.1 
                 fuUfuUfuAfL96 
                   
                 131838.1 
                 Gfgsusg 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 CfsasCfcAfgCfaCfCfAfuGfcA 
                 1714 
                 A- 
                 asAfsaAfgUfuGfcAfuggUfgCfuGfg 
                 1760 
               
               
                 65761 
                 131841.1 
                 faCfuUfuUfL96 
                   
                 131842.1 
                 Ufgscsg 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 CfsasCfcAfuGfcAfAfCfuUfuU 
                 1715 
                 A- 
                 asGfsgUfgAfaAfaAfguuGfcAfuGfg 
                 1761 
               
               
                 65786 
                 131849.1 
                 fuCfaCfcUfL96 
                   
                 131850.1 
                 Ufgscsu 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 CfsasAfuGfuCfaAfCfGfaCfcG 
                 1716 
                 A- 
                 usAfsaGfgUfcGfgUfcguUfgAfcAfu 
                 1762 
               
               
                 65785 
                 131835.1 
                 faCfcUfuAfL96 
                   
                 131836.1 
                 Ufgscsa 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 CfsgsCfuUfcAfcCfUfCfuGfcA 
                 1717 
                 A- 
                 usCfsgAfcGfuGfcAfgagGfuGfaAfg 
                 1763 
               
               
                 65787 
                 131863.1 
                 fcGfuCfgAfL96 
                   
                 131864.1 
                 Cfgsasa 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 AfscsCfuUfgAfgGfCfAfuAfcU 
                 1718 
                 A- 
                 csUfsuUfgAfaGfuAfugcCfuCfaAfg 
                 1764 
               
               
                 65770 
                 131845.1 
                 fuCfaAfaGfL96 
                   
                 131846.1 
                 Gfuscsg 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 CfscsGfaCfcUfuGfAfGfgCfaU 
                 1719 
                 A- 
                 usGfsaAfgUfaUfgCfcucAfaGfgUfc 
                 1765 
               
               
                 65766 
                 131843.1 
                 faCfuUfcAfL96 
                   
                 131844.1 
                 Gfgsusc 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 GfsasCfcUfuGfaGfGfCfaUfaC 
                 1720 
                 A- 
                 usUfsuGfaAfgUfaUfgccUfcAfaGfg 
                 1766 
               
               
                 61555 
                 123521.2 
                 fuUfcAfaAfL96 
                   
                 123522.2 
                 Ufcsgsg 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 AfscsCfgAfcCfuUfGfAfgGfcA 
                 1721 
                 A- 
                 usAfsaGfuAfuGfcCfucaAfgGfuCfg 
                 1767 
               
               
                 65762 
                 131855.1 
                 fuAfcUfuAfL96 
                   
                 131856.1 
                 Gfuscsg 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 UfscsGfcAfuGfgAfGfAfcCfaC 
                 1722 
                 A- 
                 usUfscAfcGfgUfgGfucuCfcAfuGfc 
                 1768 
               
               
                 65755 
                 131827.1 
                 fcGfuGfaAfL96 
                   
                 131828.1 
                 Gfascsg 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 UfsusAfcAfuAfaGfAfGfgAfcU 
                 1723 
                 A- 
                 usCfscAfaGfaGfuCfcucUfuAfuGfu 
                 1769 
               
               
                 65788 
                 131811.1 
                 fcUfuGfgAfL96 
                   
                 131812.1 
                 Afasgsa 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 UfscsUfuAfcAfuAfAfGfaGfgA 
                 1724 
                 A- 
                 usAfsaGfaGfuCfcUfcuuAfuGfuAfa 
                 1770 
               
               
                 65768 
                 131803.1 
                 fcUfcUfuAfL96 
                   
                 131804.1 
                 Gfascsc 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 AfscsUfuCfaAfaGfAfCfuGfuU 
                 1725 
                 A- 
                 usAfsaAfcAfaAfcAfgucUfuUfgAfa 
                 1771 
               
               
                 61561 
                 123523.2 
                 fuGfuUfuAfL96 
                   
                 123524.2 
                 Gfusasu 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 UfsasCfuUfcAfaAfGfAfcUfgU 
                 1726 
                 A- 
                 asAfsaCfaAfaCfaGfucuUfuGfaAfg 
                 1772 
               
               
                 65764 
                 131801.1 
                 fuUfgUfuUfL96 
                   
                 131802.1 
                 Ufasusg 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 AfsusAfcUfuCfaAfAfGfaCfuG 
                 1727 
                 A- 
                 asAfscAfaAfcAfgUfcuuUfgAfaGfu 
                 1773 
               
               
                 65753 
                 131799.1 
                 fuUfuGfuUfL96 
                   
                 131800.1 
                 Afusgsc 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 UfsusGfuUfuAfaAfGfAfcUfgG 
                 1728 
                 A- 
                 usUfscCfuCfcCfaGfucuUfuAfaAfc 
                 1774 
               
               
                 65765 
                 131817.1 
                 fgAfgGfaAfL96 
                   
                 131818.1 
                 Afasasc 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 GfscsAfuAfcUfuCfAfAfaGfaC 
                 1729 
                 A- 
                 usAfsaAfcAfgUfcUfuugAfaGfuAfu 
                 1775 
               
               
                 65769 
                 131819.1 
                 fuGfuUfuAfL96 
                   
                 131820.1 
                 Gfcscsu 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 CfsasAfaGfaCfuGfUfUfuGfuU 
                 1730 
                 A- 
                 usCfsuUfuAfaAfcAfaacAfgUfcUfu 
                 1776 
               
               
                 65759 
                 131815.1 
                 fuAfaAfgAfL96 
                   
                 131816.1 
                 Ufgsasa 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 AfsgsAfcUfgUfuUfGfUfuUfaA 
                 1731 
                 A- 
                 usAfsgUfcUfuUfaAfacaAfaCfaGfu 
                 1777 
               
               
                 65774 
                 131831.1 
                 faGfaCfuAfL96 
                   
                 131832.1 
                 Cfususu 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 GfsusUfuGfuUfuAfAfAfgAfcU 
                 1732 
                 A- 
                 usCfsuCfcCfaGfuCfuuuAfaAfcAfa 
                 1778 
               
               
                 65778 
                 131807.1 
                 fgGfgAfgAfL96 
                   
                 131808.1 
                 Afcsasg 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 GfsgsGfgGfaGfgAfGfAfuUfaG 
                 1733 
                 A- 
                 usUfsuAfaUfcUfaAfucuCfcUfcCfc 
                 1779 
               
               
                 65773 
                 131805.1 
                 faUfuAfaAfL96 
                   
                 131806.1 
                 Cfcsasa 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 GfsgsGfgAfgGfaGfAfUfuAfgA 
                 1734 
                 A- 
                 csUfsuUfaAfuCfuAfaucUfcCfuCfc 
                 1780 
               
               
                 65789 
                 131825.1 
                 fuUfaAfaGfL96 
                   
                 131826.1 
                 Cfcscsa 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 GfsusUfgGfgGfgAfGfGfaGfaU 
                 1735 
                 A- 
                 asAfsuCfuAfaUfcUfccuCfcCfcCfa 
                 1781 
               
               
                 65783 
                 131809.1 
                 fuAfgAfuUfL96 
                   
                 131810.1 
                 Afcsusc 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 UfsusGfgGfgGfaGfGfAfgAfuU 
                 1736 
                 A- 
                 usAfsaUfcUfaAfuCfuccUfcCfcCfc 
                 1782 
               
               
                 65754 
                 131813.1 
                 faGfaUfuAfL96 
                   
                 131814.1 
                 Afascsu 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 GfsgsGfaGfgAfgAfUfUfaGfaU 
                 1737 
                 A- 
                 usCfsuUfuAfaUfcUfaauCfuCfcUfc 
                 1783 
               
               
                 65779 
                 131821.1 
                 fuAfaAfgAfL96 
                   
                 131822.1 
                 Cfcscsc 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 UfsusAfgAfuUfaAfAfGfgUfcU 
                 1738 
                 A- 
                 usUfsaCfaAfaGfaCfcuuUfaAfuCfu 
                 1784 
               
               
                 65791 
                 131851.1 
                 fuUfgUfaAfL96 
                   
                 131852.1 
                 Afasusc 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 UfsasGfaUfuAfaAfGfGfuCfuU 
                 1739 
                 A- 
                 asGfsuAfcAfaAfgAfccuUfuAfaUfc 
                 1785 
               
               
                 65760 
                 131829.1 
                 fuGfuAfcUfL96 
                   
                 131830.1 
                 Ufasasu 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 AfsusUfaGfaUfuAfAfAfgGfuC 
                 1740 
                 A- 
                 usAfscAfaAfgAfcCfuuuAfaUfcUfa 
                 1786 
               
               
                 65784 
                 131823.1 
                 fuUfuGfuAfL96 
                   
                 131824.1 
                 Afuscsu 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 GfsasGfgAfgAfuUfAfGfaUfuA 
                 1741 
                 A- 
                 usAfscCfuUfuAfaUfcuaAfuCfuCfc 
                 1787 
               
               
                 65757 
                 131853.1 
                 faAfgGfuAfL96 
                   
                 131854.1 
                 Ufcscsc 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 GfsgsAfcUfcUfuGfGfAfcUfcU 
                 1742 
                 A- 
                 usUfsgCfaGfaGfaGfuccAfaGfaGfu 
                 1788 
               
               
                 65775 
                 131847.1 
                 fcUfgCfaAfL96 
                   
                 131848.1 
                 Cfcsusc 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 AfscsUfcUfuGfgAfCfUfcUfcU 
                 1743 
                 A- 
                 usAfsuUfgCfaGfaGfaguCfcAfaGfa 
                 1789 
               
               
                 65780 
                 131833.1 
                 fgCfaAfuAfL96 
                   
                 131834.1 
                 Gfuscsc 
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 AfsgsAfuUfaAfaGfGfUfcUfuU 
                 1744 
                 A- 
                 usAfsgUfaCfaAfaGfaccUfuUfaAfu 
                 1790 
               
               
                 65756 
                 131839.1 
                 fgUfaCfuAfL96 
                   
                 131840.1 
                 Cfusasa 
               
               
                   
               
            
           
         
       
     
     A single dose screen of these duplexes was performed in Cos7 cells at 1 nm and 50 nm using the Dual-Glo® Luciferase assay described above. The results of the assays are provided in Table 26. 
     
       
         
           
               
             
               
                 TABLE 26 
               
             
            
               
                   
               
               
                 HBV single dose screen using Dual-Glo Luciferase ® Assay 
               
            
           
           
               
               
               
               
               
            
               
                 Duplex ID 
                 50 nM 
                 STDEV 
                 1 nM 
                 STDEV 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 AD-65776 
                 20.11 
                 4.21 
                 40.79 
                 1.89 
               
               
                 AD-65782 
                 26.31 
                 3.10 
                 61.07 
                 9.16 
               
               
                 AD-65792 
                 43.31 
                 5.24 
                 61.09 
                 6.02 
               
               
                 AD-65781 
                 25.77 
                 3.66 
                 39.63 
                 2.87 
               
               
                 AD-64304 
                 18.87 
                 1.26 
                 29.72 
                 3.37 
               
               
                 AD-65771 
                 17.16 
                 1.78 
                 37.55 
                 2.20 
               
               
                 AD-65758 
                 31.74 
                 8.26 
                 65.77 
                 11.05 
               
               
                 AD-65777 
                 59.76 
                 11.15 
                 77.63 
                 5.14 
               
               
                 AD-61567 
                 17.69 
                 5.29 
                 26.45 
                 5.66 
               
               
                 AD-65772 
                 58.07 
                 9.67 
                 75.66 
                 4.92 
               
               
                 AD-65767 
                 29.65 
                 1.60 
                 39.64 
                 4.36 
               
               
                 AD-65763 
                 25.10 
                 5.77 
                 47.78 
                 9.99 
               
               
                 AD-64281 
                 39.07 
                 6.80 
                 51.46 
                 4.19 
               
               
                 AD-64311 
                 20.51 
                 1.96 
                 37.80 
                 3.53 
               
               
                 AD-65790 
                 50.41 
                 7.00 
                 70.30 
                 1.95 
               
               
                 AD-65761 
                 13.30 
                 4.38 
                 21.14 
                 3.49 
               
               
                 AD-65786 
                 12.45 
                 3.51 
                 22.62 
                 0.33 
               
               
                 AD-65785 
                 36.87 
                 6.04 
                 51.49 
                 4.18 
               
               
                 AD-65787 
                 27.97 
                 5.73 
                 48.18 
                 7.65 
               
               
                 AD-65770 
                 22.67 
                 5.39 
                 41.48 
                 8.52 
               
               
                 AD-65766 
                 31.44 
                 3.35 
                 50.25 
                 0.45 
               
               
                 AD-61555 
                 18.43 
                 10.83 
                 22.61 
                 0.57 
               
               
                 AD-65762 
                 18.87 
                 4.86 
                 34.94 
                 4.81 
               
               
                 AD-65755 
                 47.03 
                 9.38 
                 83.19 
                 9.68 
               
               
                 AD-65788 
                 35.85 
                 10.13 
                 58.07 
                 4.78 
               
               
                 AD-65768 
                 24.02 
                 2.49 
                 28.55 
                 2.53 
               
               
                 AD-61561 
                 8.11 
                 1.29 
                 14.26 
                 2.27 
               
               
                 AD-65764 
                 16.89 
                 3.99 
                 29.10 
                 1.03 
               
               
                 AD-65753 
                 19.10 
                 2.87 
                 29.79 
                 5.26 
               
               
                 AD-65765 
                 55.40 
                 10.72 
                 76.93 
                 8.79 
               
               
                 AD-65769 
                 19.24 
                 4.47 
                 23.18 
                 2.54 
               
               
                 AD-65759 
                 48.86 
                 4.81 
                 87.31 
                 13.75 
               
               
                 AD-65774 
                 102.27 
                 12.33 
                 100.79 
                 3.24 
               
               
                 AD-65778 
                 64.39 
                 2.60 
                 80.67 
                 2.59 
               
               
                 AD-65773 
                 72.64 
                 7.87 
                 80.80 
                 4.83 
               
               
                 AD-65789 
                 73.59 
                 4.35 
                 94.72 
                 3.32 
               
               
                 AD-65783 
                 54.41 
                 7.15 
                 84.46 
                 4.32 
               
               
                 AD-65754 
                 62.51 
                 4.12 
                 102.63 
                 21.42 
               
               
                 AD-65779 
                 47.40 
                 7.51 
                 76.20 
                 2.05 
               
               
                 AD-65791 
                 12.09 
                 0.70 
                 19.19 
                 3.46 
               
               
                 AD-65760 
                 13.50 
                 4.84 
                 25.37 
                 2.09 
               
               
                 AD-65784 
                 19.84 
                 1.27 
                 31.04 
                 3.49 
               
               
                 AD-65757 
                 22.66 
                 3.97 
                 24.50 
                 5.81 
               
               
                 AD-65775 
                 47.78 
                 3.30 
                 58.81 
                 3.05 
               
               
                 AD-65780 
                 29.10 
                 2.87 
                 42.85 
                 2.73 
               
               
                 AD-65756 
                 10.49 
                 1.62 
                 19.95 
                 2.58 
               
               
                   
               
            
           
         
       
     
     Based on these assays, RNAi agents targeting five sites in the HBV X ORF (nucleotides 1551, 1577, 1580, 1806, and 1812 of GenBank Accession No. NC_003977.1) were selected for lead optimization and additional agents were designed and synthesized. These additional agents are evaluated in in vitro assays as described above. A detailed list of the additional unmodified sense and antisense strand sequences targeting the HBV X ORF is shown in Table 27. A detailed list of the additional modified sense and antisense strand sequences targeting the HBV X ORF is shown in Table 28. 
     These iRNA agents were also assessed for in vivo efficacy using an AAV-HBV mouse model (see, e.g., Yang, et al. (2014)  Cell and Mol Immunol  11:71). This mouse model exhibits sustained HBV viremia after infection with a recombinant adeno-associated virus (AAV) carrying a replicable HBV genome. Liver expression of the HBV gene in these mice mimics HBV infection in humans and these mice exhibit significant liver inflammation and liver damage, manifested by increased ALT levels, fibrosis and steatosis. 
     These AAV-HBV mice were subcutaneously administered a single 3 mg/kg dose of AD-66808, AD-66809, AD-66810, AD-66811, AD-66812, AD-66813, AD-66814, AD-66815, AD-66816, and AD-66817 and the level of HBsAg was determined in the serum of the animals pre-dose, and at day 14/15 post-dose. The results of these experiments are provided in Table 29 and demonstrate that serum levels of HBsAg are decrease following a single administration of these agents. Table 29 also provides the results of a single dose screen in Cos7 cells transfected with the indicated HBV iRNAs using the Dual-Glo® Luciferase assay, as described above, for the same RNAi agents. Data are expressed as percent of mRNA remaining relative to negative control at 24 hours. 
     
       
         
           
               
             
               
                 TABLE 27 
               
             
            
               
                   
               
               
                 Unmodified HBV X ORF Sense and Antisense Sequences. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                   
                 SEQ 
               
               
                 Duplex 
                 Sense Sequence 
                 ID 
                 Antisense Sequence 
                 ID 
               
               
                 ID 
                 (5′ to 3′) 
                 NO: 
                 (5′ to 3′) 
                 NO: 
               
               
                   
               
               
                 AD-66808 
                 GUCUGUGCCUUCUCAUCUA 
                 1791 
                 UAGAUGAGAAGGCACAGACUU 
                 1801 
               
               
                   
               
               
                 AD-66809 
                 GUCUGUGCCUUCUCAUCUA 
                 1792 
                 UAGAUGAGAAGGCACAGACUU 
                 1802 
               
               
                   
               
               
                 AD-66810 
                 GUGUGCACUUCGCUUCACA 
                 1793 
                 UGUGAAGCGAAGUGCACACUU 
                 1803 
               
               
                   
               
               
                 AD-66811 
                 GUGUGCACUUCGCUUCACA 
                 1794 
                 UGUGAAGCGAAGUGCACACUU 
                 1804 
               
               
                   
               
               
                 AD-66812 
                 UGUGCACUUCGCUUCACCUCU 
                 1795 
                 AGAGGUGAAGCGAAGUGCACAUU 
                 1805 
               
               
                   
               
               
                 AD-66813 
                 UGUGCACUUCGCUUCACCUCU 
                 1796 
                 AGAGGUGAAGCGAAGUGCACAUU 
                 1806 
               
               
                   
               
               
                 AD-66814 
                 CACCAGCACCAUGCAACUUUU 
                 1797 
                 AAAAGUUGCAUGGUGCUGGUGUU 
                 1807 
               
               
                   
               
               
                 AD-66815 
                 CACCAGCACCAUGCAACUUUU 
                 1798 
                 AAAAGUUGCAUGGUGCUGGUGUU 
                 1808 
               
               
                   
               
               
                 AD-66816 
                 CACCAUGCAACUUUUUCACCU 
                 1799 
                 AGGUGAAAAAGUUGCAUGGUGUU 
                 1809 
               
               
                   
               
               
                 AD-66817 
                 CACCAUGCAACUUUUUCACCU 
                 1800 
                 AGGUGAAAAAGUUGCAUGGUGUU 
                 1810 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 Table 28 
               
             
            
               
                   
               
               
                 Modified HBV X ORF Sense and Antisense Sequences. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 SEQ 
                   
                 SEQ 
               
               
                 Duplex 
                   
                 ID 
                   
                 ID 
               
               
                 ID 
                 Sense Segue nce (5′ to 3′) 
                 NO: 
                 Antisense Sequence (5′ to 3′) 
                 NO: 
               
               
                   
               
               
                 AD-66808 
                 gsuscuGfuGfCfCfuucucaucuaL96 
                 1811 
                 usAfsgauGfaGfAfaggcAfcAfgacsusu 
                 1821 
               
               
                   
               
               
                 AD-66809 
                 gsuscuGfuGfCfCfuucucaucuaL96 
                 1812 
                 UfsAfsgauGfaGfAfaggcAfcAfgacsusu 
                 1822 
               
               
                   
               
               
                 AD-66810 
                 gsusguGfcAfCfUfucgcuucacaL96 
                 1813 
                 usGfsugaAfgCfGfaaguGfcAfcacsusu 
                 1823 
               
               
                   
               
               
                 AD-66811 
                 gsusguGfcAfCfUfucgcuucacaL96 
                 1814 
                 UfsGfsugaAfgCfGfaaguGfcAfcacsusu 
                 1824 
               
               
                   
               
               
                 AD-66812 
                 usgsugcaCfuUfCfGfcuucaccucuL96 
                 1815 
                 asGfsaggUfgAfAfgcgaAfgUfgcacasusu 
                 1825 
               
               
                   
               
               
                 AD-66813 
                 usgsugcaCfuUfCfGfcuucaccucuL96 
                 1816 
                 AfsGfsaggUfgAfAfgcgaAfgUfgcacasusu 
                 1826 
               
               
                   
               
               
                 AD-66814 
                 csasccagCfaCfCfAfugcaacuuuuL96 
                 1817 
                 asAfsaagUfuGfCfauggUfgCfuggugsusu 
                 1827 
               
               
                   
               
               
                 AD-66815 
                 csasccagCfaCfCfAfugcaacuuuuL96 
                 1818 
                 AfsAfsaagUfuGfCfauggUfgCfuggugsusu 
                 1828 
               
               
                   
               
               
                 AD-66816 
                 csasccauGfcAfAfCfuuuuucaccuL96 
                 1819 
                 asGfsgugAfaAfAfaguuGfcAfuggugsusu 
                 1829 
               
               
                   
               
               
                 AD-66817 
                 csasccauGfcAfAfCfuuuuucaccuL96 
                 1820 
                 AfsGfsgugAfaAfAfaguuGfcAfuggugsusu 
                 1830 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                   
                 TABLE 29 
               
               
                   
                   
               
               
                   
                 Site 
                   
                 In vitro IC 50   
                 Log 10  HBsAg KD 
               
               
                   
                 (# vRNA 1 ) 
                 Duplex ID 
                 Luc HBV (nM) 
                 In Vivo @3 mg/kg 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 1551 
                 AD-66808 
                 0.187 
                 2.4 
               
               
                   
                 (4) 
                 AD-66809 
                 0.014 
                 1.46 
               
               
                   
                 1577 
                 AD-66810 
                 0.290 
                 1.7 
               
               
                   
                 (4) 
                 AD-66811 
                 0.029 
                 1.3 
               
               
                   
                 1580 
                 AD-66812 
                 0.795 
                 2.19 
               
               
                   
                 (4) 
                 AD-66813 
                 0.074 
                 &gt;&gt;1.14 
               
               
                   
                 1806 
                 AD-66814 
                 0.0002 
                 1.5 
               
               
                   
                 (4) 
                 AD-66815 
                 0.0001 
                 &gt;&gt;1.56 
               
               
                   
                 1812 
                 AD-66816 
                 0.047 
                 1.61 
               
               
                   
                 (4) 
                 AD-66817 
                 0.0001 
                 1.60 
               
               
                   
                   
               
               
                   
                   1 Number of viral RNAs silenced 
               
            
           
         
       
     
     Example 6. In Vivo Screening of iRNA Duplexes 
     A subset of lead iRNA agents was assessed for in vivo efficacy using the AAV-HBV mouse model described above. AAV-HBV mice were administered a single 3 mg/kg dose of AD-66019, AD-65375, AD-65047, AD-65377, AD-66111, AD-65421, or AD-66110 and the level of HBsAg was determined in the serum of the animals pre-dose, and at days 5 and 10 post-dose. As a control, AAV-HBV mice were administered a 3 mg/kg dose of a dsRNA targeting mouse/rat transtherytin (mrTTR). The results of these experiments demonstrate that serum levels of HBsAg are decreased following a single administration of these agents. 
     The percent of pre-dose HBsAg remaining at days 5 and 10 was determined in these animals following administration of a single 3 mg/kg dose. A significant decrease in HBsA at both days 5 and 10 after administration were observed in at least AD-65375, AD-65403, AD-65407, AD-65421, AD-66019, and AD-66111. 
     Based, at least in part, on the results of the in vitro and in vivo assays described above, AD-65403, which silences 3 HBV RNAs, and AD-66810, which silences the X gene, were selected for further analysis for use in a monotherapy or in a combination therapy of HBV. 
     In the AAV-HBV mouse model of HBV infection, a single 3 mg/kg dose of AD-65403 achieved potent and specific knockdown of HBsAg. In particular, a single 3 mg/kg subcutaneous dose of AD-65403 achieved up to a 3.9 log 10  reduction in HBsAg levels, with a mean HBsAg reduction of 1.8 log 10  5-10 days after a single dose. 
     In the AAV-HBV mouse model of HBV infection, a single 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 9 mg/kg dose of AD-66810 achieved potent and specific knockdown of HBsAg, especially at the higher doses of AD-66810. 
     In the AAV-HBV mouse model of HBV infection, AD-66810 administered in three weekly 3 mg/kg doses, achieved potent and specific knockdown of HBsAg for a period of greater than 4 months. 
     Example 7. In Vitro Screening of Additional iRNA Duplexes Targeting HDV 
     In Vitro Screening: 
     Cell Culture and Transfections: 
     Cos7 cells (ATCC, Manassas, Va.) were grown to near confluence at 37° C. in an atmosphere of 5% CO 2  in DMEM (ATCC) supplemented with 10% FBS, before being released from the plate by trypsinization. Dual-Glo® Luciferase constructs generated in the psiCHECK2 plasmid containing HDV AY633627 derived sequences (Table 30) were transfected into approximately 4×10 3  cells using Lipofectamine 2000 (Invitrogen, Carlsbad Calif. cat #11668-019). For each well of a 384 well plate, 0.15 μl of Lipofectamine, 4 ng of vector, and an appropriate amount of one of the modified siRNA agents provided in Table 32 were mixed in 15 μl final volume of Opti-MEM and allowed to complex at room temperature for 15 minutes. Subsequently the mixture was then supplemented with the suspention of cells (35 ul in complete media). Cells were incubated for 48 hours before luciferase was measured. 
     The unmodified sequences of the agents provided in Table 32 are provided in Table 3, which were synthesized as described above. 
     Dual-Glo® Luciferase Assay 
     Firefly (transfection control) and Renilla (fused to HBV target sequence) luciferases were measured using Dual-Glo® Luciferase Assay (Promega, Madison, Wis., # E2980). First, media was removed from cells. Then Firefly luciferase activity was measured by adding a mixture of 10 μl of the complete media and 10 μl of Dual-Glo® Luciferase Reagent per well. The mixture was incubated at room temperature for 10-15 minutes before luminescence (500 nm) was measured on a Spectramax (Molecular Devices) to detect the Firefly luciferase signal. Renilla luciferase activity was measured by adding 10l of room temperature Dual-Glo® Stop &amp; Glo® Reagent to each well and the plates were incubated for 10-15 minutes before luminescence was again measured to determine the Renilla luciferase signal. The Dual-Glo® Stop &amp; Glo® Reagent quenches the firefly luciferase signal and sustained luminescence for the Renilla luciferase reaction. siRNA activity was determined by normalizing the Renilla (HDV) signal to the Firefly (control) signal within each well. The magnitude of siRNA activity was then assessed relative to cells that were transfected with the same vector but were not treated with siRNA (mock). All transfections were done at n=2 or greater. siRNA concentration sufficient to inhibit relative Renilla luciferase expression by 50% (IC 50 ) was determined by the method described above at a range of concentrations (40 fM-10 nM). 
     The results of the single dose screen are provided in Table 33 and the results of the dose response screens are provided in Table 34. 
     
       
         
           
               
             
               
                 TABLE 30 
               
             
            
               
                   
               
               
                 HDV sequences used in luciferase plasmids 
               
            
           
           
               
               
            
               
                 Vector Name 
                 HDV sequence 
               
               
                   
               
               
                 psiCHECK2- 
                 GCGATCGCCTCGAACTTGGGCGGCGAGTCCAGCAGTCTCCTCTTTATCAGAAAAGAGTAAGA 
               
               
                 HDV- 
                 GCACTGAGGACTGCCGCCTCTTGTCGAGATGAGCCGGTCCGAGTTGAAGAAGAAGCGCGATG 
               
               
                 antigenome 
                 GAAGAGAAGATATTCTCGAGAAGTGGGTGAGTGGAAGAAAGAAAGCGGAGGAACTCGAGAGG 
               
               
                   
                 GATCTCCGGAAGACAAAGAAGAAGATCAAGAAACTTGAGGTCGAAAATCCCTGGCTGGGAAA 
               
               
                   
                 CATCAAAGGAATTCTCGGAAAGAAGGACAGGGATGGAGAGGGGGCTCCCCCGGCGAAGAGGG 
               
               
                   
                 CCCGGACGGACCAGATGGAGATAGACTCCGGGCCTAGGAAGAGGCCTCTCAGGGGAGGATTC 
               
               
                   
                 ACCGACAGGGAGAGGCAGGATCACCGACGAAGGAAGGCCCTCGAGAACAAGAAGAAGCAGCT 
               
               
                   
                 AGCCGCGGGAGGGAAGAGCCTGAGCAAGGAGGAGGAAGAGGAACTCGGAAGGTTGACCCGGG 
               
               
                   
                 AAGACGAGGAAAGGAAAAGAAGAGTAGCCGGCCCGCGGGTTGGGGGTGTGAACCCCCTCGAA 
               
               
                   
                 GGCGGATCGAGGGGAGCGCCCGGGGGCGGCTTCGTCCCCAGCATGCAAGGAGTCCCGGAGTC 
               
               
                   
                 CCCCTTCGCTCGGACGGGGGAGGGGCTGGACATAAGAGGAACCCGGGGATTCCCATAGGATA 
               
               
                   
                 TACTCTTCCCATCCGATCCACCCTTCTCTCCCCAGAGTTGTCGTCCCCAGTGAATAAAGCGG 
               
               
                   
                 GTTTCCACTCACAGGTTCACCGTCTCGCGTCCTTCTTTCCTCTTCGGGTCGGCATGGCATCT 
               
               
                   
                 CCACCTCCTCGCGGTCCGACCTGGGCATCCGAAGGAGGACGCACGTCCACTCGGATGGCTAA 
               
               
                   
                 GGGAGAGCCACTTTTCTCTCGATTCTCTATCGGAATCTAGAGAGATTTGTGGGTCCCATTCG 
               
               
                   
                 CCATTACCGAGGGGACGGTCCCCTCGGAATGTTGCCCAGCCGGCGCCAGCGAGGAGGCTGGG 
               
               
                   
                 ACCATGCCGGCCATCAGGTAAGAAAGGATGGAACGCGGACCCTGCAGAGTGGGGTCCCGCCA 
               
               
                   
                 TTCCTGGGCGACCCTTGGGGGGGGAGTCGGAATCGAGCATCGGGAAGGGCATCCCATGGCTC 
               
               
                   
                 CACTGGTCCCCGGTGTTCCCAGCACCCCCTCCGGTCACTTTCGAAGGGGGTCCGGGGTCCCG 
               
               
                   
                 CTAGATGGGGACGATAAGTCGAGTTCCCCGGGATAAGCCTCACTCGTCCCCTCTCGGGGGGC 
               
               
                   
                 GGAACACCCACCGGCTAGCCCCGTTGCTTTCTTTGCTTTCCTCCTCGCTTCGGTCTCCCCCT 
               
               
                   
                 ACTCCTAGCATCTCCTCCTATCGCTATGGCCTTACTCCTACCGCTCGAAGCGCCTCTGTTCG 
               
               
                   
                 CTGAAGGGGTCCTCTGGAGGTGATTTCTCTGCTCATCTCCGAGTGTGTTCCTCCCTCTGGTG 
               
               
                   
                 TTCTCAACCCTTCGGCCGGAGTGCTCTCCAAACTTGGGCGTCGGGCCTTTCGGATCGGGGGG 
               
               
                   
                 GCCCCCCCTTCTCTTCCATCTGTCCTCTTTCCCCTTCCGAGATGTCTCCAGCGTTATGGGGA 
               
               
                   
                 AAGCTTCCGACTCTTGTATTCTCTTTTGGCCTTCTTGGGAGACATCTCCTCGGCGTTCCAAT 
               
               
                   
                 ACTCTTTACCACTTTACCCCTCTCGGGCACTGATCCTTCCCCCGCGGACTCTTCGCTCGGAA 
               
               
                   
                 TTGGCCCATGGCGGCCGC (SEQ ID NO: 1835) 
               
               
                   
               
               
                 psiCHECK2- 
                 GCGATCGCCATGGGCCAATTCCGAGCGAAGAGTCCGCGGGGGAAGGATCAGTGCCCGAGAGG 
               
               
                 HDV-genome 
                 GGTAAAGTGGTAAAGAGTATTGGAACGCCGAGGAGATGTCTCCCAAGAAGGCCAAAAGAGAA 
               
               
                   
                 TACAAGAGTCGGAAGCTTTCCCCATAACGCTGGAGACATCTCGGAAGGGGAAAGAGGACAGA 
               
               
                   
                 TGGAAGAGAAGGGGGGGCCCCCCCGATCCGAAAGGCCCGACGCCCAAGTTTGGAGAGCACTC 
               
               
                   
                 CGGCCGAAGGGTTGAGAACACCAGAGGGAGGAACACACTCGGAGATGAGCAGAGAAATCACC 
               
               
                   
                 TCCAGAGGACCCCTTCAGCGAACAGAGGCGCTTCGAGCGGTAGGAGTAAGGCCATAGCGATA 
               
               
                   
                 GGAGGAGATGCTAGGAGTAGGGGGAGACCGAAGCGAGGAGGAAAGCAAAGAAAGCAACGGGG 
               
               
                   
                 CTAGCCGGTGGGTGTTCCGCCCCCCGAGAGGGGACGAGTGAGGCTTATCCCGGGGAACTCGA 
               
               
                   
                 CTTATCGTCCCCATCTAGCGGGACCCCGGACCCCCTTCGAAAGTGACCGGAGGGGGTGCTGG 
               
               
                   
                 GAACACCGGGGACCAGTGGAGCCATGGGATGCCCTTCCCGATGCTCGATTCCGACTCCCCCC 
               
               
                   
                 CCAAGGGTCGCCCAGGAATGGCGGGACCCCACTCTGCAGGGTCCGCGTTCCATCCTTTCTTA 
               
               
                   
                 CCTGATGGCCGGCATGGTCCCAGCCTCCTCGCTGGCGCCGGCTGGGCAACATTCCGAGGGGA 
               
               
                   
                 CCGTCCCCTCGGTAATGGCGAATGGGACCCACAAATCTCTCTAGATTCCGATAGAGAATCGA 
               
               
                   
                 GAGAAAAGTGGCTCTCCCTTAGCCATCCGAGTGGACGTGCGTCCTCCTTCGGATGCCCAGGT 
               
               
                   
                 CGGACCGCGAGGAGGTGGAGATGCCATGCCGACCCGAAGAGGAAAGAAGGACGCGAGACGGT 
               
               
                   
                 GAACCTGTGAGTGGAAACCCGCTTTATTCACTGGGGACGACAACTCTGGGGAGAGAAGGGTG 
               
               
                   
                 GATCGGATGGGAAGAGTATATCCTATGGGAATCCCCGGGTTCCTCTTATGTCCAGCCCCTCC 
               
               
                   
                 CCCGTCCGAGCGAAGGGGGACTCCGGGACTCCTTGCATGCTGGGGACGAAGCCGCCCCCGGG 
               
               
                   
                 CGCTCCCCTCGATCCGCCTTCGAGGGGGTTCACACCCCCAACCCGCGGGCCGGCTACTCTTC 
               
               
                   
                 TTTTCCTTTCCTCGTCTTCCCGGGTCAACCTTCCGAGTTCCTCTTCCTCCTCCTTGCTCAGG 
               
               
                   
                 CTCTTCCCTCCCGCGGCTAGCTGCTTCTTCTTGTTCTCGAGGGCCTTCCTTCGTCGGTGATC 
               
               
                   
                 CTGCCTCTCCCTGTCGGTGAATCCTCCCCTGAGAGGCCTCTTCCTAGGCCCGGAGTCTATCT 
               
               
                   
                 CCATCTGGTCCGTCCGGGCCCTCTTCGCCGGGGGAGCCCCCTCTCCATCCCTGTCCTTCTTT 
               
               
                   
                 CCGAGAATTCCTTTGATGTTTCCCAGCCAGGGATTTTCGACCTCAAGTTTCTTGATCTTCTT 
               
               
                   
                 CTTTGTCTTCCGGAGATCCCTCTCGAGTTCCTCCGCTTTCTTTCTTCCACTCACCCACTTCT 
               
               
                   
                 CGAGAATATCTTCTCTTCCATCGCGCTTCTTCTTCAACTCGGACCGGCTCATCTCGACAAGA 
               
               
                   
                 GGCGGCAGTCCTCAGTGCTCTTACTCTTTTCTGATAAAGAGGAGACTGCTGGACTCGCCGCC 
               
               
                   
                 CAAGTTCGAGGCGGCCGC (SEQ ID NO: 1836) 
               
               
                   
               
               
                 psiCHECK2- 
                 GCGATCGCGAAGACAAAGAAGAAGATCAAGAAACTTGAGGTCGAAAATCCCTGGCTGGGAAA 
               
               
                 HDV- 
                 CATCAAAGGAATTCTCGGAAAGAAGGACAGGGATGGCGGCCGC (SEQ ID NO: 1837) 
               
               
                 antigenome 
                   
               
               
                 hot spot 
                   
               
               
                   
               
               
                 psiCHECK2- 
                 GCGATCGCCATCCCTGTCCTTCTTTCCGAGAATTCCTTTGATGTTTCCCAGCCAGGGATTTT 
               
               
                 HDV-genome 
                 CGACCTCAAGTTTCTTGATCTTCTTCTTTGTCTTCGCGGCCGC (SEQ ID NO: 1838) 
               
               
                 hot spot 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 31 
               
             
            
               
                   
               
               
                 Unmodified Sense and Antisense Strand Sequences of HDV dsRNAs 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Sense 
                   
                 SEQ 
                 Antisense 
                   
                 SEQ 
               
               
                   
                 Oligo 
                 Senses Sequence 
                 ID 
                 Oligo 
                 Antisense Sequence 
                 ID 
               
               
                 Duple Name 
                 Name 
                 (5′ to 3′) 
                 NO: 
                 Name 
                 (5′ to 3′) 
                 NO: 
               
               
                   
               
               
                 AD-67176.1 
                 A-134242.1 
                 UCCCAAGAAGGCCAAAAGAGA 
                 1839 
                 A-134243.1 
                 UCUCUUUUGGCCUUCUUGGGAGA 
                 2017 
               
               
                   
               
               
                 AD-67177.1 
                 A-134244.1 
                 AGUUUCUUGAUCUUCUUCUUU 
                 1840 
                 A-134245.1 
                 AAAGAAGAAGAUCAAGAAACUUG 
                 2018 
               
               
                   
               
               
                 AD-67178.1 
                 A-134246.1 
                 UCUUUUCUGAUAAAGAGGAGA 
                 1841 
                 A-134247.1 
                 UCUCCUCUUUAUCAGAAAAGAGU 
                 2019 
               
               
                   
               
               
                 AD-67179.1 
                 A-134248.1 
                 AGUGGUAAAGAGUAUUGGAAA 
                 1842 
                 A-134249.1 
                 UUUCCAAUACUCUUUACCACUUU 
                 2020 
               
               
                   
               
               
                 AD-67180.1 
                 A-134250.1 
                 CUCAAGUUUCUUGAUCUUCUU 
                 1843 
                 A-134251.1 
                 AAGAAGAUCAAGAAACUUGAGGU 
                 2021 
               
               
                   
               
               
                 AD-67181.1 
                 A-134252.1 
                 AAGGCCAAAAGAGAAUACAAA 
                 1844 
                 A-134253.1 
                 UUUGUAUUCUCUUUUGGCCUUCU 
                 2022 
               
               
                   
               
               
                 AD-67182.1 
                 A-134254.1 
                 GACCUCAAGUUUCUUGAUCUU 
                 1845 
                 A-134255.1 
                 AAGAUCAAGAAACUUGAGGUCGA 
                 2023 
               
               
                   
               
               
                 AD-67183.1 
                 A-134256.1 
                 AGGCCAAAAGAGAAUACAAGA 
                 1846 
                 A-134257.1 
                 UCUUGUAUUCUCUUUUGGCCUUC 
                 2024 
               
               
                   
               
               
                 AD-67184.1 
                 A-134258.1 
                 CGAUAGAGAAUCGAGAGAAAA 
                 1847 
                 A-134259.1 
                 UUUUCUCUCGAUUCUCUAUCGGA 
                 2025 
               
               
                   
               
               
                 AD-67185.1 
                 A-134260.1 
                 GAUAGAGAAUCGAGAGAAAAG 
                 1848 
                 A-134261.1 
                 CUUUUCUCUCGAUUCUCUAUCGG 
                 2026 
               
               
                   
               
               
                 AD-67186.1 
                 A-134262.1 
                 ACCCACAAAUCUCUCUAGAUU 
                 1849 
                 A-134263.1 
                 AAUCUAGAGAGAUUUGUGGGUCC 
                 2027 
               
               
                   
               
               
                 AD-67187.1 
                 A-134264.1 
                 GGAUGGGAAGAGUAUAUCCUA 
                 1850 
                 A-134265.1 
                 UAGGAUAUACUCUUCCCAUCCGA 
                 2028 
               
               
                   
               
               
                 AD-67188.1 
                 A-134266.1 
                 CCGAUAGAGAAUCGAGAGAAA 
                 1851 
                 A-134267.1 
                 UUUCUCUCGAUUCUCUAUCGGAA 
                 2029 
               
               
                   
               
               
                 AD-67189.1 
                 A-134268.1 
                 UCCGAUAGAGAAUCGAGAGAA 
                 1852 
                 A-134269.1 
                 UUCUCUCGAUUCUCUAUCGGAAU 
                 2030 
               
               
                   
               
               
                 AD-67190.1 
                 A-134270.1 
                 UGAGUGGAAACCCGCUUUAUU 
                 1853 
                 A-134271.1 
                 AAUAAAGCGGGUUUCCACUCACA 
                 2031 
               
               
                   
               
               
                 AD-67191.1 
                 A-134272.1 
                 CCUUCUUUCCGAGAAUUCCUU 
                 1854 
                 A-134273.1 
                 AAGGAAUUCUCGGAAAGAAGGAC 
                 2032 
               
               
                   
               
               
                 AD-67192.1 
                 A-134274.1 
                 CUGUGAGUGGAAACCCGCUUU 
                 1855 
                 A-134275.1 
                 AAAGCGGGUUUCCACUCACAGGU 
                 2033 
               
               
                   
               
               
                 AD-67193.1 
                 A-134276.1 
                 GACCCACAAAUCUCUCUAGAU 
                 1856 
                 A-134277.1 
                 AUCUAGAGAGAUUUGUGGGUCCC 
                 2034 
               
               
                   
               
               
                 AD-67194.1 
                 A-134278.1 
                 GCUGGGAAACAUCAAAGGAAU 
                 1857 
                 A-134279.1 
                 AUUCCUUUGAUGUUUCCCAGCCA 
                 2035 
               
               
                   
               
               
                 AD-67195.1 
                 A-134280.1 
                 ACAGUUGGAAGGCUCAAGGAG 
                 1858 
                 A-134281.1 
                 UGUCAACCUUCCGAGUUCCUCUU 
                 2036 
               
               
                   
               
               
                 AD-67196.1 
                 A-134282.1 
                 AAGGAGGAGGAACGAGUCCGA 
                 1859 
                 A-134283.1 
                 UUCCUCCUCCUUGCUCAGGCUCU 
                 2037 
               
               
                   
               
               
                 AD-67197.1 
                 A-134284.1 
                 UCUCCUCUUUAUCAGAAAAGA 
                 1860 
                 A-134285.1 
                 UCUUUUCUGAUAAAGAGGAGACU 
                 2038 
               
               
                   
               
               
                 AD-67198.1 
                 A-134286.1 
                 UCCAGCAGUCUCCUCUUUAUA 
                 1861 
                 A-134287.1 
                 UAUAAAGAGGAGACUGCUGGACU 
                 2039 
               
               
                   
               
               
                 AD-67199.1 
                 A-134288.1 
                 AAAGAAGAAGAUCAAGAAACU 
                 1862 
                 A-134289.1 
                 AGUUUCUUGAUCUUCUUCUUUGU 
                 2040 
               
               
                   
               
               
                 AD-67200.1 
                 A-134290.1 
                 AAGAAGAAGAUCAAGAAACUU 
                 1863 
                 A-134291.1 
                 AAGUUUCUUGAUCUUCUUCUUUG 
                 2041 
               
               
                   
               
               
                 AD-67201.1 
                 A-134292.1 
                 GAGGUCGAAAAUCCCUGGCUA 
                 1864 
                 A-134293.1 
                 UAGCCAGGGAUUUUCGACCUCAA 
                 2042 
               
               
                   
               
               
                 AD-67202.1 
                 A-134294.1 
                 CCCUGGCUGGGAAACAUCAAA 
                 1865 
                 A-134295.1 
                 UUUGAUGUUUCCCAGCCAGGGAU 
                 2043 
               
               
                   
               
               
                 AD-67203.1 
                 A-134296.1 
                 CUGGCUGGGAAACAUCAAAGA 
                 1866 
                 A-134297.1 
                 UCUUUGAUGUUUCCCAGCCAGGG 
                 2044 
               
               
                   
               
               
                 AD-67204.1 
                 A-134298.1 
                 UGGCUGGGAAACAUCAAAGGA 
                 1867 
                 A-134299.1 
                 UCCUUUGAUGUUUCCCAGCCAGG 
                 2045 
               
               
                   
               
               
                 AD-67205.1 
                 A-134300.1 
                 GGCUGGGAAACAUCAAAGGAA 
                 1868 
                 A-134301.1 
                 UUCCUUUGAUGUUUCCCAGCCAG 
                 2046 
               
               
                   
               
               
                 AD-67206.1 
                 A-134302.1 
                 UCAAAGGAAUUCUCGGAAAGA 
                 1869 
                 A-134303.1 
                 UCUUUCCGAGAAUUCCUUUGAUG 
                 2047 
               
               
                   
               
               
                 AD-67207.1 
                 A-134304.1 
                 UGGGAAACAUCAAAGGAAUUA 
                 1870 
                 A-134305.1 
                 UAAUUCCUUUGAUGUUUCCCAGC 
                 2048 
               
               
                   
               
               
                 AD-67208.1 
                 A-134306.1 
                 GGAAACAUCAAAGGAAUUCUA 
                 1871 
                 A-134307.1 
                 UAGAAUUCCUUUGAUGUUUCCCA 
                 2049 
               
               
                   
               
               
                 AD-67209.1 
                 A-134308.1 
                 GAAACAUCAAAGGAAUUCUCA 
                 1872 
                 A-134309.1 
                 UGAGAAUUCCUUUGAUGUUUCCC 
                 2050 
               
               
                   
               
               
                 AD-67210.1 
                 A-134310.1 
                 AAACAUCAAAGGAAUUCUCGA 
                 1873 
                 A-134311.1 
                 UCGAGAAUUCCUUUGAUGUUUCC 
                 2051 
               
               
                   
               
               
                 AD-67211.1 
                 A-134312.1 
                 CAUCAAAGGAAUUCUCGGAAA 
                 1874 
                 A-134313.1 
                 UUUCCGAGAAUUCCUUUGAUGUU 
                 2052 
               
               
                   
               
               
                 AD-67212.1 
                 A-134314.1 
                 AAAGGAAUUCUCGGAAAGAAA 
                 1875 
                 A-134315.1 
                 UUUCUUUCCGAGAAUUCCUUUGA 
                 2053 
               
               
                   
               
               
                 AD-67213.1 
                 A-134316.1 
                 AAGGAAUUCUCGGAAAGAAGA 
                 1876 
                 A-134317.1 
                 UCUUCUUUCCGAGAAUUCCUUUG 
                 2054 
               
               
                   
               
               
                 AD-67214.1 
                 A-134320.1 
                 GGCCCUCGAGAACAAGAAGAA 
                 1877 
                 A-134321.1 
                 UUCUUCUUGUUCUCGAGGGCCUU 
                 2055 
               
               
                   
               
               
                 AD-67215.1 
                 A-134322.1 
                 GCCCUCGAGAACAAGAAGAAA 
                 1878 
                 A-134323.1 
                 UUUCUUCUUGUUCUCGAGGGCCU 
                 2056 
               
               
                   
               
               
                 AD-67216.1 
                 A-134324.1 
                 CCCUCGAGAACAAGAAGAAGA 
                 1879 
                 A-134325.1 
                 UCUUCUUCUUGUUCUCGAGGGCC 
                 2057 
               
               
                   
               
               
                 AD-67217.1 
                 A-134326.1 
                 GGAAAGGAAAAGAAGAGUAGA 
                 1880 
                 A-134327.1 
                 UCUACUCUUCUUUUCCUUUCCUC 
                 2058 
               
               
                   
               
               
                 AD-67218.1 
                 A-134328.1 
                 AAGGAAAAGAAGAGUAGCCGA 
                 1881 
                 A-134329.1 
                 UCGGCUACUCUUCUUUUCCUUUC 
                 2059 
               
               
                   
               
               
                 AD-67219.1 
                 A-134330.1 
                 GGGGGUGUGAACCCCCUCGAA 
                 1882 
                 A-134331.1 
                 UUCGAGGGGGUUCACACCCCCAA 
                 2060 
               
               
                   
               
               
                 AD-67220.1 
                 A-134332.1 
                 GGGUGUGAACCCCCUCGAAGA 
                 1883 
                 A-134333.1 
                 UCUUCGAGGGGGUUCACACCCCC 
                 2061 
               
               
                   
               
               
                 AD-67250.1 
                 A-134346.1 
                 AGUUUCUUGAUCUUCUUCUUU 
                 1884 
                 A-134347.1 
                 AAAGAAGAAGAUCAAGAAACUUG 
                 2062 
               
               
                   
               
               
                 AD-67251.1 
                 A-134348.1 
                 UCUUUUCUGAUAAAGAGGAGA 
                 1885 
                 A-134349.1 
                 UCUCCUCUUUAUCAGAAAAGAGU 
                 2063 
               
               
                   
               
               
                 AD-67252.1 
                 A-134350.1 
                 AGUGGUAAAGAGUAUUGGAAA 
                 1886 
                 A-134351.1 
                 UUUCCAAUACUCUUUACCACUUU 
                 2064 
               
               
                   
               
               
                 AD-67253.1 
                 A-134352.1 
                 CUCAAGUUUCUUGAUCUUCUU 
                 1887 
                 A-134353.1 
                 AAGAAGAUCAAGAAACUUGAGGU 
                 2065 
               
               
                   
               
               
                 AD-67254.1 
                 A-134354.1 
                 AAGGCCAAAAGAGAAUACAAA 
                 1888 
                 A-134355.1 
                 UUUGUAUUCUCUUUUGGCCUUCU 
                 2066 
               
               
                   
               
               
                 AD-67255.1 
                 A-134358.1 
                 AGGCCAAAAGAGAAUACAAGA 
                 1889 
                 A-134359.1 
                 UCUUGUAUUCUCUUUUGGCCUUC 
                 2067 
               
               
                   
               
               
                 AD-67256.1 
                 A-134360.1 
                 CGAUAGAGAAUCGAGAGAAAA 
                 1890 
                 A-134361.1 
                 UUUUCUCUCGAUUCUCUAUCGGA 
                 2068 
               
               
                   
               
               
                 AD-67257.1 
                 A-134362.1 
                 GAUAGAGAAUCGAGAGAAAAG 
                 1891 
                 A-134363.1 
                 CUUUUCUCUCGAUUCUCUAUCGG 
                 2069 
               
               
                   
               
               
                 AD-67258.1 
                 A-134364.1 
                 ACCCACAAAUCUCUCUAGAUU 
                 1892 
                 A-134365.1 
                 AAUCUAGAGAGAUUUGUGGGUCC 
                 2070 
               
               
                   
               
               
                 AD-67259.1 
                 A-134366.1 
                 GGAUGGGAAGAGUAUAUCCUA 
                 1893 
                 A-134367.1 
                 UAGGAUAUACUCUUCCCAUCCGA 
                 2071 
               
               
                   
               
               
                 AD-67260.1 
                 A-134368.1 
                 CCGAUAGAGAAUCGAGAGAAA 
                 1894 
                 A-134369.1 
                 UUUCUCUCGAUUCUCUAUCGGAA 
                 2072 
               
               
                   
               
               
                 AD-67261.1 
                 A-134370.1 
                 UCCGAUAGAGAAUCGAGAGAA 
                 1895 
                 A-134371.1 
                 UUCUCUCGAUUCUCUAUCGGAAU 
                 2073 
               
               
                   
               
               
                 AD-67262.1 
                 A-134372.1 
                 UGAGUGGAAACCCGCUUUAUU 
                 1896 
                 A-134373.1 
                 AAUAAAGCGGGUUUCCACUCACA 
                 2074 
               
               
                   
               
               
                 AD-67263.1 
                 A-134374.1 
                 CCUUCUUUCCGAGAAUUCCUU 
                 1897 
                 A-134375.1 
                 AAGGAAUUCUCGGAAAGAAGGAC 
                 2075 
               
               
                   
               
               
                 AD-67264.1 
                 A-134376.1 
                 CUGUGAGUGGAAACCCGCUUU 
                 1898 
                 A-134377.1 
                 AAAGCGGGUUUCCACUCACAGGU 
                 2076 
               
               
                   
               
               
                 AD-67265.1 
                 A-134378.1 
                 GACCCACAAAUCUCUCUAGAU 
                 1899 
                 A-134379.1 
                 AUCUAGAGAGAUUUGUGGGUCCC 
                 2077 
               
               
                   
               
               
                 AD-67266.1 
                 A-134380.1 
                 GCUGGGAAACAUCAAAGGAAU 
                 1900 
                 A-134381.1 
                 AUUCCUUUGAUGUUUCCCAGCCA 
                 2078 
               
               
                   
               
               
                 AD-67267.1 
                 A-134382.1 
                 ACAGUUGGAAGGCUCAAGGAG 
                 1901 
                 A-134383.1 
                 UGUCAACCUUCCGAGUUCCUCUU 
                 2079 
               
               
                   
               
               
                 AD-67268.1 
                 A-134384.1 
                 AAGGAGGAGGAACGAGUCCGA 
                 1902 
                 A-134385.1 
                 UUCCUCCUCCUUGCUCAGGCUCU 
                 2080 
               
               
                   
               
               
                 AD-67269.1 
                 A-134386.1 
                 UCUCCUCUUUAUCAGAAAAGA 
                 1903 
                 A-134387.1 
                 UCUUUUCUGAUAAAGAGGAGACU 
                 2081 
               
               
                   
               
               
                 AD-67270.1 
                 A-134388.1 
                 UCCAGCAGUCUCCUCUUUAUA 
                 1904 
                 A-134389.1 
                 UAUAAAGAGGAGACUGCUGGACU 
                 2082 
               
               
                   
               
               
                 AD-67271.1 
                 A-134390.1 
                 AAAGAAGAAGAUCAAGAAACU 
                 1905 
                 A-134391.1 
                 AGUUUCUUGAUCUUCUUCUUUGU 
                 2083 
               
               
                   
               
               
                 AD-67272.1 
                 A-134392.1 
                 AAGAAGAAGAUCAAGAAACUU 
                 1906 
                 A-134393.1 
                 AAGUUUCUUGAUCUUCUUCUUUG 
                 2084 
               
               
                   
               
               
                 AD-67273.1 
                 A-134394.1 
                 GAGGUCGAAAAUCCCUGGCUA 
                 1907 
                 A-134395.1 
                 UAGCCAGGGAUUUUCGACCUCAA 
                 2085 
               
               
                   
               
               
                 AD-67274.1 
                 A-134396.1 
                 CCCUGGCUGGGAAACAUCAAA 
                 1908 
                 A-134397.1 
                 UUUGAUGUUUCCCAGCCAGGGAU 
                 2086 
               
               
                   
               
               
                 AD-67275.1 
                 A-134398.1 
                 CUGGCUGGGAAACAUCAAAGA 
                 1909 
                 A-134399.1 
                 UCUUUGAUGUUUCCCAGCCAGGG 
                 2087 
               
               
                   
               
               
                 AD-67276.1 
                 A-134400.1 
                 UGGCUGGGAAACAUCAAAGGA 
                 1910 
                 A-134401.1 
                 UCCUUUGAUGUUUCCCAGCCAGG 
                 2088 
               
               
                   
               
               
                 AD-67277.1 
                 A-134402.1 
                 GGCUGGGAAACAUCAAAGGAA 
                 1911 
                 A-134403.1 
                 UUCCUUUGAUGUUUCCCAGCCAG 
                 2089 
               
               
                   
               
               
                 AD-67278.1 
                 A-134404.1 
                 UCAAAGGAAUUCUCGGAAAGA 
                 1912 
                 A-134405.1 
                 UCUUUCCGAGAAUUCCUUUGAUG 
                 2090 
               
               
                   
               
               
                 AD-67279.1 
                 A-134406.1 
                 UGGGAAACAUCAAAGGAAUUA 
                 1913 
                 A-134407.1 
                 UAAUUCCUUUGAUGUUUCCCAGC 
                 2091 
               
               
                   
               
               
                 AD-67280.1 
                 A-134408.1 
                 GGAAACAUCAAAGGAAUUCUA 
                 1914 
                 A-134409.1 
                 UAGAAUUCCUUUGAUGUUUCCCA 
                 2092 
               
               
                   
               
               
                 AD-67281.1 
                 A-134410.1 
                 GAAACAUCAAAGGAAUUCUCA 
                 1915 
                 A-134411.1 
                 UGAGAAUUCCUUUGAUGUUUCCC 
                 2093 
               
               
                   
               
               
                 AD-67282.1 
                 A-134414.1 
                 CAUCAAAGGAAUUCUCGGAAA 
                 1916 
                 A-134415.1 
                 UUUCCGAGAAUUCCUUUGAUGUU 
                 2094 
               
               
                   
               
               
                 AD-67283.1 
                 A-134416.1 
                 AAAGGAAUUCUCGGAAAGAAA 
                 1917 
                 A-134417.1 
                 UUUCUUUCCGAGAAUUCCUUUGA 
                 2095 
               
               
                   
               
               
                 AD-67284.1 
                 A-134418.1 
                 AAGGAAUUCUCGGAAAGAAGA 
                 1918 
                 A-134419.1 
                 UCUUCUUUCCGAGAAUUCCUUUG 
                 2096 
               
               
                   
               
               
                 AD-67285.1 
                 A-134420.1 
                 ACGAAGGAAGGCCCUCGAGAA 
                 1919 
                 A-134421.1 
                 UUCUCGAGGGCCUUCCUUCGUCG 
                 2097 
               
               
                   
               
               
                 AD-67286.1 
                 A-134422.1 
                 GGCCCUCGAGAACAAGAAGAA 
                 1920 
                 A-134423.1 
                 UUCUUCUUGUUCUCGAGGGCCUU 
                 2098 
               
               
                   
               
               
                 AD-67287.1 
                 A-134424.1 
                 GCCCUCGAGAACAAGAAGAAA 
                 1921 
                 A-134425.1 
                 UUUCUUCUUGUUCUCGAGGGCCU 
                 2099 
               
               
                   
               
               
                 AD-67288.1 
                 A-134426.1 
                 CCCUCGAGAACAAGAAGAAGA 
                 1922 
                 A-134427.1 
                 UCUUCUUCUUGUUCUCGAGGGCC 
                 2100 
               
               
                   
               
               
                 AD-67289.1 
                 A-134428.1 
                 GGAAAGGAAAAGAAGAGUAGA 
                 1923 
                 A-134429.1 
                 UCUACUCUUCUUUUCCUUUCCUC 
                 2101 
               
               
                   
               
               
                 AD-67290.1 
                 A-134430.1 
                 AAGGAAAAGAAGAGUAGCCGA 
                 1924 
                 A-134431.1 
                 UCGGCUACUCUUCUUUUCCUUUC 
                 2102 
               
               
                   
               
               
                 AD-67291.1 
                 A-134432.1 
                 GGGGGUGUGAACCCCCUCGAA 
                 1925 
                 A-134433.1 
                 UUCGAGGGGGUUCACACCCCCAA 
                 2103 
               
               
                   
               
               
                 AD-67292.1 
                 A-134434.1 
                 GGGUGUGAACCCCCUCGAAGA 
                 1926 
                 A-134435.1 
                 UCUUCGAGGGGGUUCACACCCCC 
                 2104 
               
               
                   
               
               
                 AD-70224.1 
                 A-141079.1 
                 AAACUUGAGGUCGAAAAUA 
                 1927 
                 A-141080.1 
                 UAUUUUCGACCUCAAGUUUUU 
                 2105 
               
               
                   
               
               
                 AD-70225.1 
                 A-141081.1 
                 AAACUUGAGGUCGAAAAUA 
                 1928 
                 A-141082.1 
                 UAUUUUCGACCUCAAGUUUUU 
                 2106 
               
               
                   
               
               
                 AD-70226.1 
                 A-141083.1 
                 AAACUUGAGGUCGAAAAUA 
                 1929 
                 A-141084.1 
                 UAUUUUCGACCTCAAGUUUUU 
                 2107 
               
               
                   
               
               
                 AD-70227.1 
                 A-141085.1 
                 AAACUUGAGGUCGAAAAUA 
                 1930 
                 A-141084.1 
                 UAUUUUCGACCTCAAGUUUUU 
                 2108 
               
               
                   
               
               
                 AD-70228.1 
                 A-141086.1 
                 AGAAACUUGAGGUCGAAAAUA 
                 1931 
                 A-141087.1 
                 UAUUUUCGACCUCAAGUUUCU 
                 2109 
               
               
                   
               
               
                 AD-70229.1 
                 A-141090.1 
                 GAUCAAGAAACUUGAGGUA 
                 1932 
                 A-141091.1 
                 UACCUCAAGUUUCUUGAUCUU 
                 2110 
               
               
                   
               
               
                 AD-70230.1 
                 A-141092.1 
                 GAUCAAGAAACUUGAGGUA 
                 1933 
                 A-141093.1 
                 UACCUCAAGUUTCUUGAUCUU 
                 2111 
               
               
                   
               
               
                 AD-70231.1 
                 A-141094.1 
                 GAUCAAGAAACUUGAGGUA 
                 1934 
                 A-141093.1 
                 UACCUCAAGUUTCUUGAUCUU 
                 2112 
               
               
                   
               
               
                 AD-70232.1 
                 A-141095.1 
                 AAGAUCAAGAAACUUGAGGUA 
                 1935 
                 A-141096.1 
                 UACCUCAAGUUUCUUGAUCUU 
                 2113 
               
               
                   
               
               
                 AD-70233.1 
                 A-141097.1 
                 UCAAGAAACUUGAGGUCGA 
                 1936 
                 A-141098.1 
                 UCGACCUCAAGUUUCUUGAUU 
                 2114 
               
               
                   
               
               
                 AD-70234.1 
                 A-141097.1 
                 UCAAGAAACUUGAGGUCGA 
                 1937 
                 A-141099.1 
                 UCGACCUCAAGUUUCUUGAUU 
                 2115 
               
               
                   
               
               
                 AD-70235.1 
                 A-141100.1 
                 UCAAGAAACUUGAGGUCGA 
                 1938 
                 A-141101.1 
                 UCGACCUCAAGUUUCUUGAUU 
                 2116 
               
               
                   
               
               
                 AD-70236.1 
                 A-141102.1 
                 UCAAGAAACUUGAGGUCGA 
                 1939 
                 A-141103.1 
                 UCGACCUCAAGTUUCUUGAUU 
                 2117 
               
               
                   
               
               
                 AD-70237.1 
                 A-141104.1 
                 UCAAGAAACUUGAGCUCGA 
                 1940 
                 A-141103.1 
                 UCGACCUCAAGTUUCUUGAUU 
                 2118 
               
               
                   
               
               
                 AD-70238.1 
                 A-141105.1 
                 UCAAGAAACUUGAGGUCGA 
                 1941 
                 A-141106.1 
                 UCGACCUCAAGUUUCUUGA 
                 2119 
               
               
                   
               
               
                 AD-70239.1 
                 A-141107.1 
                 AAGAUCAAGAAACUUGAGA 
                 1942 
                 A-141108.1 
                 UCUCAAGUUUCUUGAUCUUUU 
                 2120 
               
               
                   
               
               
                 AD-70240.1 
                 A-141107.1 
                 AAGAUCAAGAAACUUGAGA 
                 1943 
                 A-141109.1 
                 UCUCAAGUUUCUUGAUCUUUU 
                 2121 
               
               
                   
               
               
                 AD-70241.1 
                 A-141110.1 
                 AAGAUCAAGAAACUUGAGA 
                 1944 
                 A-141111.1 
                 UCUCAAGUUUCUUGAUCUUUU 
                 2122 
               
               
                   
               
               
                 AD-70242.1 
                 A-141112.1 
                 AAGAUCAAGAAACUUGAGA 
                 1945 
                 A-141113.1 
                 UCUCAAGUUUCTUGAUCUUUU 
                 2123 
               
               
                   
               
               
                 AD-70243.1 
                 A-141114.1 
                 AAGAUCAAGAAACUAGAGA 
                 1946 
                 A-141113.1 
                 UCUCAAGUUUCTUGAUCUUUU 
                 2124 
               
               
                   
               
               
                 AD-70244.1 
                 A-141115.1 
                 AGAAGAUCAAGAAACUUGAGA 
                 1947 
                 A-141116.1 
                 UCUCAAGUUUCUUGAUCUUCU 
                 2125 
               
               
                   
               
               
                 AD-70245.1 
                 A-141117.1 
                 CAUCAAAGGAAUUCUCGGA 
                 1948 
                 A-141118.1 
                 UCCGAGAAUUCCUUUGAUGUU 
                 2126 
               
               
                   
               
               
                 AD-70246.1 
                 A-141119.1 
                 CAUCAAAGGAAUUCUCGGA 
                 1949 
                 A-141120.1 
                 UCCGAGAAUUCCUUUGAUGUU 
                 2127 
               
               
                   
               
               
                 AD-70247.1 
                 A-141121.1 
                 CAUCAAAGGAAUUCUCGGA 
                 1950 
                 A-141122.1 
                 UCCGAGAAUUCCUUUGAUGUU 
                 2128 
               
               
                   
               
               
                 AD-70248.1 
                 A-141123.1 
                 CAUCAAAGGAAUUCTCGGA 
                 1951 
                 A-141122.1 
                 UCCGAGAAUUCCUUUGAUGUU 
                 2129 
               
               
                   
               
               
                 AD-70249.1 
                 A-141124.1 
                 AACAUCAAAGGAAUUCUCGGA 
                 1952 
                 A-141125.1 
                 UCCGAGAAUUCCUUUGAUGUU 
                 2130 
               
               
                   
               
               
                 AD-70250.1 
                 A-141126.1 
                 AUCAAGAAACUUGAGGUCA 
                 1953 
                 A-141127.1 
                 UGACCUCAAGUUUCUUGAUUU 
                 2131 
               
               
                   
               
               
                 AD-70251.1 
                 A-141126.1 
                 AUCAAGAAACUUGAGGUCA 
                 1954 
                 A-141128.1 
                 UGACCUCAAGUUUCUUGAUUU 
                 2132 
               
               
                   
               
               
                 AD-70252.1 
                 A-141129.1 
                 AUCAAGAAACUUGAGGUCA 
                 1955 
                 A-141130.1 
                 UGACCUCAAGUUUCUUGAUUU 
                 2133 
               
               
                   
               
               
                 AD-70253.1 
                 A-141131.1 
                 AUCAAGAAACUUGAGGUCA 
                 1956 
                 A-141132.1 
                 UGACCUCAAGUTUCUUGAUUU 
                 2134 
               
               
                   
               
               
                 AD-70254.1 
                 A-141133.1 
                 AUCAAGAAACUUGACGUCA 
                 1957 
                 A-141132.1 
                 UGACCUCAAGUTUCUUGAUUU 
                 2135 
               
               
                   
               
               
                 AD-70255.1 
                 A-141134.1 
                 AGAUCAAGAAACUUGAGGUCA 
                 1958 
                 A-141135.1 
                 UGACCUCAAGUUUCUUGAUCU 
                 2136 
               
               
                   
               
               
                 AD-70256.1 
                 A-141136.1 
                 GAAGAUCAAGAAACUUGAA 
                 1959 
                 A-141137.1 
                 UUCAAGUUUCUUGAUCUUCUU 
                 2137 
               
               
                   
               
               
                 AD-70257.1 
                 A-141138.1 
                 GAAGAUCAAGAAACUUGAA 
                 1960 
                 A-141139.1 
                 UUCAAGUUUCUUGAUCUUCUU 
                 2138 
               
               
                   
               
               
                 AD-70258.1 
                 A-141140.1 
                 GAAGAUCAAGAAACUUGAA 
                 1961 
                 A-141141.1 
                 UUCAAGUUUCUTGAUCUUCUU 
                 2139 
               
               
                   
               
               
                 AD-70259.1 
                 A-141142.1 
                 GAAGAUCAAGAAACTUGAA 
                 1962 
                 A-141141.1 
                 UUCAAGUUUCUTGAUCUUCUU 
                 2140 
               
               
                   
               
               
                 AD-70260.1 
                 A-141143.1 
                 AAGAAGAUCAAGAAACUUGAA 
                 1963 
                 A-141144.1 
                 UUCAAGUUUCUUGAUCUUCUU 
                 2141 
               
               
                   
               
               
                 AD-70261.1 
                 A-141145.1 
                 CAAAGGAAUUCUCGGAAAG 
                 1964 
                 A-141146.1 
                 CUUUCCGAGAAUUCCUUUGAU 
                 2142 
               
               
                   
               
               
                 AD-70262.1 
                 A-141145.1 
                 CAAAGGAAUUCUCGGAAAG 
                 1965 
                 A-141147.1 
                 CUUUCCGAGAAUUCCUUUGAU 
                 2143 
               
               
                   
               
               
                 AD-70263.1 
                 A-141148.1 
                 CAAAGGAAUUCUCGGAAAG 
                 1966 
                 A-141149.1 
                 CUUUCCGAGAAUUCCUUUGAU 
                 2144 
               
               
                   
               
               
                 AD-70264.1 
                 A-141150.1 
                 CAAAGGAAUUCUCGGAAAG 
                 1967 
                 A-141151.1 
                 CUUUCCGAGAATUCCUUUGAU 
                 2145 
               
               
                   
               
               
                 AD-70265.1 
                 A-141152.1 
                 CAAAGGAAUUCUCGCAAAG 
                 1968 
                 A-141151.1 
                 CUUUCCGAGAATUCCUUUGAU 
                 2146 
               
               
                   
               
               
                 AD-70266.1 
                 A-141153.1 
                 AUCAAAGGAAUUCUCGGAAAG 
                 1969 
                 A-141154.1 
                 CUUUCCGAGAAUUCCUUUGAU 
                 2147 
               
               
                   
               
               
                 AD-70267.1 
                 A-141155.1 
                 CAAGAAACUUGAGGUCGAA 
                 1970 
                 A-141156.1 
                 UUCGACCUCAAGUUUCUUGAU 
                 2148 
               
               
                   
               
               
                 AD-70268.1 
                 A-141155.1 
                 CAAGAAACUUGAGGUCGAA 
                 1971 
                 A-141157.1 
                 UUCGACCUCAAGUUUCUUGAU 
                 2149 
               
               
                   
               
               
                 AD-70269.1 
                 A-141158.1 
                 CAAGAAACUUGAGGUCGAA 
                 1972 
                 A-141159.1 
                 UUCGACCUCAAGUUUCUUGAU 
                 2150 
               
               
                   
               
               
                 AD-70270.1 
                 A-141160.1 
                 CAAGAAACUUGAGGUCGAA 
                 1973 
                 A-141161.1 
                 UUCGACCUCAAGUUUCUUGAU 
                 2151 
               
               
                   
               
               
                 AD-70271.1 
                 A-141162.1 
                 CAAGAAACUUGAGGTCGAA 
                 1974 
                 A-141161.1 
                 UUCGACCUCAAGUUUCUUGAU 
                 2152 
               
               
                   
               
               
                 AD-70272.1 
                 A-141163.1 
                 AUCAAGAAACUUGAGGUCGAA 
                 1975 
                 A-141164.1 
                 UUCGACCUCAAGUUUCUUGAU 
                 2153 
               
               
                   
               
               
                 AD-70273.1 
                 A-141165.1 
                 GAAGAAGAUCAAGAAACUU 
                 1976 
                 A-141166.1 
                 AAGUUUCUUGAUCUUCUUCUU 
                 2154 
               
               
                   
               
               
                 AD-70274.1 
                 A-141165.1 
                 GAAGAAGAUCAAGAAACUU 
                 1977 
                 A-141167.1 
                 AAGUUUCUUGAUCUUCUUCUU 
                 2155 
               
               
                   
               
               
                 AD-70275.1 
                 A-141168.1 
                 GAAGAAGAUCAAGAAACUU 
                 1978 
                 A-141169.1 
                 AAGUUUCUUGAUCUUCUUCUU 
                 2156 
               
               
                   
               
               
                 AD-70276.1 
                 A-141170.1 
                 GAAGAAGAUCAAGAAACUU 
                 1979 
                 A-141171.1 
                 AAGUUUCUUGATCUUCUUCUU 
                 2157 
               
               
                   
               
               
                 AD-70277.1 
                 A-141172.1 
                 GAAGAAGAUCAAGAAACUU 
                 1980 
                 A-141171.1 
                 AAGUUUCUUGATCUUCUUCUU 
                 2158 
               
               
                   
               
               
                 AD-70278.1 
                 A-141173.1 
                 AAGAAGAAGAUCAAGAAACUU 
                 1981 
                 A-141174.1 
                 AAGUUUCUUGAUCUUCUUCUU 
                 2159 
               
               
                   
               
               
                 AD-70279.1 
                 A-141175.1 
                 GGAAACAUCAAAGGAAUUA 
                 1982 
                 A-141176.1 
                 UAAUUCCUUUGAUGUUUCCUU 
                 2160 
               
               
                   
               
               
                 AD-70280.1 
                 A-141175.1 
                 GGAAACAUCAAAGGAAUUA 
                 1983 
                 A-141177.1 
                 UAAUUCCUUUGAUGUUUCCUU 
                 2161 
               
               
                   
               
               
                 AD-70281.1 
                 A-141178.1 
                 GGAAACAUCAAAGGAAUUA 
                 1984 
                 A-141179.1 
                 UAAUUCCUUUGAUGUUUCCUU 
                 2162 
               
               
                   
               
               
                 AD-70282.1 
                 A-141180.1 
                 GGAAACAUCAAAGGAAUUA 
                 1985 
                 A-141181.1 
                 UAAUUCCUUUGAUGUUUCUU 
                 2163 
               
               
                   
               
               
                 AD-70283.1 
                 A-141182.1 
                 GGAAACAUCAAAGGAAUUA 
                 1986 
                 A-141183.1 
                 UAAUUCCUUUGAUGUUUCCUU 
                 2164 
               
               
                   
               
               
                 AD-70284.1 
                 A-141184.1 
                 UGGGAAACAUCAAAGGAAUUA 
                 1987 
                 A-141185.1 
                 UAAUUCCUUUGAUGUUUCCCA 
                 2165 
               
               
                   
               
               
                 AD-70285.1 
                 A-134288.1 
                 AAAGAAGAAGAUCAAGAAACU 
                 1988 
                 A-141186.1 
                 AGUUUCUUGAUCUUCUUCUUUGU 
                 2166 
               
               
                   
               
               
                 AD-70286.1 
                 A-141187.1 
                 AAAGAAGAAGAUCAAGAAACU 
                 1989 
                 A-141188.1 
                 AGUUUCUUGAUCUUCUUCUUUGU 
                 2167 
               
               
                   
               
               
                 AD-70287.1 
                 A-141189.1 
                 AAAGAAGAAGAUCAAGAAACU 
                 1990 
                 A-141190.1 
                 AGUUUCUUGAUCUUCUUCUUUGU 
                 2168 
               
               
                   
               
               
                 AD-70288.1 
                 A-141191.1 
                 AAAGAAGAAGAUCAAGAAACU 
                 1991 
                 A-141190.1 
                 AGUUUCUUGAUCUUCUUCUUUGU 
                 2169 
               
               
                   
               
               
                 AD-70289.1 
                 A-141192.1 
                 AAAGAAGAAGAUCAAGAAACU 
                 1992 
                 A-141193.1 
                 AGUUUCUUGAUCUUCUUCUUU 
                 2170 
               
               
                   
               
               
                 AD-70290.1 
                 A-141194.1 
                 AGAAGAAGAUCAAGAAACU 
                 1993 
                 A-141195.1 
                 AGUUUCUUGAUCUUCUUCUUU 
                 2171 
               
               
                   
               
               
                 AD-70291.1 
                 A-141194.1 
                 AGAAGAAGAUCAAGAAACU 
                 1994 
                 A-141196.1 
                 AGUUUCUUGAUCUUCUUCUUU 
                 2172 
               
               
                   
               
               
                 AD-70292.1 
                 A-141197.1 
                 AGAAGAAGAUCAAGAAACU 
                 1995 
                 A-141198.1 
                 AGUUUCUUGAUCUUCUUCUUU 
                 2173 
               
               
                   
               
               
                 AD-70293.1 
                 A-141199.1 
                 AGAAGAAGAUCAAGAAACU 
                 1996 
                 A-141200.1 
                 AGUUUCUUGAUCUUCUUCUUU 
                 2174 
               
               
                   
               
               
                 AD-70294.1 
                 A-141201.1 
                 AGAAGAAGAUCAAGAAACU 
                 1997 
                 A-141200.1 
                 AGUUUCUUGAUCUUCUUCUUU 
                 2175 
               
               
                   
               
               
                 AD-70295.1 
                 A-141202.1 
                 AGAAGAAGAUCAAGAAACU 
                 1998 
                 A-141203.1 
                 AGUUUCUUGAUCUUCUUCU 
                 2176 
               
               
                   
               
               
                 AD-70296.1 
                 A-141204.1 
                 AACAUCAAAGGAAUUCUCA 
                 1999 
                 A-141205.1 
                 UGAGAAUUCCUUUGAUGUUUU 
                 2177 
               
               
                   
               
               
                 AD-70297.1 
                 A-141204.1 
                 AACAUCAAAGGAAUUCUCA 
                 2000 
                 A-141206.1 
                 UGAGAAUUCCUUUGAUGUUUU 
                 2178 
               
               
                   
               
               
                 AD-70298.1 
                 A-141207.1 
                 AACAUCAAAGGAAUUCUCA 
                 2001 
                 A-141208.1 
                 UGAGAAUUCCUUUGAUGUUUU 
                 2179 
               
               
                   
               
               
                 AD-70299.1 
                 A-141209.1 
                 AACAUCAAAGGAAUUCUCA 
                 2002 
                 A-141210.1 
                 UGAGAAUUCCUTUGAUGUUUU 
                 2180 
               
               
                   
               
               
                 AD-70300.1 
                 A-141211.1 
                 AACAUCAAAGGAAUTCUCA 
                 2003 
                 A-141210.1 
                 UGAGAAUUCCUTUGAUGUUUU 
                 2181 
               
               
                   
               
               
                 AD-70301.1 
                 A-141212.1 
                 AACAUCAAAGGAAUUCUCA 
                 2004 
                 A-141213.1 
                 UGAGAAUUCCUUUGAUGUU 
                 2182 
               
               
                   
               
               
                 AD-70302.1 
                 A-141214.1 
                 AGGAAUUCUCGGAAAGAAA 
                 2005 
                 A-141215.1 
                 UUUCUUUCCGAGAAUUCCUUU 
                 2183 
               
               
                   
               
               
                 AD-70303.1 
                 A-141214.1 
                 AGGAAUUCUCGGAAAGAAA 
                 2006 
                 A-141216.1 
                 UUUCUUUCCGAGAAUUCCUUU 
                 2184 
               
               
                   
               
               
                 AD-70304.1 
                 A-141217.1 
                 AGGAAUUCUCGGAAAGAAA 
                 2007 
                 A-141218.1 
                 UUUCUUUCCGAGAAUUCCUUU 
                 2185 
               
               
                   
               
               
                 AD-70305.1 
                 A-141219.1 
                 AGGAAUUCUCGGAAAGAAA 
                 2008 
                 A-141220.1 
                 UUUCUUUCCGAGAAUUCCUUU 
                 2186 
               
               
                   
               
               
                 AD-70306.1 
                 A-141221.1 
                 AGGAAUUCUCGGAAAGAAA 
                 2009 
                 A-141220.1 
                 UUUCUUUCCGAGAAUUCCUUU 
                 2187 
               
               
                   
               
               
                 AD-70307.1 
                 A-141222.1 
                 AAAGGAAUUCUCGGAAAGAAA 
                 2010 
                 A-141223.1 
                 UUUCUUUCCGAGAAUUCCUUU 
                 2188 
               
               
                   
               
               
                 AD-70308.1 
                 A-141224.1 
                 AAAGGAAUUCUCGGAAAGA 
                 2011 
                 A-141225.1 
                 UCUUUCCGAGAAUUCCUUUUU 
                 2189 
               
               
                   
               
               
                 AD-70309.1 
                 A-141224.1 
                 AAAGGAAUUCUCGGAAAGA 
                 2012 
                 A-141226.1 
                 UCUUUCCGAGAAUUCCUUUUU 
                 2190 
               
               
                   
               
               
                 AD-70310.1 
                 A-141227.1 
                 AAAGGAAUUCUCGGAAAGA 
                 2013 
                 A-141228.1 
                 UCUUUCCGAGAAUUCCUUUUU 
                 2191 
               
               
                   
               
               
                 AD-70311.1 
                 A-141229.1 
                 AAAGGAAUUCUCGGAAAGA 
                 2014 
                 A-141230.1 
                 UCUUUCCGAGAAUUCCUUUUU 
                 2192 
               
               
                   
               
               
                 AD-70312.1 
                 A-141231.1 
                 AAAGGAAUUCUCGGAAAGA 
                 2015 
                 A-141230.1 
                 UCUUUCCGAGAAUUCCUUUUU 
                 2193 
               
               
                   
               
               
                 AD-70313.1 
                 A-141232.1 
                 UCAAAGGAAUUCUCGGAAAGA 
                 2016 
                 A-141233.1 
                 UCUUUCCGAGAAUUCCUUUGA 
                 2194 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 32 
               
             
            
               
                   
               
               
                 Modified Sense and Antisense Strand Sequences of HDV dsRNAs 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Anti- 
                   
                   
               
               
                   
                 Sense 
                   
                 SEQ 
                 sense 
                   
                 SEQ 
               
               
                 Duplex 
                 Oligo 
                   
                 ID 
                 Oligo 
                   
                 ID 
               
               
                 Name 
                 Name 
                 Sense Sequence (5′3′ 
                 NO: 
                 Name 
                 Antisense Sequence (5′3′ 
                 NO: 
               
               
                   
               
               
                 AD- 
                 A- 
                 uscsccaaGfaAfGfGfccaaaagagaL96 
                 2195 
                 A- 
                 usCfsucuUfuuggccuUfcUfugggasgsa 
                 2373 
               
               
                 67176.1 
                 134242.1 
                   
                   
                 134243.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asgsuuucUfuGfAfUfcuucuucuuuL96 
                 2196 
                 A- 
                 asAfsagaAfgaagaucAfaGfaaacususg 
                 2374 
               
               
                 67177.1 
                 134244.1 
                   
                   
                 134245.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 uscsuuuuCfuGfAfUfaaagaggagaL96 
                 2197 
                 A- 
                 usCfsuccUfcuuuaucAfgAfaaagasgsu 
                 2375 
               
               
                 67178.1 
                 134246.1 
                   
                   
                 134247.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asgsugguAfaAfGfAfguauuggaaaL96 
                 2198 
                 A- 
                 usUfsuccAfauacucuUfuAfccacususu 
                 2376 
               
               
                 67179.1 
                 134248.1 
                   
                   
                 134249.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csuscaagUfuUfCfUfugaucuucuuL96 
                 2199 
                 A- 
                 asAfsgaaGfaucaagaAfaCfuugagsgsu 
                 2377 
               
               
                 67180.1 
                 134250.1 
                   
                   
                 134251.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasggccAfaAfAfGfagaauacaaaL96 
                 2200 
                 A- 
                 usUfsuguAfuucucuuUfuGfgccuuscsu 
                 2378 
               
               
                 67181.1 
                 134252.1 
                   
                   
                 134253.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasccucAfaGfUfUfucuugaucuuL96 
                 2201 
                 A- 
                 asAfsgauCfaagaaacUfuGfaggucsgsa 
                 2379 
               
               
                 67182.1 
                 134254.1 
                   
                   
                 134255.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asgsgccaAfaAfGfAfgaauacaagaL96 
                 2202 
                 A- 
                 usCfsuugUfauucucuUfuUfggccususc 
                 2380 
               
               
                 67183.1 
                 134256.1 
                   
                   
                 134257.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csgsauagAfgAfAfUfcgagagaaaaL96 
                 2203 
                 A- 
                 usUfsuucUfcucgauuCfuCfuaucgsgsa 
                 2381 
               
               
                 67184.1 
                 134258.1 
                   
                   
                 134259.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasuagaGfaAfUfCfgagagaaaagL96 
                 2204 
                 A- 
                 csUfsuuuCfucucgauUfcUfcuaucsgsg 
                 2382 
               
               
                 67185.1 
                 134260.1 
                   
                   
                 134261.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 ascsccacAfaAfUfCfucucuagauuL96 
                 2205 
                 A- 
                 asAfsucuAfgagagauUfuGfuggguscsc 
                 2383 
               
               
                 67186.1 
                 134262.1 
                   
                   
                 134263.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsgsauggGfaAfGfAfguauauccuaL96 
                 2206 
                 A- 
                 usAfsggaUfauacucuUfcCfcauccsgsa 
                 2384 
               
               
                 67187.1 
                 134264.1 
                   
                   
                 134265.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 cscsgauaGfaGfAfAfucgagagaaaL96 
                 2207 
                 A- 
                 usUfsucuCfucgauucUfcUfaucggsasa 
                 2385 
               
               
                 67188.1 
                 134266.1 
                   
                   
                 134267.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 uscscgauAfgAfGfAfaucgagagaaL96 
                 2208 
                 A- 
                 usUfscucUfcgauucuCfuAfucggasasu 
                 2386 
               
               
                 67189.1 
                 134268.1 
                   
                   
                 134269.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 usgsagugGfaAfAfCfccgcuuuauuL96 
                 2209 
                 A- 
                 asAfsuaaAfgcggguuUfcCfacucascsa 
                 2387 
               
               
                 67190.1 
                 134270.1 
                   
                   
                 134271.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 cscsuucuUfuCfCfGfagaauuccuuL96 
                 2210 
                 A- 
                 asAfsggaAfuucucggAfaAfgaaggsasc 
                 2388 
               
               
                 67191.1 
                 134272.1 
                   
                   
                 134273.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csusgugaGfuGfGfAfaacccgcuuuL96 
                 2211 
                 A- 
                 asAfsagcGfgguuuccAfcUfcacagsgsu 
                 2389 
               
               
                 67192.1 
                 134274.1 
                   
                   
                 134275.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsascccaCfaAfAfUfcucucuagauL96 
                 2212 
                 A- 
                 asUfscuaGfagagauuUfgUfgggucscsc 
                 2390 
               
               
                 67193.1 
                 134276.1 
                   
                   
                 134277.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gscsugggAfaAfCfAfucaaaggaauL96 
                 2213 
                 A- 
                 asUfsuccUfuugauguUfuCfccagcscsa 
                 2391 
               
               
                 67194.1 
                 134278.1 
                   
                   
                 134279.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 ascsaguuGfgAfAfGfgcucaaggagL96 
                 2214 
                 A- 
                 usGfsucaAfccuuccgAfgUfuccucsusu 
                 2392 
               
               
                 67195.1 
                 134280.1 
                   
                   
                 134281.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasggagGfaGfGfAfacgaguccgaL96 
                 2215 
                 A- 
                 usUfsccuCfcuccuugCfuCfaggcuscsu 
                 2393 
               
               
                 67196.1 
                 134282.1 
                   
                   
                 134283.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 uscsuccuCfuUfUfAfucagaaaagaL96 
                 2216 
                 A- 
                 usCfsuuuUfcugauaaAfgAfggagascsu 
                 2394 
               
               
                 67197.1 
                 134284.1 
                   
                   
                 134285.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 uscscagcAfgUfCfUfccucuuuauaL96 
                 2217 
                 A- 
                 usAfsuaaAfgaggagaCfuGfcuggascsu 
                 2395 
               
               
                 67198.1 
                 134286.1 
                   
                   
                 134287.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasagaaGfaAfGfAfucaagaaacuL96 
                 2218 
                 A- 
                 asGfsuuuCfuugaucuUfcUfucuuusgsu 
                 2396 
               
               
                 67199.1 
                 134288.1 
                   
                   
                 134289.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasgaagAfaGfAfUfcaagaaacuuL96 
                 2219 
                 A- 
                 asAfsguuUfcuugaucUfuCfuucuususg 
                 2397 
               
               
                 67200.1 
                 134290.1 
                   
                   
                 134291.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasggucGfaAfAfAfucccuggcuaL96 
                 2220 
                 A- 
                 usAfsgccAfgggauuuUfcGfaccucsasa 
                 2398 
               
               
                 67201.1 
                 134292.1 
                   
                   
                 134293.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 cscscuggCfuGfGfGfaaacaucaaaL96 
                 2221 
                 A- 
                 usUfsugaUfguuucccAfgCfcagggsasu 
                 2399 
               
               
                 67202.1 
                 134294.1 
                   
                   
                 134295.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csusggcuGfgGfAfAfacaucaaagaL96 
                 2222 
                 A- 
                 usCfsuuuGfauguuucCfcAfgccagsgsg 
                 2400 
               
               
                 67203.1 
                 134296.1 
                   
                   
                 134297.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 usgsgcugGfgAfAfAfcaucaaaggaL96 
                 2223 
                 A- 
                 usCfscuuUfgauguuuCfcCfagccasgsg 
                 2401 
               
               
                 67204.1 
                 134298.1 
                   
                   
                 134299.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsgscuggGfaAfAfCfaucaaaggaaL96 
                 2224 
                 A- 
                 usUfsccuUfugauguuUfcCfcagccsasg 
                 2402 
               
               
                 67205.1 
                 134300.1 
                   
                   
                 134301.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 uscsaaagGfaAfUfUfcucggaaagaL96 
                 2225 
                 A- 
                 usCfsuuuCfcgagaauUfcCfuuugasusg 
                 2403 
               
               
                 67206.1 
                 134302.1 
                   
                   
                 134303.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 usgsggaaAfcAfUfCfaaaggaauuaL96 
                 2226 
                 A- 
                 usAfsauuCfcuuugauGfuUfucccasgsc 
                 2404 
               
               
                 67207.1 
                 134304.1 
                   
                   
                 134305.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsgsaaacAfuCfAfAfaggaauucuaL96 
                 2227 
                 A- 
                 usAfsgaaUfuccuuugAfuGfuuuccscsa 
                 2405 
               
               
                 67208.1 
                 134306.1 
                   
                   
                 134307.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasaacaUfcAfAfAfggaauucucaL96 
                 2228 
                 A- 
                 usGfsagaAfuuccuuuGfaUfguuucscsc 
                 2406 
               
               
                 67209.1 
                 134308.1 
                   
                   
                 134309.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasacauCfaAfAfGfgaauucucgaL96 
                 2229 
                 A- 
                 usCfsgagAfauuccuuUfgAfuguuuscsc 
                 2407 
               
               
                 67210.1 
                 134310.1 
                   
                   
                 134311.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csasucaaAfgGfAfAfuucucggaaaL96 
                 2230 
                 A- 
                 usUfsuccGfagaauucCfuUfugaugsusu 
                 2408 
               
               
                 67211.1 
                 134312.1 
                   
                   
                 134313.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasaggaAfuUfCfUfcggaaagaaaL96 
                 2231 
                 A- 
                 usUfsucuUfuccgagaAfuUfccuuusgsa 
                 2409 
               
               
                 67212.1 
                 134314.1 
                   
                   
                 134315.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasggaaUfuCfUfCfggaaagaagaL96 
                 2232 
                 A- 
                 usCfsuucUfuuccgagAfaUfuccuususg 
                 2410 
               
               
                 67213.1 
                 134316.1 
                   
                   
                 134317.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsgscccuCfgAfGfAfacaagaagaaL96 
                 2233 
                 A- 
                 usUfscuuCfuuguucuCfgAfgggccsusu 
                 2411 
               
               
                 67214.1 
                 134320.1 
                   
                   
                 134321.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gscsccucGfaGfAfAfcaagaagaaaL96 
                 2234 
                 A- 
                 usUfsucuUfcuuguucUfcGfagggcscsu 
                 2412 
               
               
                 67215.1 
                 134322.1 
                   
                   
                 134323.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 cscscucgAfgAfAfCfaagaagaagaL96 
                 2235 
                 A- 
                 usCfsuucUfucuuguuCfuCfgagggscsc 
                 2413 
               
               
                 67216.1 
                 134324.1 
                   
                   
                 134325.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsgsaaagGfaAfAfAfgaagaguagaL96 
                 2236 
                 A- 
                 usCfsuacUfcuucuuuUfcCfuuuccsusc 
                 2414 
               
               
                 67217.1 
                 134326.1 
                   
                   
                 134327.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasggaaAfaGfAfAfgaguagccgaL96 
                 2237 
                 A- 
                 usCfsggcUfacucuucUfuUfuccuususc 
                 2415 
               
               
                 67218.1 
                 134328.1 
                   
                   
                 134329.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsgsggguGfuGfAfAfcccccucgaaL96 
                 2238 
                 A- 
                 usUfscgaGfgggguucAfcAfcccccsasa 
                 2416 
               
               
                 67219.1 
                 134330.1 
                   
                   
                 134331.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsgsguguGfaAfCfCfcccucgaagaL96 
                 2239 
                 A- 
                 usCfsuucGfaggggguUfcAfcacccscsc 
                 2417 
               
               
                 67220.1 
                 134332.1 
                   
                   
                 134333.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44AGUUUCUUGAUCUUCUUCUUu 
                 2240 
                 A- 
                 AAAGAAGAAGAUCAAGAAACUUg 
                 2418 
               
               
                 67250.1 
                 134346.1 
                   
                   
                 134347.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44UCUUUUCUGAUAAAGAGGAGa 
                 2241 
                 A- 
                 UCUCCUCUUUAUCAGAAAAGAGu 
                 2419 
               
               
                 67251.1 
                 134348.1 
                   
                   
                 134349.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44AGUGGUAAAGAGUAUUGGAAa 
                 2242 
                 A- 
                 UUUCCAAUACUCUUUACCACUUu 
                 2420 
               
               
                 67252.1 
                 134350.1 
                   
                   
                 134351.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44CUCAAGUUUCUUGAUCUUCUu 
                 2243 
                 A- 
                 AAGAAGAUCAAGAAACUUGAGGu 
                 2421 
               
               
                 67253.1 
                 134352.1 
                   
                   
                 134353.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44AAGGCCAAAAGAGAAUACAAa 
                 2244 
                 A- 
                 UUUGUAUUCUCUUUUGGCCUUCu 
                 2422 
               
               
                 67254.1 
                 134354.1 
                   
                   
                 134355.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44AGGCCAAAAGAGAAUACAAGa 
                 2245 
                 A- 
                 UCUUGUAUUCUCUUUUGGCCUUc 
                 2423 
               
               
                 67255.1 
                 134358.1 
                   
                   
                 134359.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44CGAUAGAGAAUCGAGAGAAAa 
                 2246 
                 A- 
                 UUUUCUCUCGAUUCUCUAUCGGa 
                 2424 
               
               
                 67256.1 
                 134360.1 
                   
                   
                 134361.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44GAUAGAGAAUCGAGAGAAAAg 
                 2247 
                 A- 
                 CUUUUCUCUCGAUUCUCUAUCGg 
                 2425 
               
               
                 67257.1 
                 134362.1 
                   
                   
                 134363.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44ACCCACAAAUCUCUCUAGAUu 
                 2248 
                 A- 
                 AAUCUAGAGAGAUUUGUGGGUCc 
                 2426 
               
               
                 67258.1 
                 134364.1 
                   
                   
                 134365.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44GGAUGGGAAGAGUAUAUCCUa 
                 2249 
                 A- 
                 UAGGAUAUACUCUUCCCAUCCGa 
                 2427 
               
               
                 67259.1 
                 134366.1 
                   
                   
                 134367.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44CCGAUAGAGAAUCGAGAGAAa 
                 2250 
                 A- 
                 UUUCUCUCGAUUCUCUAUCGGAa 
                 2428 
               
               
                 67260.1 
                 134368.1 
                   
                   
                 134369.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44UCCGAUAGAGAAUCGAGAGAa 
                 2251 
                 A- 
                 UUCUCUCGAUUCUCUAUCGGAAu 
                 2429 
               
               
                 67261.1 
                 134370.1 
                   
                   
                 134371.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44UGAGUGGAAACCCGCUUUAUu 
                 2252 
                 A- 
                 AAUAAAGCGGGUUUCCACUCACa 
                 2430 
               
               
                 67262.1 
                 134372.1 
                   
                   
                 134373.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44CCUUCUUUCCGAGAAUUCCUu 
                 2253 
                 A- 
                 AAGGAAUUCUCGGAAAGAAGGAc 
                 2431 
               
               
                 67263.1 
                 134374.1 
                   
                   
                 134375.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44CUGUGAGUGGAAACCCGCUUu 
                 2254 
                 A- 
                 AAAGCGGGUUUCCACUCACAGGu 
                 2432 
               
               
                 67264.1 
                 134376.1 
                   
                   
                 134377.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44GACCCACAAAUCUCUCUAGAu 
                 2255 
                 A- 
                 AUCUAGAGAGAUUUGUGGGUCCc 
                 2433 
               
               
                 67265.1 
                 134378.1 
                   
                   
                 134379.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44GCUGGGAAACAUCAAAGGAAu 
                 2256 
                 A- 
                 AUUCCUUUGAUGUUUCCCAGCCa 
                 2434 
               
               
                 67266.1 
                 134380.1 
                   
                   
                 134381.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44ACAGUUGGAAGGCUCAAGGAg 
                 2257 
                 A- 
                 UGUCAACCUUCCGAGUUCCUCUu 
                 2435 
               
               
                 67267.1 
                 134382.1 
                   
                   
                 134383.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44AAGGAGGAGGAACGAGUCCGa 
                 2258 
                 A- 
                 UUCCUCCUCCUUGCUCAGGCUCu 
                 2436 
               
               
                 67268.1 
                 134384.1 
                   
                   
                 134385.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44UCUCCUCUUUAUCAGAAAAGa 
                 2259 
                 A- 
                 UCUUUUCUGAUAAAGAGGAGACu 
                 2437 
               
               
                 67269.1 
                 134386.1 
                   
                   
                 134387.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44UCCAGCAGUCUCCUCUUUAUa 
                 2260 
                 A- 
                 UAUAAAGAGGAGACUGCUGGACu 
                 2438 
               
               
                 67270.1 
                 134388.1 
                   
                   
                 134389.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44AAAGAAGAAGAUCAAGAAACu 
                 2261 
                 A- 
                 AGUUUCUUGAUCUUCUUCUUUGu 
                 2439 
               
               
                 67271.1 
                 134390.1 
                   
                   
                 134391.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44AAGAAGAAGAUCAAGAAACUu 
                 2262 
                 A- 
                 AAGUUUCUUGAUCUUCUUCUUUg 
                 2440 
               
               
                 67272.1 
                 134392.1 
                   
                   
                 134393.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44GAGGUCGAAAAUCCCUGGCUa 
                 2263 
                 A- 
                 UAGCCAGGGAUUUUCGACCUCAa 
                 2441 
               
               
                 67273.1 
                 134394.1 
                   
                   
                 134395.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44CCCUGGCUGGGAAACAUCAAa 
                 2264 
                 A- 
                 UUUGAUGUUUCCCAGCCAGGGAu 
                 2442 
               
               
                 67274.1 
                 134396.1 
                   
                   
                 134397.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44CUGGCUGGGAAACAUCAAAGa 
                 2265 
                 A- 
                 UCUUUGAUGUUUCCCAGCCAGGg 
                 2443 
               
               
                 67275.1 
                 134398.1 
                   
                   
                 134399.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44UGGCUGGGAAACAUCAAAGGa 
                 2266 
                 A- 
                 UCCUUUGAUGUUUCCCAGCCAGg 
                 2444 
               
               
                 67276.1 
                 134400.1 
                   
                   
                 134401.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44GGCUGGGAAACAUCAAAGGAa 
                 2267 
                 A- 
                 UUCCUUUGAUGUUUCCCAGCCAg 
                 2445 
               
               
                 67277.1 
                 134402.1 
                   
                   
                 134403.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44UCAAAGGAAUUCUCGGAAAGa 
                 2268 
                 A- 
                 UCUUUCCGAGAAUUCCUUUGAUg 
                 2446 
               
               
                 67278.1 
                 134404.1 
                   
                   
                 134405.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44UGGGAAACAUCAAAGGAAUUa 
                 2269 
                 A- 
                 UAAUUCCUUUGAUGUUUCCCAGc 
                 2447 
               
               
                 67279.1 
                 134406.1 
                   
                   
                 134407.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44GGAAACAUCAAAGGAAUUCUa 
                 2270 
                 A- 
                 UAGAAUUCCUUUGAUGUUUCCCa 
                 2448 
               
               
                 67280.1 
                 134408.1 
                   
                   
                 134409.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44GAAACAUCAAAGGAAUUCUCa 
                 2271 
                 A- 
                 UGAGAAUUCCUUUGAUGUUUCCc 
                 2449 
               
               
                 67281.1 
                 134410.1 
                   
                   
                 134411.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44CAUCAAAGGAAUUCUCGGAAa 
                 2272 
                 A- 
                 UUUCCGAGAAUUCCUUUGAUGUu 
                 2450 
               
               
                 67282.1 
                 134414.1 
                   
                   
                 134415.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44AAAGGAAUUCUCGGAAAGAAa 
                 2273 
                 A- 
                 UUUCUUUCCGAGAAUUCCUUUGa 
                 2451 
               
               
                 67283.1 
                 134416.1 
                   
                   
                 134417.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44AAGGAAUUCUCGGAAAGAAGa 
                 2274 
                 A- 
                 UCUUCUUUCCGAGAAUUCCUUUg 
                 2452 
               
               
                 67284.1 
                 134418.1 
                   
                   
                 134419.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44ACGAAGGAAGGCCCUCGAGAa 
                 2275 
                 A- 
                 UUCUCGAGGGCCUUCCUUCGUCg 
                 2453 
               
               
                 67285.1 
                 134420.1 
                   
                   
                 134421.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44GGCCCUCGAGAACAAGAAGAa 
                 2276 
                 A- 
                 UUCUUCUUGUUCUCGAGGGCCUu 
                 2454 
               
               
                 67286.1 
                 134422.1 
                   
                   
                 134423.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44GCCCUCGAGAACAAGAAGAAa 
                 2277 
                 A- 
                 UUUCUUCUUGUUCUCGAGGGCCu 
                 2455 
               
               
                 67287.1 
                 134424.1 
                   
                   
                 134425.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44CCCUCGAGAACAAGAAGAAGa 
                 2278 
                 A- 
                 UCUUCUUCUUGUUCUCGAGGGCc 
                 2456 
               
               
                 67288.1 
                 134426.1 
                   
                   
                 134427.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44GGAAAGGAAAAGAAGAGUAGa 
                 2279 
                 A- 
                 UCUACUCUUCUUUUCCUUUCCUc 
                 2457 
               
               
                 67289.1 
                 134428.1 
                   
                   
                 134429.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44AAGGAAAAGAAGAGUAGCCGa 
                 2280 
                 A- 
                 UCGGCUACUCUUCUUUUCCUUUc 
                 2458 
               
               
                 67290.1 
                 134430.1 
                   
                   
                 134431.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44GGGGGUGUGAACCCCCUCGAa 
                 2281 
                 A- 
                 UUCGAGGGGGUUCACACCCCCAa 
                 2459 
               
               
                 67291.1 
                 134432.1 
                   
                   
                 134433.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 Y44GGGUGUGAACCCCCUCGAAGa 
                 2282 
                 A- 
                 UCUUCGAGGGGGUUCACACCCCc 
                 2460 
               
               
                 67292.1 
                 134434.1 
                   
                   
                 134435.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasacUfuGfAfGfgucgaaaauaL96 
                 2283 
                 A- 
                 usAfsuuuUfcgaccucAfaGfuuususu 
                 2461 
               
               
                 70224.1 
                 141079.1 
                   
                   
                 141080.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasacuuGfAfGfgucgaaaauaL96 
                 2284 
                 A- 
                 usAfsuuuucgaccucAfaGfuuususu 
                 2462 
               
               
                 70225.1 
                 141081.1 
                   
                   
                 141082.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasacuuGfaGfgucgaaaauaL96 
                 2285 
                 A- 
                 usAfsuuuucgaccdTcAfaguuususu 
                 2463 
               
               
                 70226.1 
                 141083.1 
                   
                   
                 141084.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasacuuGfaGfgucga(Agn)aauaL96 
                 2286 
                 A- 
                 usAfsuuuucgaccdTcAfaguuususu 
                 2464 
               
               
                 70227.1 
                 141085.1 
                   
                   
                 141084.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asGfsaaacuuGfaGfguCfgAfaaausa 
                 2287 
                 A- 
                 usAfsuuuucgAfcCfucAfaGfuuucsu 
                 2465 
               
               
                 70228.1 
                 141086.1 
                   
                   
                 141087.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasucaaGfAfAfacuugagguaL96 
                 2288 
                 A- 
                 usAfsccucaaguuucUfuGfaucsusu 
                 2466 
               
               
                 70229.1 
                 141090.1 
                   
                   
                 141091.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasucaaGfaAfacuugagguaL96 
                 2289 
                 A- 
                 usAfsccucaaguudTcUfugaucsusu 
                 2467 
               
               
                 70230.1 
                 141092.1 
                   
                   
                 141093.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasucaaGfaAfacuug(Agn)gguaL96 
                 2290 
                 A- 
                 usAfsccucaaguudTcUfugaucsusu 
                 2468 
               
               
                 70231.1 
                 141094.1 
                   
                   
                 141093.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asAfsgaucaaGfaAfacUfuGfaggusa 
                 2291 
                 A- 
                 usAfsccucaaGfuUfucUfuGfaucusu 
                 2469 
               
               
                 70232.1 
                 141095.1 
                   
                   
                 141096.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 uscsaaGfaAfAfCfuugaggucgaL96 
                 2292 
                 A- 
                 usCfsgacCfuCfAfaguuUfcUfugasusu 
                 2470 
               
               
                 70233.1 
                 141097.1 
                   
                   
                 141098.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 uscsaaGfaAfAfCfuugaggucgaL96 
                 2293 
                 A- 
                 usCfsgacCfucaaguuUfcUfugasusu 
                 2471 
               
               
                 70234.1 
                 141097.1 
                   
                   
                 141099.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 uscsaagaAfAfCfuugaggucgaL96 
                 2294 
                 A- 
                 usCfsgaccucaaguuUfcUfugasusu 
                 2472 
               
               
                 70235.1 
                 141100.1 
                   
                   
                 141101.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 uscsaagaAfaCfuugaggucgaL96 
                 2295 
                 A- 
                 usCfsgaccucaagdTuUfcuugasusu 
                 2473 
               
               
                 70236.1 
                 141102.1 
                   
                   
                 141103.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 uscsaagaAfaCfuugagdCucgaL96 
                 2296 
                 A- 
                 usCfsgaccucaagdTuUfcuugasusu 
                 2474 
               
               
                 70237.1 
                 141104.1 
                   
                   
                 141103.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 usCfsaagaAfaCfuugaGfgUfcgsa 
                 2297 
                 A- 
                 usCfsgaccucAfaGfuuUfcUfugsa 
                 2475 
               
               
                 70238.1 
                 141105.1 
                   
                   
                 141106.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasgaUfcAfAfGfaaacuugagaL96 
                 2298 
                 A- 
                 usCfsucaAfgUfUfucuuGfaUfcuususu 
                 2476 
               
               
                 70239.1 
                 141107.1 
                   
                   
                 141108.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasgaUfcAfAfGfaaacuugagaL96 
                 2299 
                 A- 
                 usCfsucaAfguuucuuGfaUfcuususu 
                 2477 
               
               
                 70240.1 
                 141107.1 
                   
                   
                 141109.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasgaucAfAfGfaaacuugagaL96 
                 2300 
                 A- 
                 usCfsucaaguuucuuGfaUfcuususu 
                 2478 
               
               
                 70241.1 
                 141110.1 
                   
                   
                 141111.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasgaucAfaGfaaacuugagaL96 
                 2301 
                 A- 
                 usCfsucaaguuucdTuGfaucuususu 
                 2479 
               
               
                 70242.1 
                 141112.1 
                   
                   
                 141113.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasgaucAfaGfaaacu(Agn)gagaL96 
                 2302 
                 A- 
                 usCfsucaaguuucdTuGfaucuususu 
                 2480 
               
               
                 70243.1 
                 141114.1 
                   
                   
                 141113.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asGfsaagaucAfaGfaaAfcUfugagsa 
                 2303 
                 A- 
                 usCfsucaaguUfuCfuuGfaUfcuucsu 
                 2481 
               
               
                 70244.1 
                 141115.1 
                   
                   
                 141116.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csasucAfaAfGfGfaauucucggaL96 
                 2304 
                 A- 
                 usCfscgaGfaauuccuUfuGfaugsusu 
                 2482 
               
               
                 70245.1 
                 141117.1 
                   
                   
                 141118.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csasucaaAfGfGfaauucucggaL96 
                 2305 
                 A- 
                 usCfscgagaauuccuUfuGfaugsusu 
                 2483 
               
               
                 70246.1 
                 141119.1 
                   
                   
                 141120.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csasucaaAfgGfaauucucggaL96 
                 2306 
                 A- 
                 usCfscgagaauucdCuUfugaugsusu 
                 2484 
               
               
                 70247.1 
                 141121.1 
                   
                   
                 141122.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csasucaaAfgGfaauuc(Tgn)cggaL96 
                 2307 
                 A- 
                 usCfscgagaauucdCuUfugaugsusu 
                 2485 
               
               
                 70248.1 
                 141123.1 
                   
                   
                 141122.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asAfscaucaaAfgGfaaUfuCfucggsa 
                 2308 
                 A- 
                 usCfscgagaaUfuCfcuUfuGfaugusu 
                 2486 
               
               
                 70249.1 
                 141124.1 
                   
                   
                 141125.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asuscaAfgAfAfAfcuugaggucaL96 
                 2309 
                 A- 
                 usGfaccUfcAfAfguuuCfuUfgaususu 
                 2487 
               
               
                 70250.1 
                 141126.1 
                   
                   
                 141127.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asuscaAfgAfAfAfcuugaggucaL96 
                 2310 
                 A- 
                 usGfaccUfcaaguuuCfuUfgaususu 
                 2488 
               
               
                 70251.1 
                 141126.1 
                   
                   
                 141128.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asuscaagAfAfAfcuugaggucaL96 
                 2311 
                 A- 
                 usGfaccucaaguuuCfuUfgaususu 
                 2489 
               
               
                 70252.1 
                 141129.1 
                   
                   
                 141130.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asuscaagAfaAfcuugaggucaL96 
                 2312 
                 A- 
                 usGfaccucaagudTuCfuugaususu 
                 2490 
               
               
                 70253.1 
                 141131.1 
                   
                   
                 141132.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asuscaagAfaAfcuugadCgucaL96 
                 2313 
                 A- 
                 usGfaccucaagudTuCfuugaususu 
                 2491 
               
               
                 70254.1 
                 141133.1 
                   
                   
                 141132.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asGfsaucaagAfaAfcuUfgAfggucsa 
                 2314 
                 A- 
                 usGfaccucaAfgUfuuCfuUfgaucsu 
                 2492 
               
               
                 70255.1 
                 141134.1 
                   
                   
                 141135.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasagAfuCfAfAfgaaacuugaaL96 
                 2315 
                 A- 
                 usUfscaaGfuuucuugAfuCfuucsusu 
                 2493 
               
               
                 70256.1 
                 141136.1 
                   
                   
                 141137.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasagauCfAfAfgaaacuugaaL96 
                 2316 
                 A- 
                 usUfscaaguuucuugAfuCfuucsusu 
                 2494 
               
               
                 70257.1 
                 141138.1 
                   
                   
                 141139.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasagauCfaAfgaaacuugaaL96 
                 2317 
                 A- 
                 usUfscaaguuucudTgAfucuucsusu 
                 2495 
               
               
                 70258.1 
                 141140.1 
                   
                   
                 141141.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasagauCfaAfgaaac(Tgn)ugaaL96 
                 2318 
                 A- 
                 usUfscaaguuucudTgAfucuucsusu 
                 2496 
               
               
                 70259.1 
                 141142.1 
                   
                   
                 141141.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asAfsgaagauCfaAfgaAfaCfuugasa 
                 2319 
                 A- 
                 usUfscaaguuUfcUfugAfuCfuucusu 
                 2497 
               
               
                 70260.1 
                 141143.1 
                   
                   
                 141144.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csasaagGfaAfUfUfcucggaaagL96 
                 2320 
                 A- 
                 csUfuucCfgAfGfaauuCfcUfuugsasu 
                 2498 
               
               
                 70261.1 
                 141145.1 
                   
                   
                 141146.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csasaagGfaAfUfUfcucggaaagL96 
                 2321 
                 A- 
                 csUfuucCfgagaauuCfcUfuugsasu 
                 2499 
               
               
                 70262.1 
                 141145.1 
                   
                   
                 141147.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csasaaggaAfUfUfcucggaaagL96 
                 2322 
                 A- 
                 csUfuuccgagaauuCfcUfuugsasu 
                 2500 
               
               
                 70263.1 
                 141148.1 
                   
                   
                 141149.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csasaaggaAfuUfcucggaaagL96 
                 2323 
                 A- 
                 csUfuuccgagaadTuCfcuuugsasu 
                 2501 
               
               
                 70264.1 
                 141150.1 
                   
                   
                 141151.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csasaaggaAfuUfcucgdCaaagL96 
                 2324 
                 A- 
                 csUfuuccgagaadTuCfcuuugsasu 
                 2502 
               
               
                 70265.1 
                 141152.1 
                   
                   
                 141151.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asUfscaaaggaAfuUfcuCfgGfaaasg 
                 2325 
                 A- 
                 csUfuuccgaGfaAfuuCfcUfuugasu 
                 2503 
               
               
                 70266.1 
                 141153.1 
                   
                   
                 141154.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csasagAfaAfCfUfugaggucgaaL96 
                 2326 
                 A- 
                 usUfscgaCfcUfCfaaguUfuCfuugsasu 
                 2504 
               
               
                 70267.1 
                 141155.1 
                   
                   
                 141156.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csasagAfaAfCfUfugaggucgaaL96 
                 2327 
                 A- 
                 usUfscgaCfcucaaguUfuCfuugsasu 
                 2505 
               
               
                 70268.1 
                 141155.1 
                   
                   
                 141157.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csasagaaAfCfUfugaggucgaaL96 
                 2328 
                 A- 
                 usUfscgaccucaaguUfuCfuugsasu 
                 2506 
               
               
                 70269.1 
                 141158.1 
                   
                   
                 141159.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csasagaaAfcUfugaggucgaaL96 
                 2329 
                 A- 
                 usUfscgaccucaadGuUfucuugsasu 
                 2507 
               
               
                 70270.1 
                 141160.1 
                   
                   
                 141161.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 csasagaaAfcUfugagg(Tgn)cgaaL96 
                 2330 
                 A- 
                 usUfscgaccucaadGuUfucuugsasu 
                 2508 
               
               
                 70271.1 
                 141162.1 
                   
                   
                 141161.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asUfscaagaaAfcUfugAfgGfucgasa 
                 2331 
                 A- 
                 usUfscgaccuCfaAfguUfuCfuugasu 
                 2509 
               
               
                 70272.1 
                 141163.1 
                   
                   
                 141164.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasagAfaGfAfUfcaagaaacuuL96 
                 2332 
                 A- 
                 asAfsguuUfcUfUfgaucUfuCfuucsusu 
                 2510 
               
               
                 70273.1 
                 141165.1 
                   
                   
                 141166.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasagAfaGfAfUfcaagaaacuuL96 
                 2333 
                 A- 
                 asAfsguuUfcuugaucUfuCfuucsusu 
                 2511 
               
               
                 70274.1 
                 141165.1 
                   
                   
                 141167.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasagaaGfAfUfcaagaaacuuL96 
                 2334 
                 A- 
                 asAfsguuucuugaucUfuCfuucsusu 
                 2512 
               
               
                 70275.1 
                 141168.1 
                   
                   
                 141169.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasagaaGfaUfcaagaaacuuL96 
                 2335 
                 A- 
                 asAfsguuucuugadTcUfucuucsusu 
                 2513 
               
               
                 70276.1 
                 141170.1 
                   
                   
                 141171.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsasagaaGfaUfcaaga(Agn)acuuL96 
                 2336 
                 A- 
                 asAfsguuucuugadTcUfucuucsusu 
                 2514 
               
               
                 70277.1 
                 141172.1 
                   
                   
                 141171.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asAfsgaagaaGfaUfcaAfgAfaacusu 
                 2337 
                 A- 
                 asAfsguuucuUfgAfucUfuCfuucusu 
                 2515 
               
               
                 70278.1 
                 141173.1 
                   
                   
                 141174.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsgsaaAfcAfUfCfaaaggaauuaL96 
                 2338 
                 A- 
                 usAfsauuCfcUfUfugauGfuUfuccsusu 
                 2516 
               
               
                 70279.1 
                 141175.1 
                   
                   
                 141176.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsgsaaAfcAfUfCfaaaggaauuaL96 
                 2339 
                 A- 
                 usAfsauuCfcuuugauGfuUfuccsusu 
                 2517 
               
               
                 70280.1 
                 141175.1 
                   
                   
                 141177.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsgsaaacAfUfCfaaaggaauuaL96 
                 2340 
                 A- 
                 usAfsauuccuuugauGfuUfuccsusu 
                 2518 
               
               
                 70281.1 
                 141178.1 
                   
                   
                 141179.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsgsaaacAfuCfaaaggaauuaL96 
                 2341 
                 A- 
                 usAfsauuccuuugdAuGfuuucsusu 
                 2519 
               
               
                 70282.1 
                 141180.1 
                   
                   
                 141181.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 gsgsaaacAfuCfaaagg(Agn)auuaL96 
                 2342 
                 A- 
                 usAfsauuccuuugdAuGfuuuccsusu 
                 2520 
               
               
                 70283.1 
                 141182.1 
                   
                   
                 141183.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 usGfsggaaacAfuCfaaAfgGfaauusa 
                 2343 
                 A- 
                 usAfsauuccuUfuGfauGfuUfucccsa 
                 2521 
               
               
                 70284.1 
                 141184.1 
                   
                   
                 141185.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasagaaGfaAfGfAfucaagaaacuL96 
                 2344 
                 A- 
                 asGfsuuuCfuUfGfaucuUfcUfucuuusgsu 
                 2522 
               
               
                 70285.1 
                 134288.1 
                   
                   
                 141186.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasagaagaAfGfAfucaagaaacuL96 
                 2345 
                 A- 
                 asGfsuuucuugaucuUfcUfucuuusgsu 
                 2523 
               
               
                 70286.1 
                 141187.1 
                   
                   
                 141188.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasagaagaAfgAfucaagaaacuL96 
                 2346 
                 A- 
                 asGfsuuucuugaudCuUfcuucuuusgsu 
                 2524 
               
               
                 70287.1 
                 141189.1 
                   
                   
                 141190.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasagaagaAfgAfucaag(Agn)aacuL96 
                 2347 
                 A- 
                 asGfsuuucuugaudCuUfcuucuuusgsu 
                 2525 
               
               
                 70288.1 
                 141191.1 
                   
                   
                 141190.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asAfsagaagaAfgAfucAfaGfaaacsu 
                 2348 
                 A- 
                 asGfsuuucuuGfaUfcuUfcUfucuusu 
                 2526 
               
               
                 70289.1 
                 141192.1 
                   
                   
                 141193.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asgsaaGfaAfGfAfucaagaaacuL96 
                 2349 
                 A- 
                 asGfsuuuCfuUfGfaucuUfcUfucususu 
                 2527 
               
               
                 70290.1 
                 141194.1 
                   
                   
                 141195.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asgsaaGfaAfGfAfucaagaaacuL96 
                 2350 
                 A- 
                 asGfsuuuCfuugaucuUfcUfucususu 
                 2528 
               
               
                 70291.1 
                 141194.1 
                   
                   
                 141196.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asgsaagaAfGfAfucaagaaacuL96 
                 2351 
                 A- 
                 asGfsuuucuugaucuUfcUfucususu 
                 2529 
               
               
                 70292.1 
                 141197.1 
                   
                   
                 141198.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asgsaagaAfgAfucaagaaacuL96 
                 2352 
                 A- 
                 asGfsuuucuugaudCuUfcuucususu 
                 2530 
               
               
                 70293.1 
                 141199.1 
                   
                   
                 141200.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asgsaagaAfgAfucaag(Agn)aacuL96 
                 2353 
                 A- 
                 asGfsuuucuugaudCuUfcuucususu 
                 2531 
               
               
                 70294.1 
                 141201.1 
                   
                   
                 141200.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asGfsaagaAfgAfucaaGfaAfacsu 
                 2354 
                 A- 
                 asGfsuuucuuGfaUfcuUfcUfucsu 
                 2532 
               
               
                 70295.1 
                 141202.1 
                   
                   
                 141203.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asascaUfcAfAfAfggaauucucaL96 
                 2355 
                 A- 
                 usGfsagaAfuUfCfcuuuGfaUfguususu 
                 2533 
               
               
                 70296.1 
                 141204.1 
                   
                   
                 141205.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asascaUfcAfAfAfggaauucucaL96 
                 2356 
                 A- 
                 usGfsagaAfuuccuuuGfaUfguususu 
                 2534 
               
               
                 70297.1 
                 141204.1 
                   
                   
                 141206.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asascaucAfAfAfggaauucucaL96 
                 2357 
                 A- 
                 usGfsagaauuccuuuGfaUfguususu 
                 2535 
               
               
                 70298.1 
                 141207.1 
                   
                   
                 141208.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asascaucAfaAfggaauucucaL96 
                 2358 
                 A- 
                 usGfsagaauuccudTuGfauguususu 
                 2536 
               
               
                 70299.1 
                 141209.1 
                   
                   
                 141210.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asascaucAfaAfggaau(Tgn)cucaL96 
                 2359 
                 A- 
                 usGfsagaauuccudTuGfauguususu 
                 2537 
               
               
                 70300.1 
                 141211.1 
                   
                   
                 141210.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asAfscaucAfaAfggaaUfuCfucsa 
                 2360 
                 A- 
                 usGfsagaauuCfcUfuuGfaUfgusu 
                 2538 
               
               
                 70301.1 
                 141212.1 
                   
                   
                 141213.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asgsgaAfuUfCfUfcggaaagaaaL96 
                 2361 
                 A- 
                 usUfsucuUfuCfCfgagaAfuUfccususu 
                 2539 
               
               
                 70302.1 
                 141214.1 
                   
                   
                 141215.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asgsgaAfuUfCfUfcggaaagaaaL96 
                 2362 
                 A- 
                 usUfsucuUfuccgagaAfuUfccususu 
                 2540 
               
               
                 70303.1 
                 141214.1 
                   
                   
                 141216.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asgsgaauUfCfUfcggaaagaaaL96 
                 2363 
                 A- 
                 usUfsucuuuccgagaAfuUfccususu 
                 2541 
               
               
                 70304.1 
                 141217.1 
                   
                   
                 141218.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asgsgaauUfcUfcggaaagaaaL96 
                 2364 
                 A- 
                 usUfsucuuuccgadGaAfuuccususu 
                 2542 
               
               
                 70305.1 
                 141219.1 
                   
                   
                 141220.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asgsgaauUfcUfcggaa(Agn)gaaaL96 
                 2365 
                 A- 
                 usUfsucuuuccgadGaAfuuccususu 
                 2543 
               
               
                 70306.1 
                 141221.1 
                   
                   
                 141220.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asAfsaggaauUfcUfcgGfaAfagaasa 
                 2366 
                 A- 
                 usUfsucuuucCfgAfgaAfuUfccuusu 
                 2544 
               
               
                 70307.1 
                 141222.1 
                   
                   
                 141223.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasagGfaAfUfUfcucggaaagaL96 
                 2367 
                 A- 
                 usCfsuuuCfcGfAfgaauUfcCfuuususu 
                 2545 
               
               
                 70308.1 
                 141224.1 
                   
                   
                 141225.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasagGfaAfUfUfcucggaaagaL96 
                 2368 
                 A- 
                 usCfsuuuCfcgagaauUfcCfuuususu 
                 2546 
               
               
                 70309.1 
                 141224.1 
                   
                   
                 141226.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasaggaAfUfUfcucggaaagaL96 
                 2369 
                 A- 
                 usCfsuuuccgagaauUfcCfuuususu 
                 2547 
               
               
                 70310.1 
                 141227.1 
                   
                   
                 141228.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasaggaAfuUfcucggaaagaL96 
                 2370 
                 A- 
                 usCfsuuuccgagadAuUfccuuususu 
                 2548 
               
               
                 70311.1 
                 141229.1 
                   
                   
                 141230.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 asasaggaAfuUfcucgg(Agn)aagaL96 
                 2371 
                 A- 
                 usCfsuuuccgagadAuUfccuuususu 
                 2549 
               
               
                 70312.1 
                 141231.1 
                   
                   
                 141230.1 
                   
                   
               
               
                   
               
               
                 AD- 
                 A- 
                 usCfsaaaggaAfuUfcuCfgGfaaagsa 
                 2372 
                 A- 
                 usCfsuuuccgAfgAfauUfcCfuuugsa 
                 2550 
               
               
                 70313.1 
                 141232.1 
                   
                   
                 141233.1 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 33 
               
             
            
               
                   
               
               
                 HDV Single dose screen in Cos7 Cells against Antigenome and Genome constructs 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 10 nM 
                 1 nM 
                 0.1 nM 
                 10 nM 
                 1 nM 
                 0.1 nM 
                   
                 1 nM 
                   
                 10 nM 
                   
                 0.1 nM 
               
               
                   
                 Avg 
                 Avg 
                 Avg 
                 Avg 
                 Avg 
                 Avg 
                 10 nM 
                 SD 
                 0.1 nM 
                 SD 
                 1 nM SD 
                 SD 
               
               
                 Duplex 
                 Anti 
                 Anti 
                 Anti 
                 Genome 
                 Genome 
                 Genome 
                 SD Anti 
                 Anti 
                 SD Anti 
                 Genome 
                 Genome 
                 Genome 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 AD-67176.1 
                 79.3 
                   
                 89.6 
                 59.9 
                   
                 77.2 
                 22.9 
                   
                 3.4 
                 9.10 
                   
                 20.6 
               
               
                 AD-67177.1 
                 101.5 
                   
                 99.1 
                 39.3 
                   
                 83.6 
                 39.7 
                   
                 14.9 
                 10.76 
                   
                 28.7 
               
               
                 AD-67178.1 
                 99.6 
                   
                 97.4 
                 90.5 
                   
                 86.7 
                 12.0 
                   
                 20.1 
                 40.51 
                   
                 41.6 
               
               
                 AD-67179.1 
                 84.8 
                   
                 88.6 
                 63.2 
                   
                 81.3 
                 12.1 
                   
                 15.2 
                 19.52 
                   
                 28.2 
               
               
                 AD-67180.1 
                 77.7 
                   
                 108.6 
                 41.0 
                   
                 93.2 
                 15.1 
                   
                 26.8 
                 13.25 
                   
                 33.6 
               
               
                 AD-67181.1 
                 169.3 
                   
                 92.9 
                 47.9 
                   
                 92.3 
                 6.2 
                   
                 8.9 
                 8.51 
                   
                 25.0 
               
               
                 AD-67182.1 
                 62.1 
                   
                 102.6 
                 43.6 
                   
                 86.3 
                 11.4 
                   
                 22.0 
                 12.92 
                   
                 28.7 
               
               
                 AD-67183.1 
                 89.3 
                   
                 105.0 
                 65.4 
                   
                 99.2 
                 13.9 
                   
                 14.7 
                 4.65 
                   
                 34.1 
               
               
                 AD-67184.1 
                 49.9 
                   
                 102.4 
                 96.4 
                   
                 102.7 
                 10.6 
                   
                 16.4 
                 25.05 
                   
                 20.7 
               
               
                 AD-67185.1 
                 87.1 
                   
                 87.7 
                 80.9 
                   
                 81.0 
                 23.9 
                   
                 4.5 
                 18.19 
                   
                 19.7 
               
               
                 AD-67186.1 
                 102.4 
                   
                 109.4 
                 81.7 
                   
                 82.6 
                 20.2 
                   
                 12.7 
                 12.49 
                   
                 4.9 
               
               
                 AD-67187.1 
                 72.0 
                   
                 93.2 
                 87.7 
                   
                 95.4 
                 7.4 
                   
                 11.1 
                 13.69 
                   
                 23.2 
               
               
                 AD-67188.1 
                 68.1 
                   
                 110.5 
                 127.7 
                   
                 97.3 
                 12.8 
                   
                 14.9 
                 18.70 
                   
                 26.5 
               
               
                 AD-67189.1 
                 84.3 
                   
                 95.9 
                 104.7 
                   
                 98.9 
                 16.9 
                   
                 15.0 
                 23.72 
                   
                 26.2 
               
               
                 AD-67190.1 
                 104.5 
                   
                 115.3 
                 110.5 
                   
                 101.5 
                 2.7 
                   
                 7.2 
                 24.53 
                   
                 5.1 
               
               
                 AD-67191.1 
                 72.9 
                   
                 99.8 
                 72.8 
                   
                 92.2 
                 8.4 
                   
                 8.1 
                 21.61 
                   
                 14.0 
               
               
                 AD-67192.1 
                 124.2 
                   
                 106.4 
                 96.4 
                   
                 113.5 
                 25.6 
                   
                 18.2 
                 22.27 
                   
                 36.9 
               
               
                 AD-67193.1 
                 91.3 
                   
                 105.3 
                 105.2 
                   
                 121.4 
                 12.8 
                   
                 21.7 
                 25.63 
                   
                 41.9 
               
               
                 AD-67194.1 
                 39.4 
                   
                 84.8 
                 97.5 
                   
                 105.9 
                 9.0 
                   
                 3.1 
                 12.31 
                   
                 32.6 
               
               
                 AD-67195.1 
                 90.1 
                   
                 110.7 
                 87.5 
                   
                 98.7 
                 11.7 
                   
                 10.4 
                 20.22 
                   
                 11.7 
               
               
                 AD-67196.1 
                 75.5 
                   
                 107.9 
                 102.1 
                   
                 85.5 
                 3.6 
                   
                 5.5 
                 2.71 
                   
                 14.3 
               
               
                 AD-67197.1 
                 68.8 
                   
                 98.6 
                 80.2 
                   
                 96.0 
                 5.3 
                   
                 13.5 
                 15.68 
                   
                 23.1 
               
               
                 AD-67198.1 
                 49.5 
                   
                 101.2 
                 106.2 
                   
                 111.0 
                 2.7 
                   
                 12.7 
                 20.42 
                   
                 15.9 
               
               
                 AD-67199.1 
                 27.1 
                   
                 72.4 
                 162.7 
                   
                 87.3 
                 4.9 
                   
                 11.4 
                 23.09 
                   
                 21.3 
               
               
                 AD-67200.1 
                 24.1 
                   
                 76.7 
                 128.5 
                   
                 114.2 
                 4.0 
                   
                 4.2 
                 13.53 
                   
                 24.3 
               
               
                 AD-67201.1 
                 58.1 
                   
                 88.6 
                 100.1 
                   
                 86.0 
                 9.9 
                   
                 17.3 
                 26.61 
                   
                 24.4 
               
               
                 AD-67202.1 
                 30.3 
                   
                 92.1 
                 107.3 
                   
                 110.5 
                 4.1 
                   
                 13.6 
                 27.71 
                   
                 17.9 
               
               
                 AD-67203.1 
                 55.3 
                   
                 99.6 
                 109.7 
                   
                 99.8 
                 4.0 
                   
                 8.0 
                 28.27 
                   
                 26.2 
               
               
                 AD-67204.1 
                 71.6 
                   
                 101.4 
                 111.1 
                   
                 107.5 
                 7.7 
                   
                 12.0 
                 49.72 
                   
                 29.2 
               
               
                 AD-67205.1 
                 54.2 
                   
                 95.4 
                 89.3 
                   
                 90.2 
                 6.4 
                   
                 14.7 
                 17.80 
                   
                 24.2 
               
               
                 AD-67206.1 
                 52.4 
                   
                 89.9 
                 106.9 
                   
                 103.8 
                 12.6 
                   
                 7.0 
                 19.47 
                   
                 36.2 
               
               
                 AD-67207.1 
                 57.6 
                   
                 99.4 
                 102.6 
                   
                 109.5 
                 11.1 
                   
                 21.9 
                 9.58 
                   
                 9.6 
               
               
                 AD-67208.1 
                 31.2 
                   
                 89.5 
                 87.4 
                   
                 102.7 
                 3.5 
                   
                 8.9 
                 15.91 
                   
                 27.3 
               
               
                 AD-67209.1 
                 47.1 
                   
                 90.6 
                 97.8 
                   
                 78.5 
                 6.3 
                   
                 10.7 
                 18.03 
                   
                 25.7 
               
               
                 AD-67210.1 
                 31.7 
                   
                 95.4 
                 96.2 
                   
                 92.8 
                 1.8 
                   
                 14.4 
                 14.11 
                   
                 28.7 
               
               
                 AD-67211.1 
                 25.4 
                   
                 79.8 
                 110.2 
                   
                 93.4 
                 6.5 
                   
                 9.5 
                 23.84 
                   
                 27.4 
               
               
                 AD-67212.1 
                 32.2 
                   
                 93.9 
                 90.7 
                   
                 67.7 
                 4.9 
                   
                 5.8 
                 22.15 
                   
                 23.4 
               
               
                 AD-67213.1 
                 49.2 
                   
                 97.7 
                 97.4 
                   
                 75.5 
                 5.2 
                   
                 9.6 
                 17.73 
                   
                 25.9 
               
               
                 AD-67214.1 
                 56.8 
                   
                 92.7 
                 97.8 
                   
                 99.4 
                 9.6 
                   
                 10.1 
                 20.89 
                   
                 21.4 
               
               
                 AD-67215.1 
                 39.0 
                   
                 99.2 
                 92.1 
                   
                 95.4 
                 11.3 
                   
                 5.5 
                 6.57 
                   
                 11.4 
               
               
                 AD-67216.1 
                 57.1 
                   
                 94.3 
                 91.2 
                   
                 87.5 
                 12.6 
                   
                 11.9 
                 18.27 
                   
                 25.2 
               
               
                 AD-67217.1 
                 63.4 
                   
                 101.4 
                 90.0 
                   
                 96.2 
                 2.1 
                   
                 10.7 
                 15.73 
                   
                 25.7 
               
               
                 AD-67218.1 
                 65.8 
                   
                 97.3 
                 91.1 
                   
                 86.6 
                 10.3 
                   
                 7.1 
                 11.42 
                   
                 21.2 
               
               
                 AD-67219.1 
                 77.3 
                   
                 100.4 
                 83.9 
                   
                 89.8 
                 1.7 
                   
                 7.8 
                 18.81 
                   
                 40.2 
               
               
                 AD-67220.1 
                 78.8 
                   
                 102.2 
                 87.6 
                   
                 77.8 
                 15.2 
                   
                 7.9 
                 7.96 
                   
                 11.5 
               
               
                 AD-67250.1 
                 85.3 
                   
                 92.4 
                 29.0 
                   
                 74.3 
                 4.4 
                   
                 11.6 
                 3.72 
                   
                 22.8 
               
               
                 AD-67251.1 
                 90.2 
                   
                 104.3 
                 101.9 
                   
                 91.7 
                 25.6 
                   
                 18.0 
                 25.07 
                   
                 12.2 
               
               
                 AD-67252.1 
                 99.6 
                   
                 108.6 
                 59.6 
                   
                 64.9 
                 8.2 
                   
                 3.6 
                 18.48 
                   
                 13.7 
               
               
                 AD-67253.1 
                 50.0 
                   
                 94.6 
                 32.9 
                   
                 73.5 
                 3.3 
                   
                 15.8 
                 14.44 
                   
                 18.2 
               
               
                 AD-67254.1 
                 193.2 
                   
                 106.8 
                 63.7 
                   
                 68.2 
                 47.1 
                   
                 6.1 
                 22.95 
                   
                 12.7 
               
               
                 AD-67255.1 
                 83.7 
                   
                 94.5 
                 38.2 
                   
                 66.7 
                 25.7 
                   
                 13.7 
                 8.71 
                   
                 9.5 
               
               
                 AD-67256.1 
                 88.8 
                   
                 94.3 
                 113.1 
                   
                 106.0 
                 22.8 
                   
                 9.4 
                 37.17 
                   
                 26.3 
               
               
                 AD-67257.1 
                 51.8 
                   
                 101.2 
                 105.6 
                   
                 93.7 
                 5.2 
                   
                 4.6 
                 26.52 
                   
                 22.3 
               
               
                 AD-67258.1 
                 81.6 
                   
                 102.7 
                 92.2 
                   
                 92.4 
                 24.4 
                   
                 6.2 
                 39.25 
                   
                 26.5 
               
               
                 AD-67259.1 
                 113.1 
                   
                 104.8 
                 81.2 
                   
                 71.9 
                 18.8 
                   
                 16.7 
                 30.40 
                   
                 9.6 
               
               
                 AD-67260.1 
                 52.1 
                   
                 112.2 
                 67.4 
                   
                 74.6 
                 8.1 
                   
                 8.8 
                 4.21 
                   
                 10.8 
               
               
                 AD-67261.1 
                 73.8 
                   
                 96.2 
                 96.1 
                   
                 99.5 
                 15.5 
                   
                 9.1 
                 7.96 
                   
                 17.8 
               
               
                 AD-67262.1 
                 110.6 
                   
                 106.5 
                 127.0 
                   
                 115.6 
                 28.0 
                   
                 15.3 
                 20.20 
                   
                 3.0 
               
               
                 AD-67263.1 
                 69.4 
                   
                 96.3 
                 49.7 
                   
                 63.1 
                 16.7 
                   
                 8.8 
                 4.00 
                   
                 14.8 
               
               
                 AD-67264.1 
                 180.6 
                   
                 104.6 
                 100.1 
                   
                 94.9 
                 43.2 
                   
                 22.3 
                 37.56 
                   
                 10.7 
               
               
                 AD-67265.1 
                 122.5 
                   
                 117.0 
                 119.1 
                   
                 99.4 
                 23.3 
                   
                 19.7 
                 13.26 
                   
                 18.6 
               
               
                 AD-67266.1 
                 24.3 
                   
                 59.3 
                 115.8 
                   
                 83.6 
                 1.0 
                   
                 3.8 
                 34.70 
                   
                 14.0 
               
               
                 AD-67267.1 
                 83.4 
                   
                 113.8 
                 92.6 
                   
                 82.7 
                 13.9 
                   
                 11.8 
                 26.19 
                   
                 10.6 
               
               
                 AD-67268.1 
                 99.2 
                   
                 101.2 
                 81.0 
                   
                 94.9 
                 14.9 
                   
                 11.1 
                 21.50 
                   
                 22.4 
               
               
                 AD-67269.1 
                 42.9 
                   
                 81.7 
                 179.2 
                   
                 86.0 
                 6.6 
                   
                 6.5 
                 50.94 
                   
                 13.2 
               
               
                 AD-67270.1 
                 33.9 
                   
                 85.7 
                 125.2 
                   
                 85.6 
                 5.9 
                   
                 10.8 
                 24.45 
                   
                 12.7 
               
               
                 AD-67271.1 
                 29.6 
                   
                 53.4 
                 156.0 
                   
                 115.8 
                 8.9 
                   
                 10.9 
                 27.82 
                   
                 27.2 
               
               
                 AD-67272.1 
                 13.4 
                   
                 46.3 
                 136.9 
                   
                 128.4 
                 2.3 
                   
                 4.4 
                 23.52 
                   
                 30.3 
               
               
                 AD-67273.1 
                 15.9 
                   
                 57.5 
                 105.1 
                   
                 82.1 
                 4.6 
                   
                 4.4 
                 26.59 
                   
                 13.3 
               
               
                 AD-67274.1 
                 25.8 
                   
                 60.4 
                 86.8 
                   
                 93.4 
                 2.0 
                   
                 10.2 
                 14.89 
                   
                 22.4 
               
               
                 AD-67275.1 
                 46.5 
                   
                 75.4 
                 131.1 
                   
                 94.3 
                 12.3 
                   
                 9.5 
                 46.37 
                   
                 18.0 
               
               
                 AD-67276.1 
                 20.8 
                   
                 59.4 
                 87.7 
                   
                 88.0 
                 2.2 
                   
                 4.4 
                 10.78 
                   
                 18.2 
               
               
                 AD-67277.1 
                 17.2 
                   
                 49.5 
                 93.4 
                   
                 92.4 
                 2.3 
                   
                 4.7 
                 44.06 
                   
                 19.4 
               
               
                 AD-67278.1 
                 25.1 
                   
                 61.3 
                 131.5 
                   
                 94.8 
                 8.4 
                   
                 6.8 
                 30.75 
                   
                 10.0 
               
               
                 AD-67279.1 
                 21.9 
                   
                 78.3 
                 111.7 
                   
                 126.9 
                 4.8 
                   
                 10.8 
                 19.15 
                   
                 15.0 
               
               
                 AD-67280.1 
                 32.8 
                   
                 78.1 
                 154.7 
                   
                 109.4 
                 4.3 
                   
                 9.1 
                 52.47 
                   
                 29.4 
               
               
                 AD-67281.1 
                 32.8 
                   
                 60.0 
                 163.7 
                   
                 110.1 
                 2.4 
                   
                 9.0 
                 20.60 
                   
                 8.6 
               
               
                 AD-67282.1 
                 19.3 
                   
                 47.6 
                 129.1 
                   
                 109.7 
                 4.8 
                   
                 9.1 
                 18.16 
                   
                 21.2 
               
               
                 AD-67283.1 
                 34.5 
                   
                 71.8 
                 193.2 
                   
                 112.4 
                 14.0 
                   
                 1.1 
                 66.11 
                   
                 10.7 
               
               
                 AD-67284.1 
                 51.2 
                   
                 76.9 
                 126.9 
                   
                 94.1 
                 5.2 
                   
                 7.9 
                 40.77 
                   
                 26.8 
               
               
                 AD-67285.1 
                 17.3 
                   
                 68.6 
                 66.9 
                   
                 110.7 
                 1.9 
                   
                 10.7 
                 26.05 
                   
                 25.3 
               
               
                 AD-67286.1 
                 29.5 
                   
                 85.5 
                 87.3 
                   
                 125.7 
                 5.8 
                   
                 10.7 
                 13.51 
                   
                 30.7 
               
               
                 AD-67287.1 
                 33.1 
                   
                 83.5 
                 84.9 
                   
                 98.8 
                 12.2 
                   
                 22.2 
                 33.27 
                   
                 12.9 
               
               
                 AD-67288.1 
                 14.4 
                   
                 75.1 
                 73.3 
                   
                 109.2 
                 6.5 
                   
                 5.2 
                 15.93 
                   
                 16.1 
               
               
                 AD-67289.1 
                 38.8 
                   
                 66.4 
                 97.9 
                   
                 102.0 
                 15.6 
                   
                 7.9 
                 22.42 
                   
                 19.0 
               
               
                 AD-67290.1 
                 20.9 
                   
                 81.2 
                 89.6 
                   
                 112.4 
                 4.8 
                   
                 9.3 
                 11.83 
                   
                 8.4 
               
               
                 AD-67291.1 
                 47.8 
                   
                 100.0 
                 107.1 
                   
                 95.2 
                 4.7 
                   
                 19.7 
                 16.82 
                   
                 9.3 
               
               
                 AD-67292.1 
                 99.9 
                   
                 99.3 
                 129.3 
                   
                 136.5 
                 22.7 
                   
                 20.8 
                 39.06 
                   
                 58.4 
               
               
                 AD-70224.1 
                 46.5 
                 68.6 
                 94.0 
                 99.6 
                 113.6 
                 103.5 
                 10.2 
                 8.7 
                 2.5 
                 13.9 
                 6.9 
                 10.0 
               
               
                 AD-70225.1 
                 49.1 
                 76.2 
                 88.9 
                 129.9 
                 107.0 
                 87.1 
                 7.2 
                 0.8 
                 5.3 
                 45.3 
                 6.1 
                 10.0 
               
               
                 AD-70226.1 
                 65.3 
                   
                   
                 105.4 
                   
                   
                 8.0 
                   
                   
                 23.9 
               
               
                 AD-70227.1 
                 37.7 
                 58.7 
                 84.3 
                 173.3 
                 111.4 
                 101.7 
                 8.2 
                 3.2 
                 5.1 
                 15.5 
                 6.2 
                 5.5 
               
               
                 AD-70228.1 
                 102.4 
                 120.8 
                 107.9 
                 46.3 
                 52.2 
                 82.3 
                 10.7 
                 5.7 
                 14.3 
                 11.4 
                 2.5 
                 3.6 
               
               
                 AD-70229.1 
                 32.0 
                 65.6 
                 96.9 
                 92.1 
                 107.2 
                 89.6 
                 3.5 
                 0.1 
                 1.9 
                 6.8 
                 25.7 
                 5.5 
               
               
                 AD-70230.1 
                 36.7 
                 66.7 
                 99.2 
                 91.8 
                 100.1 
                 91.9 
                 3.9 
                 11.4 
                 13.6 
                 8.2 
                 14.9 
                 12.5 
               
               
                 AD-70231.1 
                 26.7 
                 62.6 
                 86.3 
                 97.3 
                 93.9 
                 122.5 
                 4.0 
                 5.2 
                 2.4 
                 25.6 
                 2.7 
                 35.5 
               
               
                 AD-70232.1 
                 16.1 
                 35.2 
                 74.5 
                 40.1 
                 33.3 
                 73.9 
                 2.7 
                 2.7 
                 0.9 
                 15.0 
                 6.5 
                 10.9 
               
               
                 AD-70233.1 
                 24.8 
                 71.7 
                 96.0 
                 91.8 
                 106.4 
                 96.2 
                 1.6 
                 1.0 
                 1.2 
                 10.4 
                 9.2 
                 0.5 
               
               
                 AD-70234.1 
                 29.6 
                 63.0 
                 90.2 
                 89.4 
                 102.5 
                 99.9 
                 5.1 
                 0.1 
                 3.5 
                 8.5 
                 3.4 
                 6.3 
               
               
                 AD-70235.1 
                 35.4 
                 84.5 
                 104.2 
                 66.6 
                 101.9 
                 97.8 
                 10.5 
                 4.2 
                 9.7 
                 13.0 
                 1.2 
                 6.2 
               
               
                 AD-70236.1 
                 39.4 
                 64.8 
                 95.2 
                 86.3 
                 88.3 
                 94.0 
                 3.7 
                 3.0 
                 0.6 
                 5.7 
                 3.8 
                 6.7 
               
               
                 AD-70237.1 
                 22.1 
                 49.4 
                 83.8 
                 96.2 
                 90.3 
                 87.6 
                 2.5 
                 0.1 
                 1.7 
                 19.1 
                 9.4 
                 2.8 
               
               
                 AD-70238.1 
                 26.5 
                 61.4 
                 91.8 
                 60.9 
                 72.9 
                 82.7 
                 1.6 
                 0.8 
                 6.7 
                 6.8 
                 5.4 
                 1.9 
               
               
                 AD-70239.1 
                 73.7 
                   
                   
                 99.1 
                   
                   
                 8.4 
                   
                   
                 20.7 
               
               
                 AD-70240.1 
                 80.0 
                   
                   
                 82.4 
                   
                   
                 11.0 
                   
                   
                 8.3 
               
               
                 AD-70241.1 
                 82.5 
                   
                   
                 107.4 
                   
                   
                 2.1 
                   
                   
                 21.9 
               
               
                 AD-70242.1 
                 69.5 
                   
                   
                 90.2 
                   
                   
                 4.7 
                   
                   
                 28.9 
               
               
                 AD-70243.1 
                 33.5 
                 57.4 
                 102.5 
                 109.3 
                 106.4 
                 80.7 
                 3.5 
                 1.2 
                 8.2 
                 20.7 
                 17.0 
                 2.8 
               
               
                 AD-70244.1 
                 78.5 
                 93.3 
                 99.9 
                 22.6 
                 29.3 
                 85.9 
                 6.2 
                 1.8 
                 4.5 
                 4.2 
                 5.0 
                 12.2 
               
               
                 AD-70245.1 
                 44.7 
                 71.2 
                 83.2 
                 109.7 
                 91.5 
                 98.5 
                 3.3 
                 2.4 
                 1.5 
                 15.1 
                 3.9 
                 8.9 
               
               
                 AD-70246.1 
                 42.1 
                 79.0 
                 104.6 
                 97.2 
                 99.0 
                 97.0 
                 1.0 
                 4.9 
                 13.5 
                 25.8 
                 4.7 
                 6.9 
               
               
                 AD-70247.1 
                 60.3 
                   
                   
                 75.2 
                   
                   
                 6.5 
                   
                   
                 6.8 
               
               
                 AD-70248.1 
                 20.9 
                 45.2 
                 82.2 
                 86.5 
                 121.9 
                 98.2 
                 2.1 
                 6.9 
                 3.8 
                 10.0 
                 3.5 
                 2.4 
               
               
                 AD-70249.1 
                 72.4 
                 93.6 
                 96.7 
                 39.9 
                 38.5 
                 81.3 
                 4.2 
                 6.7 
                 1.5 
                 13.1 
                 7.4 
                 10.1 
               
               
                 AD-70250.1 
                 35.0 
                 72.9 
                 97.5 
                 81.7 
                 91.4 
                 89.8 
                 3.6 
                 3.1 
                 16.8 
                 8.5 
                 2.0 
                 5.2 
               
               
                 AD-70251.1 
                 47.2 
                 71.8 
                 92.6 
                 87.6 
                 101.5 
                 105.3 
                 5.5 
                 6.5 
                 0.8 
                 15.2 
                 1.3 
                 11.8 
               
               
                 AD-70252.1 
                 55.7 
                   
                   
                 76.2 
                   
                   
                 6.7 
                   
                   
                 6.1 
               
               
                 AD-70253.1 
                 61.5 
                   
                   
                 68.8 
                   
                   
                 3.9 
                   
                   
                 16.5 
               
               
                 AD-70254.1 
                 30.0 
                 65.2 
                 93.1 
                 83.1 
                 92.0 
                 111.6 
                 0.8 
                 1.4 
                 2.6 
                 9.8 
                 15.2 
                 0.8 
               
               
                 AD-70255.1 
                 65.0 
                 89.1 
                 90.4 
                 32.6 
                 50.7 
                 92.0 
                 5.2 
                 1.6 
                 2.6 
                 6.9 
                 8.8 
                 2.0 
               
               
                 AD-70256.1 
                 17.9 
                 45.9 
                 89.0 
                 107.7 
                 126.3 
                 95.6 
                 2.3 
                 0.6 
                 6.6 
                 17.1 
                 24.6 
                 5.3 
               
               
                 AD-70257.1 
                 19.7 
                 41.8 
                 78.1 
                 129.4 
                 104.7 
                 96.7 
                 3.8 
                 0.7 
                 3.3 
                 28.2 
                 16.6 
                 3.9 
               
               
                 AD-70258.1 
                 25.9 
                 51.4 
                 83.8 
                 120.5 
                 104.3 
                 77.0 
                 2.6 
                 3.8 
                 8.2 
                 25.8 
                 0.2 
                 7.1 
               
               
                 AD-70259.1 
                 15.0 
                 26.0 
                 70.3 
                 131.5 
                 117.4 
                 100.5 
                 1.7 
                 0.2 
                 4.0 
                 16.7 
                 3.8 
                 1.0 
               
               
                 AD-70260.1 
                 21.9 
                 43.2 
                 85.4 
                 44.7 
                 39.3 
                 103.6 
                 4.3 
                 1.3 
                 6.4 
                 9.1 
                 0.9 
                 6.7 
               
               
                 AD-70261.1 
                 83.1 
                   
                   
                 82.1 
                   
                   
                 4.2 
                   
                   
                 10.7 
               
               
                 AD-70262.1 
                 85.6 
                   
                   
                 81.5 
                   
                   
                 7.2 
                   
                   
                 13.1 
               
               
                 AD-70263.1 
                 92.8 
                   
                   
                 116.9 
                   
                   
                 4.7 
                   
                   
                 50.7 
               
               
                 AD-70264.1 
                 82.3 
                   
                   
                 120.8 
                   
                   
                 5.5 
                   
                   
                 53.7 
               
               
                 AD-70265.1 
                 38.1 
                 72.2 
                 95.2 
                 130.9 
                 98.6 
                 90.5 
                 4.1 
                 1.7 
                 3.1 
                 29.9 
                 0.8 
                 12.6 
               
               
                 AD-70266.1 
                 85.8 
                   
                   
                 90.3 
                   
                   
                 11.3 
                   
                   
                 19.5 
               
               
                 AD-70267.1 
                 15.0 
                 27.8 
                 66.1 
                 123.5 
                 122.8 
                 103.0 
                 1.3 
                 1.7 
                 2.8 
                 15.5 
                 4.1 
                 8.8 
               
               
                 AD-70268.1 
                 15.8 
                 30.3 
                 78.2 
                 116.7 
                 123.1 
                 103.6 
                 2.0 
                 1.8 
                 1.8 
                 22.7 
                 6.9 
                 5.3 
               
               
                 AD-70269.1 
                 16.0 
                 27.9 
                 71.1 
                 106.9 
                 99.8 
                 99.2 
                 1.7 
                 1.7 
                 0.6 
                 19.5 
                 9.4 
                 26.9 
               
               
                 AD-70270.1 
                 26.1 
                 54.7 
                 89.1 
                 108.8 
                 102.8 
                 93.4 
                 4.5 
                 4.4 
                 10.6 
                 31.1 
                 1.6 
                 14.2 
               
               
                 AD-70271.1 
                 15.3 
                 26.8 
                 62.8 
                 115.4 
                 125.0 
                 106.9 
                 3.3 
                 2.3 
                 4.3 
                 13.5 
                 6.9 
                 3.7 
               
               
                 AD-70272.1 
                 15.1 
                 33.3 
                 82.3 
                 53.3 
                 31.4 
                 70.3 
                 2.7 
                 2.1 
                 11.2 
                 15.0 
                 5.3 
                 12.4 
               
               
                 AD-70273.1 
                 26.8 
                 49.5 
                 85.2 
                 150.6 
                 133.9 
                 111.2 
                 4.9 
                 6.4 
                 2.1 
                 36.0 
                 0.4 
                 0.6 
               
               
                 AD-70274.1 
                 23.2 
                 36.5 
                 87.3 
                 177.6 
                 123.0 
                 109.8 
                 2.8 
                 0.5 
                 0.6 
                 27.1 
                 2.2 
                 21.5 
               
               
                 AD-70275.1 
                 20.0 
                 43.9 
                 76.1 
                 178.4 
                 151.1 
                 103.7 
                 4.1 
                 4.7 
                 3.0 
                 32.2 
                 10.4 
                 8.1 
               
               
                 AD-70276.1 
                 32.1 
                 43.6 
                 84.1 
                 183.4 
                 130.6 
                 103.7 
                 1.8 
                 2.3 
                 2.1 
                 14.9 
                 12.2 
                 5.0 
               
               
                 AD-70277.1 
                 29.7 
                 33.8 
                 73.2 
                 213.9 
                 140.7 
                 109.2 
                 6.4 
                 4.9 
                 2.8 
                 20.5 
                 8.8 
                 9.7 
               
               
                 AD-70278.1 
                 25.2 
                 41.4 
                 73.6 
                 57.8 
                 56.0 
                 95.3 
                 5.9 
                 1.1 
                 5.7 
                 12.1 
                 2.6 
                 4.7 
               
               
                 AD-70279.1 
                 79.8 
                   
                   
                 135.6 
                   
                   
                 7.4 
                   
                   
                 22.9 
               
               
                 AD-70280.1 
                 100.4 
                   
                   
                 162.0 
                   
                   
                 14.5 
                   
                   
                 17.5 
               
               
                 AD-70281.1 
                 82.2 
                   
                   
                 161.7 
                   
                   
                 13.1 
                   
                   
                 10.6 
               
               
                 AD-70282.1 
                 105.1 
                   
                   
                 116.2 
                   
                   
                 5.3 
                   
                   
                 16.9 
               
               
                 AD-70283.1 
                 64.4 
                   
                   
                 134.4 
                   
                   
                 7.7 
                   
                   
                 23.3 
               
               
                 AD-70284.1 
                 95.4 
                   
                   
                 106.1 
                   
                   
                 11.0 
                   
                   
                 5.3 
               
               
                 AD-70285.1 
                 91.6 
                   
                   
                 119.4 
                   
                   
                 11.6 
                   
                   
                 7.9 
               
               
                 AD-70286.1 
                 84.0 
                   
                   
                 110.3 
                   
                   
                 8.8 
                   
                   
                 21.6 
               
               
                 AD-70287.1 
                 89.9 
                   
                   
                 96.7 
                   
                   
                 4.4 
                   
                   
                 7.5 
               
               
                 AD-70288.1 
                 29.1 
                 74.0 
                 89.9 
                 199.1 
                 132.5 
                 110.7 
                 5.8 
                 7.8 
                 2.7 
                 58.5 
                 26.6 
                 2.8 
               
               
                 AD-70289.1 
                 32.7 
                 44.4 
                 84.5 
                 77.7 
                 60.0 
                 76.8 
                 5.3 
                 1.4 
                 2.6 
                 11.4 
                 5.7 
                 1.4 
               
               
                 AD-70290.1 
                 102.0 
                   
                   
                 102.6 
                   
                   
                 13.6 
                   
                   
                 17.4 
               
               
                 AD-70291.1 
                 100.7 
                   
                   
                 110.1 
                   
                   
                 8.5 
                   
                   
                 24.6 
               
               
                 AD-70292.1 
                 76.7 
                   
                   
                 131.9 
                   
                   
                 5.2 
                   
                   
                 20.2 
               
               
                 AD-70293.1 
                 99.7 
                   
                   
                 131.7 
                   
                   
                 5.8 
                   
                   
                 29.7 
               
               
                 AD-70294.1 
                 103.1 
                   
                   
                 124.4 
                   
                   
                 5.4 
                   
                   
                 35.4 
               
               
                 AD-70295.1 
                 101.8 
                   
                   
                 125.9 
                   
                   
                 6.3 
                   
                   
                 10.4 
               
               
                 AD-70296.1 
                 104.3 
                   
                   
                 106.8 
                   
                   
                 11.1 
                   
                   
                 11.9 
               
               
                 AD-70297.1 
                 105.2 
                   
                   
                 105.8 
                   
                   
                 6.0 
                   
                   
                 38.9 
               
               
                 AD-70298.1 
                 103.1 
                   
                   
                 99.9 
                   
                   
                 5.0 
                   
                   
                 19.1 
               
               
                 AD-70299.1 
                 108.1 
                   
                   
                 100.9 
                   
                   
                 12.9 
                   
                   
                 24.6 
               
               
                 AD-70300.1 
                 109.6 
                   
                   
                 80.5 
                   
                   
                 13.3 
                   
                   
                 8.3 
               
               
                 AD-70301.1 
                 99.4 
                   
                   
                 97.2 
                   
                   
                 7.0 
                   
                   
                 11.0 
               
               
                 AD-70302.1 
                 101.9 
                   
                   
                 104.6 
                   
                   
                 17.2 
                   
                   
                 27.3 
               
               
                 AD-70303.1 
                 77.1 
                   
                   
                 133.0 
                   
                   
                 6.4 
                   
                   
                 27.0 
               
               
                 AD-70304.1 
                 119.5 
                   
                   
                 108.7 
                   
                   
                 12.4 
                   
                   
                 10.3 
               
               
                 AD-70305.1 
                 91.1 
                   
                   
                 115.5 
                   
                   
                 8.2 
                   
                   
                 22.6 
               
               
                 AD-70306.1 
                 103.7 
                   
                   
                 140.3 
                   
                   
                 15.5 
                   
                   
                 19.8 
               
               
                 AD-70307.1 
                 75.4 
                   
                   
                 98.0 
                   
                   
                 3.8 
                   
                   
                 14.0 
               
               
                 AD-70308.1 
                 105.5 
                   
                   
                 136.1 
                   
                   
                 7.7 
                   
                   
                 30.9 
               
               
                 AD-70309.1 
                 109.5 
                   
                   
                 92.8 
                   
                   
                 23.5 
                   
                   
                 14.6 
               
               
                 AD-70310.1 
                 111.6 
                   
                   
                 109.7 
                   
                   
                 11.5 
                   
                   
                 27.1 
               
               
                 AD-70311.1 
                 101.8 
                   
                   
                 111.5 
                   
                   
                 10.2 
                   
                   
                 25.1 
               
               
                 AD-70312.1 
                 113.8 
                   
                   
                 91.0 
                   
                   
                 8.3 
                   
                   
                 26.1 
               
               
                 AD-70313.1 
                 114.8 
                   
                   
                 76.9 
                   
                   
                 10.0 
                   
                   
                 13.1 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 34 
               
             
            
               
                   
               
               
                 Dose response screen in Cos7 cells 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Antigenome 
                 Genome  
               
               
                   
                 Antigenome, 
                 Genome,  
                 hot spot,  
                 hot spot,  
               
               
                 Duplex 
                 IC50 nM 
                 IC50 nM 
                 IC50 nM 
                 IC50 nM 
               
               
                   
               
               
                 AD-67176.1 
                 not achieved 
                 not achieved 
                   
                   
               
               
                 AD-67177.1 
                 not achieved 
                 not achieved 
                   
                   
               
               
                 AD-67180.1 
                 not achieved 
                 3124.5 
                   
                   
               
               
                 AD-67181.1 
                 not achieved 
                 &gt;10000 
                   
                   
               
               
                 AD-67182.1 
                 not achieved 
                 &gt;10000 
                   
                   
               
               
                 AD-67199.1 
                 288.0 
                 not achieved 
                   
                   
               
               
                 AD-67200.1 
                 466.2 
                 not achieved 
                   
                   
               
               
                 AD-67202.1 
                 &gt;10000 
                 not achieved 
                   
                   
               
               
                 AD-67208.1 
                 not achieved 
                 not achieved 
                   
                   
               
               
                 AD-67210.1 
                 &gt;10000 
                 not achieved 
                   
                   
               
               
                 AD-67211.1 
                 1100.8 
                 not achieved 
                   
                   
               
               
                 AD-70228.1 
                   
                   
                 not achieved 
                 23.0 
               
               
                 AD-70232.1 
                 405.4 
                 5002.4 
                 33.7 
                 9.0 
               
               
                 AD-70238.1 
                   
                   
                 273.9 
                 122.4 
               
               
                 AD-70244.1 
                   
                 1589.9 
                 not achieved 
                 14.7 
               
               
                 AD-70249.1 
                   
                 2377.2 
                 2376.2 
                 13.1 
               
               
                 AD-70255.1 
                   
                   
                 3082.4 
                 26.1 
               
               
                 AD-70259.1 
                 173.2 
                   
                   
                   
               
               
                 AD-70260.1 
                 419.2 
                 7185.0 
                 50.3 
                 8.7 
               
               
                 AD-70266.1 
                   
                   
                 not achieved 
                 476.4 
               
               
                 AD-70267.1 
                 185.7 
                   
                   
                   
               
               
                 AD-70268.1 
                 174.6 
                   
                   
                   
               
               
                 AD-70269.1 
                 267.6 
                   
                   
                   
               
               
                 AD-70271.1 
                 119.6 
                   
                   
                   
               
               
                 AD-70272.1 
                 364.8 
                 3400.4 
                 30.2 
                 22.2 
               
               
                 AD-70274.1 
                 258.8 
                   
                   
                   
               
               
                 AD-70277.1 
                 190.6 
                   
                   
                   
               
               
                 AD-70278.1 
                   
                   
                 57.1 
                 30.6 
               
               
                 AD-70284.1 
                   
                   
                 not achieved 
                 4670.5 
               
               
                 AD-70289.1 
                   
                   
                 not achieved 
                 not achieved 
               
               
                 AD-70295.1 
                   
                   
                 61.8 
                 39.4 
               
               
                 AD-70301.1 
                   
                   
                 not achieved 
                 not achieved 
               
               
                 AD-70307.1 
                   
                   
                 2329.6 
                 379.0 
               
               
                 AD-70313.1 
                   
                   
                 not achieved 
                 not achieved 
               
               
                   
               
            
           
         
       
     
     EQUIVALENTS 
     Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the following claims.