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United States Patent Application 20170016000
Kind Code A1
Limphong; Pattraranee ;   et al. January 19, 2017

COMPOSITIONS AND AGENTS AGAINST HEPATITIS B VIRUS AND USES THEREOF

Abstract

This invention encompasses compounds and compositions useful in methods for medical therapy, in general, for inhibiting Hepatitis B virus in a subject. The compounds have a first strand and a second strand, each of the strands being 19-29 monomers in length, the monomers comprising UNA monomers and nucleic acid monomers, and the compounds are targeted to a sequence of an HBV genome.


Inventors: Limphong; Pattraranee; (San Diego, CA) ; Tachikawa; Kiyoshi; (San Diego, CA) ; Esau; Christine; (San Diego, CA) ; Chivukula; Padmanabh; (San Diego, CA)
Applicant:
Name City State Country Type

Arcturus Therapeutics, Inc.

San Diego

CA

US
Family ID: 1000002213904
Appl. No.: 15/212279
Filed: July 17, 2016


Related U.S. Patent Documents

Application NumberFiling DatePatent Number
62193997Jul 17, 2015

Current U.S. Class: 1/1
Current CPC Class: C12N 2310/11 20130101; C12N 15/1131 20130101
International Class: C12N 15/113 20060101 C12N015/113

Claims



1. A compound comprising a first strand and a second strand, each of the strands being 19-29 monomers in length, the monomers comprising UNA monomers and nucleic acid monomers, wherein the compound has a duplex region of from 14 to 29 contiguous monomers in length, wherein the first strand is a passenger strand for RNA interference and the second strand is a guide strand for RNA interference, and wherein the compound comprises a sequence of bases targeted to inhibit expression of an HBV genome.

2. The compound of claim 1, wherein the compound contains one to seven UNA monomers.

3. The compound of claim 1, wherein the compound contains a UNA monomer at the 1-end (5' end for non-UNA) of the first strand, a UNA monomer at the 3-end (3' end for non-UNA) of the first strand, and a UNA monomer at the second position from the 5' end of the second strand.

4. The compound of claim 1, wherein the compound contains a UNA monomer at any one or more of positions 2 to 8 from the 5' end of the second strand.

5. The compound of claim 1, wherein the sequence of bases is selected from the sense, antisense or sense-antisense pairs of the following, and substituted forms thereof: TABLE-US-00035 SEQ SEQ REF NO ID POS ID Sense (5'-3') NO Antisense (5'-3') 1578 867 UGUGCACUUCGCUUCACCU 908 AGGUGAAGCGAAGUGCACA 1777 875 GAGGCUGUAGGCAUAAAUU 916 AAUUUAUGCCUACAGCCUC 1581 869 GCACUUCGCUUCACCUCUG 910 CAGAGGUGAAGCGAAGUGC 380 887 UGUCUGCGGCGUUUUAUCA 928 UGAUAAAACGCCGCAGACA 1576 899 CGUGUGCACUUCGCUUCAC 940 GUGAAGCGAAGUGCACACG 1780 877 GCUGUAGGCAUAAAUUGGU 918 ACCAAUUUAUGCCUACAGC 1781 878 CUGUAGGCAUAAAUUGGUC 919 GACCAAUUUAUGCCUACAG 1782 879 UGUAGGCAUAAAUUGGUCU 920 AGACCAAUUUAUGCCUACA 376 885 GAUGUGUCUGCGGCGUUUU 926 AAAACGCCGCAGACACAUC 378 886 UGUGUCUGCGGCGUUUUAU 927 AUAAAACGCCGCAGACACA 411 893 UCCUGCUGCUAUGCCUCAU 934 AUGAGGCAUAGCAGCAGGA 413 895 CUGCUGCUAUGCCUCAUCU 936 AGAUGAGGCAUAGCAGCAG 1580 900 UGCACUUCGCUUCACCUCU 941 AGAGGUGAAGCGAAGUGCA 1581 869 GCACUUCGCUUCACCUCUG 910 CAGAGGUGAAGCGAAGUGC 1575 865 CCGUGUGCACUUCGCUUCA 906 UGAAGCGAAGUGCACACGG 1818 888 AACUUUUUCACCUCUGCCU 929 AGGCAGAGGUGAAAAAGUU

6. The compound of claim 1, wherein the compound comprises one of the following pairs: SEQ ID NO:987 and 988; SEQ ID NO:993 and 994; SEQ ID NO:999 and 1000; SEQ ID NO:1005 and 1006; SEQ ID NO:1009 and 1010; SEQ ID NO:1011 and 1012; SEQ ID NO:1013 and 1014; SEQ ID NO:1015 and 1016; SEQ ID NO:969 and 970; SEQ ID NO:971 and 972; SEQ ID NO:973 and 974; SEQ ID NO:977 and 978; SEQ ID NO:981 and 982; SEQ ID NO:989 and 990; SEQ ID NO:997 and 998; and SEQ ID NO:999 and 1000.

7. The compound of claim 1, wherein the compound comprises one of the following pairs: SEQ ID NO:1145 and 1146; SEQ ID NO:1175 and 1176; SEQ ID NO:1149 and 1150; SEQ ID NO:1163 and 1164; SEQ ID NO:1165 and 1166; SEQ ID NO:1167 and 1168; SEQ ID NO:1169 and 1170; SEQ ID NO:1153 and 1154; SEQ ID NO:1155 and 1156; SEQ ID NO:1157 and 1158; SEQ ID NO:1160 and 1161; SEQ ID NO:1159 and 1160; SEQ ID NO:1147 and 1148; and SEQ ID NO:1151 and 1152.

8. The compound of claim 1, wherein the compound has a 3' overhang comprising one or more UNA monomers, natural nucleotides, non-natural nucleotides, modified nucleotides, or chemically-modified nucleotides, and combinations thereof.

9. The compound of claim 1, wherein the compound has a 3' overhang comprising one or more deoxythymidine nucleotides, 2'-O-methyl nucleotides, inverted abasic monomers, inverted thymidine monomers, L-thymidine monomers, or glyceryl nucleotides.

10. The compound of claim 1, wherein one or more of the nucleic acid monomers is a non-natural nucleotide, a modified nucleotide, or a chemically-modified nucleotide.

11. The compound of claim 1, wherein each nucleic acid monomer has a 2'-O-methyl group.

12. The compound of claim 1, wherein the compound contains from one to eight nucleic acid monomers modified with a 2'-O-methyl group in the first strand and from one to eleven nucleic acid monomers modified with a 2'-O-methyl group in the second strand.

13. The compound of claim 1, wherein the compound contains one or more 2'-methoxyethoxy nucleotides.

14. The compound of claim 1, wherein the compound contains one or more 2'-deoxy-2'-fluoro ribonucleotides.

15. The compound of claim 1, wherein the compound does not contain fluorine.

16. The compound of claim 1, wherein one or more of three monomers at each end of each strand is connected by a phosphorothioate, a chiral phosphorothioate, or a phosphorodithioate linkage.

17. The compound of claim 1, wherein the compound has one phosphorothioate linkage between two monomers at the 5' end of the first strand, one phosphorothioate linkage between two monomers at the 3' end of the first strand, one phosphorothioate linkage between monomers at the second and third positions from the 3' end of the first strand, and one phosphorothioate linkage between two monomers at the 3' end of the second strand.

18. The compound of claim 1, wherein the compound is conjugated to a delivery moiety.

19. The compound of claim 1, wherein the compound is conjugated to a delivery moiety that binds to a glycoprotein receptor.

20. The compound of claim 1, wherein the compound is conjugated to a delivery moiety that binds to a glycoprotein receptor, wherein the delivery moiety comprises a galactose, a galactosamine, or a N-acetylgalactosamine.

21. The compound of claim 1, wherein the compound is conjugated to a GalNAc delivery moiety.

22. The compound of claim 1, wherein the compound is conjugated to a cholesterol delivery moiety.

23. The compound of claim 1, wherein the compound is conjugated to a delivery moiety at an end of the compound and has increased uptake in the liver as compared to an unconjugated compound.

24. A lipid nanoparticle-oligomer compound comprising one or more compounds of claim 1 attached to the lipid nanoparticle.

25. A composition comprising one or more compounds of claim 1 and a pharmaceutically acceptable carrier.

26. The composition of claim 25, wherein the carrier comprises lipid nanoparticles or liposomes.

27. A composition comprising a first compound of claim 1 targeted to a conserved region of HBV transcripts for genes X, C, P and S, a second compound of claim 1 targeted to inhibit HBsAg, a third compound of claim 1 targeted to a conserved region of HBV transcripts for genes X, C and S, and a pharmaceutically acceptable carrier.

28. The composition of claim 27, wherein the carrier comprises lipid nanoparticles or liposomes.

29. A composition comprising one or more compounds having reference positions from any of positions 1525 to 1582, 374 to 414, 1776 to 1782, 244 to 256, and 1818 to 1866.

30. The composition of claim 29, comprising a compound having a reference position from 1525 to 1582, a compound having a reference position from 374 to 414, and a compound having a reference position from 1776 to 1782.

31. A composition comprising a triad of compounds, wherein the triad is selected from the following: the first compound comprises SEQ ID NO:867 and 908, the second compound comprises SEQ ID NO:887 and 928, and the third compound comprises SEQ ID NO:875 and 916; the first compound comprises SEQ ID NO:899 and 940, the second compound comprises SEQ ID NO:887 and 928, and the third compound comprises SEQ ID NO:875 and 916; the first compound comprises SEQ ID NO:865 and 906, the second compound comprises SEQ ID NO:887 and 928, and the third compound comprises SEQ ID NO:875 and 916; the first compound comprises SEQ ID NO:869 and 910, the second compound comprises SEQ ID NO:887 and 928, and the third compound comprises SEQ ID NO:875 and 916; the first compound comprises SEQ ID NO:867 and 908, the second compound comprises SEQ ID NO:885 and 926, and the third compound comprises SEQ ID NO:875 and 916; and the first compound comprises SEQ ID NO:867 and 908, the second compound comprises SEQ ID NO:887 and 928, and the third compound comprises SEQ ID NO:877 and 918.

32. An siRNA comprising nucleotides, wherein the siRNA is targeted to HBV and has a sequence selected from the sense, antisense or sense-antisense pairs of the following, and substituted forms thereof: TABLE-US-00036 SEQ SEQ REF ID ID POS NO Sense (5'-3') NO Antisense (5'-3') 1777 875 GAGGCUGUAGGCAUAAAUU 916 AAUUUAUGCCUACAGCCUC 1581 869 GCACUUCGCUUCACCUCUG 910 CAGAGGUGAAGCGAAGUGC 380 887 UGUCUGCGGCGUUUUAUCA 928 UGAUAAAACGCCGCAGACA 1576 899 CGUGUGCACUUCGCUUCAC 940 GUGAAGCGAAGUGCACACG 1780 877 GCUGUAGGCAUAAAUUGGU 918 ACCAAUUUAUGCCUACAGC 1781 878 CUGUAGGCAUAAAUUGGUC 919 GACCAAUUUAUGCCUACAG 1782 879 UGUAGGCAUAAAUUGGUCU 920 AGACCAAUUUAUGCCUACA 376 885 GAUGUGUCUGCGGCGUUUU 926 AAAACGCCGCAGACACAUC 413 895 CUGCUGCUAUGCCUCAUCU 936 AGAUGAGGCAUAGCAGCAG 1580 900 UGCACUUCGCUUCACCUCU 941 AGAGGUGAAGCGAAGUGCA 1818 888 AACUUUUUCACCUCUGCCU 929 AGGCAGAGGUGAAAAAGUU

33. A method for preventing, ameliorating or treating a disease or condition associated with HBV infection in a subject in need, the method comprising administering to the subject an effective amount of a composition of claim 25.

34. The method of claim 33, wherein the administration of the composition reduces HBV viral titer in the subject.

35. The method of claim 33, wherein the subject has been diagnosed with a disease associated with Hepatitis B virus infection.

36. The method of claim 33, wherein the subject has been diagnosed with liver disease.

37. A method for inhibiting the replication, maturation, growth, or transmission of a Hepatitis B virus in a subject in need, the method comprising administering to the subject an effective amount of a composition of claim 25.

38. The method of claim 37, wherein the administration of the composition reduces serum concentration of HBsAg in the subject.

39. The method of claim 37, wherein the administration of the composition reduces serum concentration of HBsAg in the subject by 2-log.sub.10-fold.

40. The method of claim 37, wherein the administration of the composition reduces serum concentration of HBsAg in the subject by 2-log.sub.10-fold for at least 7 days.

41. The method of claim 37, wherein the administration of the composition reduces HBeAg in the subject.

42. The method of claim 37, wherein the administration of the composition reduces HBV DNA in the subject.

43. A method for inhibiting expression of a Hepatitis B virus polynucleotide in a subject in need, the method comprising administering to the subject a composition of claim 25.
Description



SEQUENCE LISTING

[0001] This application includes a Sequence Listing submitted electronically as an ASCII file named ARC1410US_SL.txt.

BACKGROUND OF THE INVENTION

[0002] Hepatitis B is a liver disease that results from infection with the Hepatitis B virus (HBV). Its severity can be from a mild illness lasting a few weeks, to a serious, lifelong illness. Hepatitis B can be either acute or chronic. Acute Hepatitis B virus infection is a short-term illness that may lead to chronic infection. Chronic Hepatitis B virus infection is a long-term illness that can result in long-term health problems, such as cirrhosis of the liver, liver cancer, and death.

[0003] Hepatitis B is usually spread through transfer of a body fluid by sexual contact with an infected person, or through sharing needles for drug-injection. It can also be passed from an infected mother to her baby at birth. In endemic areas, Hepatitis B is most often spread from mother to child at birth, or by exposure to infected blood, especially from an infected child to an uninfected child during the first 5 years of life.

[0004] According to the latest WHO estimates, as many as 240 million people are chronically infected with Hepatitis B, defined as Hepatitis B surface antigen positive for at least 6 months. Approximately 780,000 persons die each year from Hepatitis B infection.

[0005] There is no specific treatment for acute hepatitis B. Chronic hepatitis B infection can be treated with drugs, including oral antiviral agents. WHO recommends the use of oral treatments such as tenofovir or entecavir. In most people, the treatment suppresses replication of the virus, but does not cure hepatitis B infection. Liver cancer progresses rapidly, and treatment options are limited. Surgery and chemotherapy, or liver transplantation can prolong life for up to a few years.

[0006] Laboratory diagnosis of hepatitis B infection can be done by detecting the hepatitis B surface antigen HBsAg. Acute hepatitis B virus infection is characterized by the presence of HBsAg and immunoglobulin M (IgM) antibody to the core antigen, HBcAg. During the initial phase of infection, patients are also seropositive for hepatitis B e-antigen (HBeAg). HBeAg is usually a marker of high levels of replication of the virus. The presence of HBeAg indicates that the blood and body fluids of the infected individual are highly contagious. Chronic infection is characterized by the persistence of HBsAg for at least 6 months, with or without concurrent HBeAg. Persistence of HBsAg is the principal marker of risk for developing chronic liver disease and liver cancer later in life.

[0007] HBV is a member of the hepadnavirus family. The virus particles, which can infect liver cells, are 30-42 nm in diameter and have an outer envelope and an icosahedral nucleocapsid core. The nucleocapsid encloses the viral DNA, and a DNA polymerase that can have reverse transcriptase activity. The outer envelope contains proteins that can be involved in viral binding and entry into cells.

[0008] In general, HBV has four identified genes, C, P, S, and X. Gene C codes for a core protein, HBcAg. An extracellular protein HBeAg is processed from a pre-core protein. A DNA polymerase is encoded by gene P. Gene S codes for the small surface antigen HBsAg, which is one of three polypeptide surface proteins: large, middle, and small. Gene X may be associated with development of liver cancer.

[0009] HBV is a pararetrovirus, which is a non-retrovirus that uses reverse transcription in the replication process. The virus can enter the cell and multiply using RNA made by a host process. The viral genomic DNA can be transferred to the cell nucleus, acted upon by viral polymerase, and provide transcription of four viral mRNAs by host RNA polymerase. A large viral mRNA is used to make the new copies of the genome by reverse transcription, and to make the core protein and the viral DNA polymerase. The viral mRNAs are further processed to form new virus particles.

[0010] HBV can be described by four major serotypes based on epitopes presented by envelope proteins: adr, adw, ayr, ayw. HBV has been identified with eight genotypes, A-H, as well as subgenotypes. The genotypes can have distinct geographical distribution, and are used in tracking evolution and transmission of the virus.

[0011] What is needed are compositions and methods for treatment of Hepatitis B.

[0012] There is an urgent need for new methods and compositions for ameliorating or treating Hepatitis B infection.

BRIEF SUMMARY

[0013] This invention relates to the fields of biopharmaceuticals and therapeutics composed of oligomers for gene silencing. More particularly, this invention relates to structures, compositions and methods for therapeutic oligomers directed against Hepatitis B virus.

[0014] This invention provides novel molecules to be used as therapeutic agents against Hepatitis B infection. The molecules of this invention can be used as active pharmaceutical ingredients in compositions for ameliorating, preventing or treating Hepatitis B infection.

[0015] Molecules of this invention for treating Hepatitis B infection may act against any of the replication, maturation, growth, or transmission modalities of the Hepatitis B virus. By preventing the Hepatitis B virus from carrying out any one or more of its processes, the molecules of this invention can be used for ameliorating or treating Hepatitis B infection.

[0016] Embodiments of this invention can provide molecules having one or more properties that advantageously provide enhanced effectiveness against HBV, as well as compositions or formulations for therapeutic agents against Hepatitis B infection, which can provide clinical agents. The properties of the molecules of this invention arise according to their structure, and the molecular structure in its entirety, as a whole, can provide significant benefits and properties.

[0017] The active agents of this invention include oligomeric molecules that can inhibit expression of an HBV genome. Oligomers of this invention can provide potent action against HBV infection in a subject by silencing expression of an HBV genome.

[0018] In some embodiments, a wide range of novel molecules are provided, which can incorporate one or more linker groups. The linker groups can be attached in a chain in the molecule. Each linker group can also be attached to a nucleobase.

[0019] In some aspects, a linker group can be a monomer. Monomers can be attached to form a chain molecule. In a chain molecule of this invention, a linker group monomer can be attached at any point in the chain.

[0020] In certain aspects, linker group monomers can be attached in a chain molecule of this invention so that the linker group monomers reside near the ends of the chain. The ends of the chain molecule can be formed by linker group monomers.

[0021] In further aspects, the linker groups of a chain molecule can each be attached to a nucleobase. The presence of nucleobases in the chain molecule can provide a sequence of nucleobases.

[0022] In certain embodiments, this invention provides oligomer molecules having chain structures that incorporate novel combinations of the linker group monomers, along with certain natural nucleotides, or non-natural nucleotides, or modified nucleotides, or chemically-modified nucleotides.

[0023] The oligomer molecules of this invention can display a sequence of nucleobases that is targeted to a component of the HBV genome.

[0024] In additional aspects, this invention provides therapeutics for preventing, ameliorating, or treating a disease caused by Hepatitis B infection. An active compound or molecule of this invention may be used in the prevention or treatment of a viral infection caused by Hepatitis B virus.

[0025] This invention provides structures, methods and compositions for oligomeric agents that incorporate the linker group monomers. The oligomeric molecules of this invention can be used as active agents in formulations for gene silencing therapeutics targeted to HBV.

[0026] Embodiments of this invention include the following:

[0027] A compound comprising a first strand and a second strand, each of the strands being 19-29 monomers in length, the monomers comprising UNA monomers and nucleic acid monomers, wherein the compound has a duplex region of from 14 to 29 contiguous monomers in length, wherein the first strand is a passenger strand for RNA interference and the second strand is a guide strand for RNA interference, and wherein the compound comprises a sequence of bases targeted to inhibit expression of an HBV genome. The compound may contain from one to seven UNA monomers.

[0028] In some embodiments, the compound may contain a UNA monomer at the 1-end (5' end for non-UNA) of the first strand, a UNA monomer at the 3-end (3' end for non-UNA) of the first strand, and a UNA monomer at the second position from the 5' end of the second strand. A compound can contain a UNA monomer at any one or more of positions 2 to 8 from the 5' end of the second strand.

[0029] In certain embodiments, a compound may have a 3' overhang with one or more UNA monomers, natural nucleotides, non-natural nucleotides, modified nucleotides, or chemically-modified nucleotides, or combinations thereof. The 3' overhang can have one or more deoxythymidine nucleotides, 2'-O-methyl nucleotides, inverted abasic monomers, inverted thymidine monomers, L-thymidine monomers, or glyceryl nucleotides.

[0030] In some aspects, a compound may have one or more nucleic acid monomers that is a non-natural nucleotide, a modified nucleotide, or a chemically-modified nucleotide. A compound may have one or more monomers connected by a phosphorothioate, a chiral phosphorothioate, or a phosphorodithioate linkage.

[0031] In further aspects, a compound may be conjugated to a delivery moiety, such as, for example, a moiety that binds to a glycoprotein receptor, a galactose, a galactosamine, a N-acetylgalactosamine, a GalNAc group, or a cholesterol delivery moiety. A compound may be conjugated to a delivery moiety and have increased uptake in the liver as compared to an unconjugated compound.

[0032] This invention includes lipid nanoparticle-oligomer compounds, in which one or more compounds are attached to a lipid nanoparticle.

[0033] A composition of this disclosure can include one or more compounds and a pharmaceutically acceptable carrier. The carrier may be lipid nanoparticles or liposomes.

[0034] A composition of this disclosure may contain a first compound targeted to a conserved region of HBV transcripts for genes X, C, P and S, a second compound targeted to inhibit HBsAg, a third compound targeted to a conserved region of HBV transcripts for genes X, C and S, and a pharmaceutically acceptable carrier.

[0035] Embodiments of this invention include compositions containing one or more compounds having reference positions from any of positions 1525 to 1582, 374 to 414, 1776 to 1782, 244 to 256, and 1818 to 1866. In certain embodiments, a composition may include a compound having a reference position from 1525 to 1582, a compound having a reference position from 374 to 414, and a compound having a reference position from 1776 to 1782.

[0036] Embodiments of this invention further contemplate methods for preventing, ameliorating or treating a disease or condition associated with HBV infection in a subject in need, by administering to the subject an effective amount of a composition above. The administration of the composition can reduce HBV viral titer in the subject. A subject may have been diagnosed with a disease associated with Hepatitis B virus infection, for example, a liver disease.

[0037] This invention includes methods for inhibiting the replication, maturation, growth, or transmission of a Hepatitis B virus in a subject in need, by administering to the subject an effective amount of a composition above. The composition may reduce serum concentration of HBsAg in the subject. In some embodiments, the administration of the composition may reduce serum concentration of HBsAg in the subject by 2-log.sub.10-fold, or by 2-log.sub.10-fold for at least 7 days. In certain embodiments, the administration of the composition can reduce HBeAg in the subject, or HBV DNA in the subject.

[0038] This invention also contemplates methods for inhibiting expression of a Hepatitis B virus polynucleotide in a subject in need, by administering to the subject a composition above, as well as the use of a composition above for preventing, ameliorating or treating a disease or condition associated with Hepatitis B infection in a subject in need.

[0039] In some aspects, this disclosure includes compositions for use in medical therapy, or for use in the treatment of the human or animal body. In certain aspects, this invention includes the use of a composition for preparing or manufacturing a medicament for preventing, ameliorating or treating a disease or condition associated with Hepatitis B infection in a subject in need.

BRIEF DESCRIPTION OF THE DRAWINGS

[0040] FIG. 1 shows a map of HBV protein coding regions and selected transcripts for a reference genome. Nucleotide position 1/3221 is designated at the top. Further designations are as follows: pre-S1, large HBsAg; pre-S2, medium HBsAg; S, HBsAg; P, polymerase; X, HBx protein; pre-C, pre-core/HBeAg; C, HB core Ag. The 2.4 kb, 2.1 kb, and 0.7 kb transcripts coding for the pre-S1/pre-S2/S, as well as the transcript coding the X protein are shown. The pre-Core/HBeAg protein is generated from a long, 3.5 kb transcript (not shown) originating at position .about.1700, while the core and polymerase proteins and the pre-genomic RNA used as a template for viral replication are generated from a .about.200 nt shorter transcript. The ranges of reference positions for certain UNA oligomers, designated UNA oligomer 1, UNA oligomer 2, and UNA oligomer 3, are shown.

[0041] FIG. 2 shows HBV inhibitory effect in vivo for UNA oligomers, observed in a humanized PXB Mouse model of HBV infection. The UNA oligomers of this invention exhibited profound reduction of HBV serum infection parameters in vivo. In this study, the UNA oligomers were contained in lipid nanoparticle formulations,-1 and -2, and an ascending dose was used. The UNA oligomers were formulated in lipid nanoparticles and injected intravenously into HBV-infected Phoenix Bio (PXB) mice containing human hepatocytes (70%). Treatment with both UNA oligomer 1576 and a UNA oligomer triad composition (1576, 380, 177) caused a rapid and sustained reduction in viral endpoint serum HBsAg.

[0042] FIG. 3 shows HBV inhibitory effect in vivo for UNA oligomers, observed in a humanized PXB Mouse model of HBV infection. Treatment with UNA oligomer triad (1576, 380, 1777) caused a rapid and sustained reduction in viral endpoint serum HBsAg. The dose-dependent response in vivo shows a pharmacological effect of the UNA oligomer composition. The study used an ascending dose in which mice were administered every 4 days, up to day 40, and viral endpoints were monitored every 4 days through day 44.

[0043] FIG. 4 shows HBV inhibitory effect in vivo for UNA oligomers, observed in a humanized PXB Mouse model of HBV infection. Treatment with UNA oligomer triad (1576, 380, 1777) caused a rapid and sustained reduction in viral endpoint serum HBeAg. The dose-dependent response in vivo shows a pharmacological effect of the UNA oligomer composition. The study used an ascending dose in which mice were administered every 4 days, up to day 40, and viral endpoints were monitored every 4 days through day 44.

[0044] FIG. 5 shows HBV inhibitory effect in vivo for UNA oligomers, observed in a humanized PXB Mouse model of HBV infection. Treatment with UNA oligomer triad (1576, 380, 1777) caused a rapid and sustained reduction in viral endpoint serum HBV DNA. The dose-dependent response in vivo shows a pharmacological effect of the UNA oligomer composition. The study used an ascending dose in which mice were administered every 4 days, up to day 40, and viral endpoints were monitored every 4 days through day 44.

[0045] FIG. 6 shows HBV inhibitory effect in vivo for UNA oligomers, observed in a humanized PXB Mouse model of HBV infection. Treatment with UNA oligomers 1777, 380 and 1578 caused a rapid and sustained reduction in viral endpoint serum HBsAg.

[0046] FIG. 7 shows HBV inhibitory effect in vivo for UNA oligomers, observed in a humanized PXB Mouse model of HBV infection. Treatment with UNA oligomers 1777, 380 and 1578 caused a rapid and sustained reduction in viral endpoint serum HBeAg.

[0047] FIG. 8 shows HBV inhibitory effect in vivo for UNA oligomers, observed in a humanized PXB Mouse model of HBV infection. Treatment with UNA oligomers 1777, 380 and 1578 caused a rapid and sustained reduction in viral endpoint serum HBV DNA.

[0048] FIG. 9 shows HBV inhibitory effect in vivo for UNA oligomers, observed in a humanized PXB Mouse model of HBV infection. Treatment with a UNA oligomer triad composition (1578, 380, 1777) caused a rapid and sustained reduction in viral endpoint serum HBsAg. The dose-dependent response in vivo shows a pharmacological effect of the UNA oligomer composition.

[0049] FIG. 10 shows HBV inhibitory effect in vivo for UNA oligomers, observed in a humanized PXB Mouse model of HBV infection. Treatment with a UNA oligomer triad composition (1578, 380, 1777) caused a rapid and sustained reduction in viral endpoint serum HBeAg. The dose-dependent response in vivo shows a pharmacological effect of the UNA oligomer composition.

[0050] FIG. 11 shows HBV inhibitory effect in vivo for UNA oligomers, observed in a humanized PXB Mouse model of HBV infection. Treatment with a UNA oligomer triad composition (1578, 380, 1777) caused a rapid and sustained reduction in viral endpoint serum HBV DNA. The dose-dependent response in vivo shows a pharmacological effect of the UNA oligomer composition.

[0051] FIG. 12 shows HBV inhibitory effect in vivo for UNA oligomers, observed in an AAV-HBV mouse model of HBV infection. The UNA oligomers of this invention exhibited profound reduction of HBV serum infection parameters in vivo. In general, the AAV-HBV mouse model is a robust model for investigating HBV infection. The UNA oligomers were formulated in lipid nanoparticles and injected intravenously into C57Bl/6 mice with active HBV replication after AAV-mediated delivery of a recombinant HBV genome to the liver. The study used an ascending dose, and serum viral endpoints were monitored 15 days before, and at least 22 days after treatment. Treatment with each of UNA oligomers 380, 1777, and 1576 caused a rapid and sustained reduction in viral endpoint serum HBsAg.

[0052] FIG. 13 shows HBV inhibitory effect in vivo for UNA oligomers, observed in an AAV-HBV mouse model of HBV infection. The UNA oligomers were formulated in lipid nanoparticles and injected intravenously into C57Bl/6 mice with active HBV replication after AAV-mediated delivery of a recombinant HBV genome to the liver. Treatment with each of UNA oligomers 380, 1777, and 1576, as well as the UNA oligomer triad composition of the same compounds (1576, 380, 1777) caused a rapid and sustained reduction in viral endpoint serum HBeAg. This head-to-head comparison shows that the triad composition provided surprisingly increased potency throughout the duration of the effect, relative to the individual oligomers.

[0053] FIG. 14 shows HBV inhibitory effect in vivo for UNA oligomers, observed in an AAV-HBV mouse model of HBV infection. The UNA oligomers were formulated in lipid nanoparticles and injected intravenously into C57Bl/6 mice with active HBV replication after AAV-mediated delivery of a recombinant HBV genome to the liver. Treatment with each of UNA oligomers 380, 1777, and 1576 caused a rapid and sustained reduction in viral endpoint serum HBV DNA.

[0054] FIG. 15 shows HBV inhibitory effect in vivo for UNA oligomers, observed in an AAV-HBV mouse model of HBV infection. The UNA oligomers were formulated in lipid nanoparticles and injected intravenously into C57Bl/6 mice with active HBV replication after AAV-mediated delivery of a recombinant HBV genome to the liver. The study was an ascending dose design in which mice were treated with 3 mg/kg on day 0, then 5 mg/kg on day 4, then 10 mg/kg on day 8, and serum viral endpoints were monitored up to day 12 after treatment. Treatment with the UNA oligomer triad composition (1777, 380, 1578) caused a rapid and sustained reduction in viral endpoint serum HBsAg. The dose-dependent response in vivo shows a pharmacological effect of the UNA oligomer composition.

[0055] FIG. 16 shows HBV inhibitory effect in vivo for UNA oligomers, observed in an AAV-HBV mouse model of HBV infection. The UNA oligomers were formulated in lipid nanoparticles and injected intravenously into C57Bl/6 mice with active HBV replication after AAV-mediated delivery of a recombinant HBV genome to the liver. Treatment with each of UNA oligomers 1578 and 1575 caused a rapid and sustained reduction in viral endpoint serum HBsAg.

[0056] FIG. 17 shows HBV inhibitory effect in vivo for UNA oligomers, observed in an AAV-HBV mouse model of HBV infection. The UNA oligomers were formulated in lipid nanoparticles and injected intravenously into C57Bl/6 mice with active HBV replication after AAV-mediated delivery of a recombinant HBV genome to the liver. Treatment with each of UNA oligomers 1578 and 1575 caused a rapid and sustained reduction in viral endpoint serum HBeAg.

[0057] FIG. 18 shows HBV inhibitory effect in vivo for UNA oligomers, observed in an AAV-HBV mouse model of HBV infection. The UNA oligomers were formulated in lipid nanoparticles and injected intravenously into C57Bl/6 mice with active HBV replication after AAV-mediated delivery of a recombinant HBV genome to the liver. Treatment with each of UNA oligomers 1578 and 1575 caused a rapid and sustained reduction in viral endpoint serum HBV DNA.

DETAILED DESCRIPTION OF THE INVENTION

[0058] This invention provides a range of novel agents and compositions to be used as therapeutics against Hepatitis B infection. Molecules of this invention can be used as active pharmaceutical ingredients in compositions for ameliorating, preventing or treating Hepatitis B infection.

[0059] The galenic molecules of this invention can prevent Hepatitis B virus from carrying out one or more of its processes. Molecules of this invention can be used for ameliorating or treating Hepatitis B infection, and may act against any of the replication, maturation, growth, or transmission modes of the Hepatitis B virus.

[0060] Novel agents of this invention include oligomeric molecules that inhibit expression of an HBV genome.

[0061] Embodiments of this invention can provide extraordinary and surprisingly enhanced efficacy against HBV infection in a subject by attacking all portions of the HBV genome. More particularly, agents and compositions of this invention can simultaneously inhibit all identified genes of HBV: C, P, S, and X. Thus, the compounds and compositions of this disclosure can inhibit the small surface antigen HBsAg, as well as the extracellular protein HBeAg, in addition to X protein and viral polymerase.

[0062] The properties of the compounds of this invention arise according to their molecular structure, and the structure of the molecule in its entirety, as a whole, can provide significant benefits based on those properties. Embodiments of this invention can provide molecules having one or more properties that advantageously provide enhanced effectiveness against HBV, as well as compositions or formulations for therapeutic agents against Hepatitis B infection, which can provide clinical agents.

[0063] A wide range of novel molecules are provided, each of which can incorporate specialized linker groups. The linker groups can be attached in a chain in the molecule. Each linker group can also be attached to a nucleobase.

[0064] In some aspects, a linker group can be a monomer. Monomers can be attached to form a chain molecule. In a chain molecule of this invention, a linker group monomer can be attached at any point in the chain.

[0065] In certain aspects, linker group monomers can be attached in a chain molecule of this invention so that the linker group monomers reside near the ends of the chain. The ends of the chain molecule can be formed by linker group monomers.

[0066] As used herein, a chain molecule can also be referred to as an oligomer.

[0067] In further aspects, the linker groups of a chain molecule can each be attached to a nucleobase. The presence of nucleobases in the chain molecule can provide a sequence of nucleobases.

[0068] In certain embodiments, this invention provides oligomer molecules having chain structures that incorporate novel combinations of the linker group monomers, along with certain natural nucleotides, or non-natural nucleotides, or modified nucleotides, or chemically-modified nucleotides.

[0069] The oligomer molecules of this invention can display a sequence of nucleobases that is targeted to a component of an HBV genome. In some embodiments, an oligomer can be targeted to a portion of the HBV genome that is conserved, or highly conserved, among a number of known HBV genomic sequences.

[0070] In some aspects, this invention provides active oligomer molecules that correspond to, or are complementary to at least a fragment of an HBV nucleic acid molecule, and that decrease expression of at least such a fragment present in a cell. In some embodiments, the active oligomer molecule can be double-stranded.

[0071] Without wishing to be bound by any one particular theory, it is believed that a cellular pathway may use active oligomers of this invention to be sequence-specific regulators in an RNA interference pathway. The active oligomers may bind to the RNA-induced silencing complex (RISC complex), where a sense strand, also referred to as the passenger strand, and an antisense strand, also referred to as the guide strand, can be unwound, and the antisense strand complexed in the RISC complex. The guide strand can bind to a complementary sequence to which it was targeted, for example, a target sequence in an mRNA, which can be subsequently cleaved, resulting in inactivation of the nucleic acid molecule containing the target sequence. As a result, the expression of mRNA containing the target sequence can be reduced.

[0072] In some embodiments, an oligomeric molecule may be attached to a delivery moiety. Examples of delivery moieties include glycoprotein receptors, galactoses, galactosamines, N-acetylgalactosamines, GalNAc groups, cholesterols, sterols, phytosterols, steroids, zoosterols, lanosterols, stigmastanols, dihydrolanosterols, zymosterols, zymostenols, desmosterols, and 7-dehydrocholesterol s.

[0073] In additional aspects, this invention provides therapeutics for preventing, ameliorating, or treating a disease caused by Hepatitis B infection. An active compound or molecule of this invention may be used in the prevention or treatment of a viral infection caused by Hepatitis B virus.

[0074] This invention provides structures, methods and compositions for oligomeric agents that incorporate the linker group monomers. The oligomeric molecules of this invention can be used as active agents in formulations for gene silencing therapeutics targeted to HBV.

[0075] This invention provides a range of molecules that are useful for providing therapeutic effects because of their activity in regulating expression of a gene. The molecules of this invention are structured to provide gene regulating or silencing activity in vitro and in vivo.

[0076] Embodiments of this invention can provide molecules for use as therapeutic agents against Hepatitis B infection. The molecules can be used as active pharmaceutical ingredients in compositions for ameliorating, preventing or treating Hepatitis B infection.

[0077] In certain embodiments, an active molecule can be structured as an oligomer composed of monomers. The oligomeric structures of this invention may contain one or more linker group monomers, along with certain nucleotides.

[0078] Modalities of Action

[0079] Molecules of this invention for treating Hepatitis B infection may act against any of the replication, maturation, growth, or transmission modalities of the Hepatitis B virus. By preventing the Hepatitis B virus from carrying out any one or more of its normal processes, the molecules of this invention can be used for ameliorating or treating Hepatitis B infection.

[0080] This invention can provide unexpectedly advantageous efficacy against HBV infection in a subject by simultaneously modulating all portions of the HBV genome.

[0081] In some embodiments, inventive UNA oligomeric agents and compositions of this disclosure can inhibit expression of each of the HBV genes C, P, S, and X.

[0082] In some aspects, inventive UNA oligomeric agents and compositions of this disclosure can simultaneously inhibit expression of all genes of HBV, including genes C, P, S, and X.

[0083] In particular aspects, inventive UNA oligomeric compositions of this disclosure can simultaneously inhibit expression of multiple genes of HBV, such as genes P and C, or P and S, or P and X.

[0084] In further aspects, inventive UNA oligomeric compositions of this disclosure can simultaneously inhibit expression of multiple genes of HBV, such as genes P, S and C, or P, X and S, or P, C and X.

[0085] In certain aspects, the compounds of this invention can inhibit the small surface antigen HBsAg in vivo, regardless of the genomic source of HBsAg in the subject.

[0086] In further aspects, compounds and compositions of this invention can inhibit the HBV extracellular protein HBeAg, the X protein, and HBV viral polymerase.

[0087] In some aspects, a therapeutic molecule of this invention can be active in preventing or inhibiting a step of the replication cycle of hepatitis B virus.

[0088] Viral components of HBV can include a nucleocapsid, fully or partially double stranded DNA (relaxed circular, rcDNA), a polymerase, surface antigens, core proteins, a regulatory X-protein, and secreted proteins.

[0089] In some embodiments, a therapeutic molecule of this invention can be active in preventing or inhibiting attachment of viral components to cell-associated proteoglycans.

[0090] Certain embodiments of this invention provide a therapeutic molecule that can be active in preventing or inhibiting binding of a viral component to a hepatocyte receptor.

[0091] In further embodiments, a therapeutic molecule of this invention can be active in preventing or inhibiting entry of a viral component into a cell by endocytosis, or fusion of a viral component to a cell membrane.

[0092] A therapeutic molecule of this invention may be active in preventing or inhibiting release of a viral component into the cytoplasm of a cell.

[0093] In additional embodiments, a therapeutic molecule of this invention can be active in preventing or inhibiting internal cell transport of an HBV nucleocapsid.

[0094] Aspects of this disclosure can provide a therapeutic molecule, which can be active in preventing or inhibiting release of HBV rcDNA in a cell.

[0095] In some embodiments, a therapeutic molecule of this invention can be active in preventing or inhibiting operation of the viral polymerase.

[0096] Certain embodiments may provide a therapeutic molecule that can be active in preventing or inhibiting development of an HBV genomic DNA in a cell.

[0097] In further embodiments, a therapeutic molecule of this invention can be active in preventing or inhibiting production of a viral RNA in a cell.

[0098] A therapeutic molecule of this invention may be active in preventing or inhibiting viral replication in a cell.

[0099] In additional embodiments, a therapeutic molecule may be active in preventing or inhibiting an HBV regulatory X-protein in a cell.

[0100] Further aspects of this disclosure can provide a therapeutic molecule that be active in preventing or inhibiting translation or reverse transcription of a viral RNA in a cell.

[0101] In some embodiments, a therapeutic molecule of this invention can be active in preventing or inhibiting maturation of a viral nucleocapsid in a cell.

[0102] UNA Monomers

[0103] In some embodiments, linker group monomers can be unlocked nucleomonomers (UNA monomers), which are small organic molecules based on a propane-1,2,3-tri-yl-trisoxy structure as shown below:

##STR00001##

where R.sup.1 and R.sup.2 are H, and R.sup.1 and R.sup.2 can be phosphodiester linkages, Base can be a nucleobase, and R.sup.3 is a functional group described below.

[0104] In another view, the UNA monomer main atoms can be drawn in IUPAC notation as follows:

##STR00002##

where the direction of progress of the oligomer chain is from the 1-end to the 3-end of the propane residue.

[0105] Examples of a nucleobase include uracil, thymine, cytosine, 5-methylcytosine, adenine, guanine, inosine, and natural and non-natural nucleobase analogues.

[0106] In general, because the UNA monomers are not nucleotides, they can exhibit at least four forms in an oligomer. First, a UNA monomer can be an internal monomer in an oligomer, where the UNA monomer is flanked by other monomers on both sides. In this form, the UNA monomer can participate in base pairing when the oligomer is a duplex, for example, and there are other monomers with nucleobases in the duplex.

[0107] Examples of UNA monomer as internal monomers flanked at both the propane-1-yl position and the propane-3-yl position, where R.sup.3 is --OH, are shown below.

##STR00003##

[0108] Second, a UNA monomer can be a monomer in an overhang of an oligomer duplex, where the UNA monomer is flanked by other monomers on both sides. In this form, the UNA monomer does not participate in base pairing. Because the UNA monomers are flexible organic structures, unlike nucleotides, the overhang containing a UNA monomer will be a flexible terminator for the oligomer.

[0109] A UNA monomer can be a terminal monomer in an overhang of an oligomer, where the UNA monomer is attached to only one monomer at either the propane-1-yl position or the propane-3-yl position. In this form, the UNA monomer does not participate in base pairing. Because the UNA monomers are flexible organic structures, unlike nucleotides, the overhang containing a UNA monomer can be a flexible terminator for the oligomer.

[0110] Examples of a UNA monomer as a terminal monomer attached at the propane-3-yl position are shown below.

##STR00004##

[0111] Because a UNA monomer can be a flexible molecule, a UNA monomer as a terminal monomer can assume widely differing conformations. An example of an energy minimized UNA monomer conformation as a terminal monomer attached at the propane-3-yl position is shown below.

##STR00005##

Thus, UNA oligomers having a terminal UNA monomer are significantly different in structure from conventional nucleic acid agents, such as siRNAs. For example, siRNAs may require that terminal monomers or overhangs in a duplex be stabilized. In contrast, the conformability of a terminal UNA monomer can provide UNA oligomers with different properties.

[0112] Among other things, the structure of the UNA monomer allows it to be attached to naturally-occurring nucleotides. A UNA oligomer can be a chain composed of UNA monomers, as well as various nucleotides that may be based on naturally-occurring nucleosides.

[0113] In some embodiments, the functional group R.sup.3 of a UNA monomer can be --OR.sup.4, --SR.sup.4, --NR.sup.4.sub.2, --NH(C.dbd.O)R.sup.4, morpholino, morpholin-1-yl, piperazin-1-yl, or 4-alkanoyl-piperazin-1-yl, where R.sup.4 is the same or different for each occurrence, and can be H, alkyl, a cholesterol, a lipid molecule, a polyamine, an amino acid, or a polypeptide.

[0114] The UNA monomers are organic molecules. UNA monomers are not nucleic acid monomers or nucleotides, nor are they naturally-occurring nucleosides or modified naturally-occurring nucleosides.

[0115] A UNA oligomer of this invention is a synthetic chain molecule. A UNA oligomer of this invention is not a nucleic acid, nor an oligonucleotide.

[0116] In some embodiments, as shown above, a UNA monomer can be UNA-A (designated ), UNA-U (designated ), UNA-C(designated {hacek over (C)}), and UNA-G (designated {hacek over (G)}).

[0117] Designations that may be used herein include mA, mG, mC, and mU, which refer to the 2'-O-Methyl modified ribonucleotides.

[0118] Designations that may be used herein include lower case c and u, which refer to the 2'-O-methyl modified ribonucleotides.

[0119] Designations that may be used herein include dT, which refers to a 2'-deoxy T nucleotide.

[0120] Additional Monomers for Oligomeric Agents

[0121] As used herein, in the context of oligomer sequences, the symbol X represents a UNA monomer.

[0122] As used herein, in the context of oligomer sequences, the symbol N represents any natural nucleotide monomer, or a modified nucleotide monomer.

[0123] As used herein, in the context of oligomer sequences, the symbol Q represents a non-natural, modified, or chemically-modified nucleotide monomer. When a Q monomer appears in one strand of the oligomer, and is unpaired with the other strand, the monomer can have any base attached. When a Q monomer appears in one strand of the oligomer, and is paired with a monomer in the other strand, the Q monomer can have any base attached that would be complementary to the monomer in the corresponding paired position in the other strand.

[0124] Examples of nucleic acid monomers include non-natural, modified, and chemically-modified nucleotides, including any such nucleotides known in the art.

[0125] Examples of non-natural, modified, and chemically-modified nucleotide monomers include any such nucleotides known in the art, for example, 2'-O-methyl ribonucleotides, 2'-O-methyl purine nucleotides, 2'-deoxy-2'-fluoro ribonucleotides, 2'-deoxy-2'-fluoro pyrimidine nucleotides, 2'-deoxy ribonucleotides, 2'-deoxy purine nucleotides, universal base nucleotides, 5-C-methyl-nucleotides, and inverted deoxyabasic monomer residues.

[0126] Examples of non-natural, modified, and chemically-modified nucleotide monomers include 3'-end stabilized nucleotides, 3'-glyceryl nucleotides, 3'-inverted abasic nucleotides, 3'-inverted thymidine, and L-thymidine.

[0127] Examples of non-natural, modified, and chemically-modified nucleotide monomers include locked nucleic acid nucleotides, 2'-O,4'-C-methylene-(D-ribofuranosyl) nucleotides, 2'-methoxyethoxy (MOE) nucleotides, 2'-methyl-thio-ethyl, 2'-deoxy-2'-fluoro nucleotides, and 2'-O-methyl nucleotides.

[0128] Examples of non-natural, modified, and chemically-modified nucleotide monomers include 2'-amino nucleotides, 2'-O-amino nucleotides, 2'-C-allyl nucleotides, and 2'-O-allyl nucleotides.

[0129] Examples of non-natural, modified, and chemically-modified nucleotide monomers include N.sup.6-methyladenosine nucleotides.

[0130] Examples of non-natural, modified, and chemically-modified nucleotide monomers include nucleotide monomers with modified bases 5-(3-amino)propyluridine, 5-(2-mercapto)ethyluridine, 5-bromouridine; 8-bromoguanosine, or 7-deazaadenosine.

[0131] Examples of non-natural, modified, and chemically-modified nucleotide monomers include 2'-O-aminopropyl substituted nucleotides.

[0132] Examples of non-natural, modified, and chemically-modified nucleotide monomers include 2'-O-guanidinopropyl substituted nucleotides.

[0133] Examples of non-natural, modified, and chemically-modified nucleotide monomers include Pseudouridines.

[0134] Examples of non-natural, modified, and chemically-modified nucleotide monomers include replacing the 2'--OH group of a nucleotide with a 2'-R, a 2'-OR, a 2'-halogen, a 2'-SR, or a 2'-amino, 2'-azido, where R can be H, alkyl, fluorine-substituted alkyl, alkenyl, or alkynyl.

[0135] Examples of non-natural, modified, and chemically-modified nucleotide monomers include replacing the 2'--OH group of a nucleotide with a 2'-R or 2'-OR, where R can be CN, CF.sub.3, alkylamino, or aralkyl.

[0136] Examples of non-natural, modified, and chemically-modified nucleotide monomers include nucleotides with a modified sugar such as an F-HNA, an HNA, a CeNA, a bicyclic sugar, or an LNA.

[0137] Examples of non-natural, modified, and chemically-modified nucleotide monomers include 2'-oxa-3'-aza-4' a-carbanucleoside monomers, 3-hydroxymethyl-5-(1H-1,2,3-triazol)-isoxazolidine monomers, and 5'-triazolyl-2'-oxa-3'-aza-4' a-carbanucleoside monomers.

[0138] Some examples of modified nucleotides are given in Saenger, Principles of Nucleic Acid Structure, Springer-Verlag, 1984.

[0139] Oligomeric Compounds Containing UNA Monomers

[0140] Aspects of this invention can provide structures and compositions for UNA-containing oligomeric compounds. The oligomeric agents may incorporate one or more UNA monomers. Oligomeric molecules of this invention can be used as active agents in formulations for gene regulating or gene silencing therapeutics.

[0141] In some embodiments, this invention provides oligomeric compounds having a structure that incorporates novel combinations of UNA monomers with certain natural nucleotides, non-natural nucleotides, modified nucleotides, or chemically-modified nucleotides.

[0142] In further aspects, the oligomeric compounds can be pharmacologically active molecules. UNA oligomers of this invention can be used as active pharmaceutical ingredients for regulating gene expression, and in RNA interference methods, as well as antisense, RNA blocking, and micro-RNA strategies.

[0143] A UNA oligomer of this invention can have the structure of Formula I

##STR00006##

wherein L.sup.1 is a linkage, n is from 19 to 29, and for each occurrence L.sup.2 is a UNA linker group having the formula --C.sup.1--C.sup.2--C.sup.3--, where R is attached to C.sup.2 and has the formula --OCH(CH.sub.2R.sup.3)R.sup.5, where R.sup.3 is --OR.sup.4, --SR.sup.4, --NR.sup.4.sub.2, --NH(C.dbd.O)R.sup.4, morpholino, morpholin-1-yl, piperazin-1-yl, or 4-alkanoyl-piperazin-1-yl, where R.sup.4 is the same or different for each occurrence and is H, alkyl, a cholesterol, a lipid molecule, a polyamine, an amino acid, or a polypeptide, and where R.sup.5 is a nucleobase, or L.sup.2(R) is a sugar such as a ribose and R is a nucleobase, or L.sup.2 is a modified sugar such as a modified ribose and R is a nucleobase. In certain embodiments, a nucleobase can be a modified nucleobase. L.sup.1 can be a phosphodiester linkage.

[0144] A UNA oligomer of this invention can be a short chain molecule. A UNA oligomer can be a duplex pair. Thus, a UNA oligomer can have a first strand of the duplex and a second strand of the duplex, which is complementary to the first strand with respect to the nucleobases, although up to three mismatches can occur. A UNA oligomer duplex can have overhangs.

[0145] Some UNA oligomers are discussed in U.S. Pat. No. 8,314,227, as well as US Patent Publication No. 20110313020 A1.

[0146] The target of a UNA oligomer can be a target nucleic acid. In some embodiments, the target can be any mRNA of a subject. A UNA oligomer can be active for gene silencing in RNA interference.

[0147] A UNA oligomer may comprise two strands that together provide a duplex. The duplex may be composed of a first strand, which may also be referred to as a passenger strand or sense strand, and a second strand, which may also be referred to as a guide strand or antisense strand.

[0148] In some aspects, a UNA oligomer of this invention can have any number of phosphorothioate intermonomer linkages in any position in any strand, or in both strands of a duplex structure.

[0149] In some embodiments, any one or more of the intermonomer linkages of a UNA oligomer can be a phosphodiester, a phosphorothioate including dithioates, a chiral phosphorothioate, and other chemically modified forms.

[0150] Examples of UNA oligomers of this invention include duplex pairs, which are in general complementary. Thus, for example, SEQ ID NO:1 can represent a first strand of a duplex and SEQ ID NO:2 can represent a second strand of the duplex, which is complementary to the first strand.

[0151] For example, the symbol "N" in the first strand can represent any nucleotide that is complementary to the monomer in the corresponding position in the second strand. Example UNA oligomers of this disclosure are shown with 2-monomer length overhangs, although overhangs of from 1 to 8 monomers, or longer, can be used.

[0152] The symbol "X" in a strand or oligomer represents a UNA monomer. When a UNA monomer appears in one strand of the oligomer, and is unpaired with the other strand, the monomer can have any base attached. When a UNA monomer appears in one strand of the oligomer, and is paired with a monomer in the other strand, the UNA monomer can have any base attached that would be complementary to the monomer in the corresponding paired position in the other strand.

[0153] Further, when the oligomer terminates in a UNA monomer, the terminal position has a 1-end, according to the positional numbering shown above, instead of a 5'-end as for a nucleotide, or the terminal position has a 3-end, according to the positional numbering shown above, instead of a 3'-end as for a nucleotide. For example, the UNA oligomer

TABLE-US-00001 SEQ ID NO: 1 1-XNNNNNNNNN-NNNNNNNNNN-XX-3 SEQ ID NO: 2 3-XXNNNNNNNNN-NNXXXXXXXN-5'

has a UNA monomer 1-end on the first strand, a UNA monomer 3-end on the first strand, a UNA monomer 3-end on the second strand, and a nucleotide 5'-end on the second strand.

[0154] Complementarity of strands can involve mismatches. In certain embodiments, complementarity of strands can include one to three, or more, mismatches.

[0155] In some embodiments, a UNA oligomer of this invention can have one or more UNA monomers at the 1-end of the first strand, and one or more UNA monomers at the 3-end of the first strand.

[0156] In further embodiments, a UNA oligomer of this invention can have one or more UNA monomers at the 3-end of the second strand.

[0157] In certain embodiments, a duplex UNA oligomer of this invention can have one or more UNA monomers at the 1-end of the first strand, one or more UNA monomers at the 3-end of the first strand, and one or more UNA monomers at the 3-end of the second strand.

[0158] A UNA oligomer of this invention the oligomer may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length.

[0159] In certain embodiments, a UNA oligomer of this invention may have a first strand that is 19-23 monomers in length.

[0160] In certain embodiments, a UNA oligomer of this invention may have a duplex region that is 19-21 monomers in length.

[0161] In further embodiments, a UNA oligomer of this invention may have a second strand that is 19-23 monomers in length.

[0162] In certain embodiments, a UNA oligomer of this invention may have a first strand that is 19 monomers in length, and a second strand that is 21 monomers in length.

[0163] In certain embodiments, a UNA oligomer of this invention may have a first strand that is 20 monomers in length, and a second strand that is 21 monomers in length.

[0164] In certain embodiments, a UNA oligomer of this invention may have a first strand that is 21 monomers in length, and a second strand that is 21 monomers in length.

[0165] In certain embodiments, a UNA oligomer of this invention may have a first strand that is 22 monomers in length, and a second strand that is 21 monomers in length.

[0166] A UNA oligomer of this invention for inhibiting gene expression can have a first strand and a second strand, each of the strands being 19-29 monomers in length. The monomers can be UNA monomers and nucleic acid nucleoside monomers. The oligomer can have a duplex structure of from 14 to 29 monomers in length. The UNA oligomer can be targeted to a target gene and can exhibit reduced off-target effects as compared to a conventional siRNA. In some embodiments, a UNA oligomer of this invention can have a first strand and a second strand, each of the strands being 19-23 monomers in length.

[0167] In another aspect, the UNA oligomer may have a blunt end, or may have one or more overhangs. In some embodiments, the first and second strands may be connected with a connecting oligomer in between the strands, and form a duplex region with a connecting loop at one end.

[0168] In certain embodiments, an overhang can be one or two monomers in length.

[0169] Examples of an overhang can contain one or more UNA monomers, natural nucleotides, non-natural nucleotides, modified nucleotides, or chemically-modified nucleotides, and combinations thereof.

[0170] Examples of an overhang can contain one or more deoxythymidine nucleotides, 2'-O-methyl nucleotides, inverted abasic monomers, inverted thymidine monomers, L-thymidine monomers, or glyceryl nucleotides.

[0171] A UNA oligomer can mediate cleavage of a target nucleic acid in a cell. In some processes, the second strand of the UNA oligomer, at least a portion of which can be complementary to the target nucleic acid, can act as a guide strand that can hybridize to the target nucleic acid.

[0172] The second strand can be incorporated into an RNA Induced Silencing Complex (RISC).

[0173] A UNA oligomer of this disclosure may comprise naturally-occurring nucleic acid nucleotides, and modifications thereof that are compatible with gene silencing activity.

[0174] In some aspects, a UNA oligomer is a double stranded construct molecule that is able to inhibit gene expression.

[0175] As used herein, the term strand refers to a single, contiguous chain of monomers, the chain having any number of internal monomers and two end monomers, where each end monomer is attached to one internal monomer on one side, and is not attached to a monomer on the other side, so that it ends the chain.

[0176] The monomers of a UNA oligomer may be attached via phosphodiester linkages, phosphorothioate linkages, gapped linkages, and other variations.

[0177] In some embodiments, a UNA oligomer can include mismatches in complementarity between the first and second strands. In other embodiments, a UNA oligomer may have 1, or 2, or 3 mismatches. The mismatches may occur at any position in the duplex region.

[0178] The target of a UNA oligomer can be a target nucleic acid of a target gene.

[0179] A UNA oligomer may have one or two overhangs outside the duplex region. The overhangs can be an unpaired portion at the end of the first strand or second strand. The lengths of the overhang portions of the first and second strands can be the same or different.

[0180] A UNA oligomer may have at least one blunt end. A blunt end does not have an overhang portion, and the duplex region at a blunt end terminates at the same position for both the first and second strands.

[0181] A UNA oligomer can be RISC length, which means that it has a duplex length of less than 25 base pairs.

[0182] In certain embodiments, a UNA oligomer can be a single strand that folds upon itself and hybridizes to itself to form a double stranded region having a connecting loop at the end of the double stranded region.

[0183] Examples of UNA oligomers containing five UNA monomers, and which contain one or more Q monomers are shown in Table 1.

TABLE-US-00002 TABLE 1 Oligomeric compounds containing five UNA monomers and additional Q monomers SEQ ID NO: OLIGOMER 3 X QNNQNNNQQQ-NQNQNQNQNX-X 4 X-XQNQNQNNNN-NQNQNQNQNQ 5 XQNNQNQNQNQ-NQNQNQNQNX-X 6 X-XQNQNQNQNQNQNQNQNQNQ 7 X-QNNQNQNNNN-NQNQNQNQNX-X 8 X-XQNQNQNQNN-NQNQNQNQNQ 9 XQNNQNQNNNN-NQNQNQNQNX-X 10 X-XQNQNQNNNN-NNNQNQNQNQ 11 XQNNQNQNNNN-NNNQNQNQNX-X 12 X-XQNQNQNNNN-NNNNNQNQNQ 13 XQNNQNQNNNN-NNNNNQNQNX-X 14 X-XQNQNQNNNN-NNNNNQNQNQ 15 XQNNQNQNNNN-NNNNNQNQNX-X 16 X-XQNQNQNNNN-NNNNNNNQNQ 17 XQNNQNNNNNN-NNNNNQNQNX-X 18 X-XQNQNQNNNN-NNNNNNNQNQ 19 X QNNQNNNNNN-NNNNNQNQNX-X 20 X-XQNQNNNNNN-NNNNNNNQNQ 21 XQNNNNNNNNN-NNNNNQNQNX-X 22 X-XQNQNNNNNN-NNNNNNNQNQ 23 X QNNNNNNNNN-NNNNNNNQNX-X 24 X-XQNQNNNNNN-NNNNNNNQNQ 25 X-QNNNNNNNNN-NNNNNNNQNX-X 26 X-XQNNNNNNNN-NNNNNNNQNQ 27 X-QNNNNNNNNN-NNNNNNNQNX-X 28 X-XQNNNNNNNN-NNNNNNNNNQ 29 XQNNNNNNNNN-NNNNNNNNNX-X 30 X-XQNNNNNNNN-NNNNNNNNNQ

[0184] Examples of UNA oligomers containing four UNA monomers and additional Q monomers are shown in Table 2.

TABLE-US-00003 TABLE 2 Oligomeric compounds containing four UNA monomers and additional Q monomers SEQ ID NO: OLIGOMER 31 X QNNQNQNQQQ-NQNQNQNQNX-Q 32 X-XQNQNQNNNN-NQNQNQNQNQ 33 X QNNQNQNQNQNQNQNQNQNX-Q 34 X-XQNQNQNQNQ-NQNQNQNQNQ 35 X-QNNQNQNNNN-NQNQNQNQNX-Q 36 X-XQNQNQNQNN-NQNQNQNQNQ 37 X-QNNQNQNNNN-NQNQNQNQNX-Q 38 X-XQNQNQNNNN-NNNQNQNQNQ 39 X QNNQNQNNNN-NNNQNQNQNX-Q 40 X-XQNQNQNNNN-NNNNNQNQNQ 41 XQNNQNQNNNN-NNNNNQNQNX-Q 42 X-XQNQNQNNNN-NNNNNQNQNQ 43 X QNNQNQNNNN-NNNNNQNQNX-Q 44 X-XQNQNQNNNN-NNNNNNNQNQ 45 X QNNQNNNNNN-NNNNNQNQNX-Q 46 X-XQNQNQNNNN-NNNNNNNQNQ 47 X QNNQNNNNNN-NNNNNQNQNX-Q 48 X-XQNQNNNNNN-NNNNNNNQNQ 49 X QNNNNNNNNN-NNNNNQNQNX-Q 50 X-XQNQNNNNNN-NNNNNNNQNQ 51 X QNNNNNNNNN-NNNNNNNQNX-Q 52 X-XQNQNNNNNN-NNNNNNNQNQ 53 XQNNNNNNNNN-NNNNNNNQNX-Q 54 X-XQNNNNNNNN-NNNNNNNQNQ 55 X QNNNNNNNNN-NNNNNNNQNX-Q 56 X-XQNNNNNNNN-NNNNNNNNNQ 57 X QNNNNNNNNN-NNNNNNNNNX-Q 58 X-XQNNNNNNNN-NNNNNNNNNQ

[0185] Examples of UNA oligomers containing four UNA Monomers and additional Q monomers are shown in Table 3.

TABLE-US-00004 TABLE 3 Oligomeric compounds containing four UNA monomers and additional Q monomers SEQ ID NO: OLIGOMER 59 XQNQNQNQQQ-NQNQNQNQNX-X 60 Q-XQNQNQNNNN-NQNQNQNQNQ 61 XQNQNQNQNQNQNQNQNQNX-X 62 Q-XQNQNQNQNQ-NQNQNQNQNQ 63 XQNQNQNNNN-NQNQNQNQNX-X 64 Q-XQNQNQNQNN-NQNQNQNQNQ 65 XQNQNQNNNN-NQNQNQNQNX-X 66 Q-XQNQNQNNNN-NNNQNQNQNQ 67 XQNQNQNNNN-NNNQNQNQNX-X 68 Q-XQNQNQNNNN-NNNNNQNQNQ 69 XQNQNQNNNN-NNNNNQNQNX-X 70 Q-XQNQNQNNNN-NNNNNQNQNQ 71 XQNQNQNNNN-NNNNNQNQNX-X 72 Q-XQNQNQNNNN-NNNNNNNQNQ 73 XQNQNNNNNN-NNNNNQNQNX-X 74 Q-XQNQNQNNNN-NNNNNNNQNQ 75 XQNQNNNNNN-NNNNNQNQNX-X 76 Q-XQNQNNNNNN-NNNNNNNQNQ 77 XQNNNNNNNN-NNNNNQNQNX-X 78 Q-XQNQNNNNNN-NNNNNNNQNQ 79 XQNNNNNNNN-NNNNNNNQNX-X 80 Q-XQNQNNNNNN-NNNNNNNQNQ 81 XQNNNNNNNN-NNNNNNNQNX-X 82 Q-XQNNNNNNNN-NNNNNNNQNQ 83 XQNNNNNNNN-NNNNNNNQNX-X 84 Q-XQNNNNNNNN-NNNNNNNNNQ 85 XQNNNNNNNN-NNNNNNNNNX-X 86 Q-XQNNNNNNNN-NNNNNNNNNQ

[0186] Examples of UNA oligomers containing three UNA monomers and additional Q monomers are shown in Table 4.

TABLE-US-00005 TABLE 4 Oligomeric compounds containing three UNA monomers and additional Q monomers SEQ ID NO: OLIGOMER 87 XQNQNQNQQQ-NQNQNQNQNX-Q 88 Q-XQNQNQNNNN-NQNQNQNQNQ 89 XQNQNQNQNQNQNQNQNQNX-Q 90 Q-XQNQNQNQNQ-NQNQNQNQNQ 91 XQNQNQNNNN-NQNQNQNQNX-Q 92 Q-XQNQNQNQNN-NQNQNQNQNQ 93 XQNQNQNNNN-NQNQNQNQNX-Q 94 Q-XQNQNQNNNN-NNNQNQNQNQ 95 XQNQNQNNNN-NNNQNQNQNX-Q 96 Q-XQNQNQNNNN-NNNNNQNQNQ 97 XQNQNQNNNN-NNNNNQNQNX-Q 98 Q-XQNQNQNNNN-NNNNNQNQNQ 99 XQNQNQNNNN-NNNNNQNQNX-Q 100 Q-XQNQNQNNNN-NNNNNNNQNQ 101 XQNQNNNNNN-NNNNNQNQNX-Q 102 Q-XQNQNQNNNN-NNNNNNNQNQ 103 XQNQNNNNNN-NNNNNQNQNX-Q 104 Q-XQNQNNNNNN-NNNNNNNQNQ 105 XQNNNNNNNN-NNNNNQNQNX-Q 106 Q-XQNQNNNNNN-NNNNNNNQNQ 107 XQNNNNNNNN-NNNNNNNQNX-Q 108 Q-XQNQNNNNNN-NNNNNNNQNQ 109 XQNNNNNNNN-NNNNNNNQNX-Q 110 Q-XQNNNNNNNN-NNNNNNNQNQ 111 XQNNNNNNNN-NNNNNNNQNX-Q 112 Q-XQNNNNNNNN-NNNNNNNNNQ 113 XQNNNNNNNN-NNNNNNNNNX-Q 114 Q-XQNNNNNNNN-NNNNNNNNNQ

[0187] Examples of UNA oligomers containing six UNA Monomers and additional Q monomers are shown in Table 5.

TABLE-US-00006 TABLE 5 Oligomeric compounds containing six UNA monomers and additional Q monomers SEQ ID NO: OLIGOMER 115 XQNQNQNQQQ-NQNQNQNQNX-X 116 X-XQNQNQNNNN-NQNQNQNQXQ 117 XQNQNQNQQQNQNQNQNQNX-X 118 X-XQNQNQNNNN-NQNQNQNXNQ 119 XQNQNQNQQQ-NQNQNQNQNX-X 120 X-XQNQNQNNNN-NQNQNQXQNQ 121 XQNQNQNQQQ-NQNQNQNQNX-X 122 X-XQNQNQNNNN-NQNQNXNQNQ 123 XQNQNQNQQQNQNQNQNQNX-X 124 X-XQNQNQNNNN-NQNQXQNQNQ 125 XQNQNQNQQQ-NQNQNQNQNX-X 126 X-XQNQNQNNNN-NQNXNQNQNQ 127 XQNQNQNQQQ-NQNQNQNQNX-X 128 X-XQNQNQNNNN-NQXQNQNQNQ

[0188] Examples of UNA oligomers containing seven UNA monomers and additional Q monomers are shown in Table 6.

TABLE-US-00007 TABLE 6 Oligomeric compounds containing seven UNA monomers and additional Q monomers SEQ ID NO: OLIGOMER 129 XQNQNQNQQQ-NQNQNQNQNX-X 130 X-XQNQNQNNNN-NQNQNQNXXQ 131 XQNQNQNQQQ-NQNQNQNQNX-X 132 X-XQNQNQNNNN-NQNQNQXQXQ 133 XQNQNQNQQQ-NQNQNQNQNX-X 134 X-XQNQNQNNNN-NQNQNXNQXQ 135 XQNQNQNQQQ-NQNQNQNQNX-X 136 X-XQNQNQNNNN-NQNQXQNXNQ 137 XQNQNQNQQQ-NQNQNQNQNX-X 138 X-XQNQNQNNNN-NQNQNXXQNQ 139 XQNQNQNQQQNQNQNQNQNX-X 140 X-XQNQNQNNNN-NQNXNQXQNQ 141 XQNQNQNQQQ-NQNQNQNQNX-X 142 X-XQNQNQNNNN-NQNQXXNQNQ

[0189] Examples of UNA oligomers containing five UNA monomers and additional Q monomers are shown in Table 7.

TABLE-US-00008 TABLE 7 Oligomeric compounds containing five UNA monomers and additional Q monomers SEQ ID NO: OLIGOMER 143 XQNQNQNQQQ-NQNQNQNQNX-Q 144 X-XQNQNQNNNN-NQNQNQNQXQ 145 XQNQNQNQQQ-NQNQNQNQNX-Q 146 X-XQNQNQNNNN-NQNQNQNXNQ 147 XQNQNQNQQQ-NQNQNQNQNX-Q 148 X-XQNQNQNNNN-NQNQNQXQNQ 149 XQNQNQNQQQ-NQNQNQNQNX-Q 150 X-XQNQNQNNNN-NQNQNXNQNQ 151 XQNQNQNQQQ-NQNQNQNQNX-Q 152 X-XQNQNQNNNN-NQNQXQNQNQ 153 XQNQNQNQQQNQNQNQNQNX-Q 154 X-XQNQNQNNNN-NQNXNQNQNQ 155 XQNQNQNQQQ-NQNQNQNQNX-Q 156 X-XQNQNQNNNN-NQXQNQNQNQ

[0190] Examples of UNA oligomers containing six UNA monomers and additional Q monomers are shown in Table 8.

TABLE-US-00009 TABLE 8 Oligomeric compounds containing six UNA monomers and additional Q monomers SEQ ID NO: OLIGOMER 157 XQNQNQNQQQ-NQNQNQNQNX-Q 158 X-XQNQNQNNNN-NQNQNQNXXQ 159 XQNQNQNQQQ-NQNQNQNQNX-Q 160 X-XQNQNQNNNN-NQNQNQXQXQ 161 XQNQNQNQQQ-NQNQNQNQNX-Q 162 X-XQNQNQNNNN-NQNQNXNQXQ 163 XQNQNQNQQQ-NQNQNQNQNX-Q 164 X-XQNQNQNNNN-NQNQXQNXNQ 165 XQNQNQNQQQ-NQNQNQNQNX-Q 166 X-XQNQNQNNNN-NQNQNXXQNQ 167 XQNQNQNQQQNQNQNQNQNX-Q 168 X-XQNQNQNNNN-NQNXNQXQNQ 169 XQNQNQNQQQ-NQNQNQNQNX-Q 170 X-XQNQNQNNNN-NQNQXXNQNQ

[0191] Examples of UNA oligomers containing five UNA monomers and additional Q monomers are shown in Table 9.

TABLE-US-00010 TABLE 9 Oligomeric compounds containing five UNA monomers and additional Q monomers SEQ ID NO: OLIGOMER 171 XQNQNQNQQQ-NQNQNQNQNX-X 172 Q-XQNQNQNNNN-NQNQNQNQXQ 173 XQNQNQNQQQ-NQNQNQNQNX-X 174 Q-XQNQNQNNNN-NQNQNQNXNQ 175 XQNQNQNQQQ-NQNQNQNQNX-X 176 Q-XQNQNQNNNN-NQNQNQXQNQ 177 XQNQNQNQQQ-NQNQNQNQNX-X 178 Q-XQ NQNQNNNN-NQNQNXNQNQ 179 XQNQNQNQQQ-NQNQNQNQNX-X 180 Q-XQNQNQNNNN-NQNQXQNQNQ 181 XQNQNQNQQQNQNQNQNQNX-X 182 Q-XQNQNQNNNN-NQNXNQNQNQ 183 XQNQNQNQQQ-NQNQNQNQNX-X 184 Q-XQNQNQNNNN-NQXQNQNQNQ

[0192] Examples of UNA oligomers containing six UNA monomers and additional Q monomers are shown in Table 10.

TABLE-US-00011 TABLE 10 Oligomeric compounds containing six UNA monomers and additional Q monomers SEQ ID NO: OLIGOMER 185 XQNQNQNQQQ-NQNQNQNQNX-X 186 Q-XQNQNQNNNN-NQNQNQNXXQ 187 XQNQNQNQQQNQNQNQNQNX-X 188 Q-XQNQNQNNNN-NQNQNQXQXQ 189 XQNQNQNQQQ-NQNQNQNQNX-X 190 Q-XQNQNQNNNN-NQNQNXNQXQ 191 XQNQNQNQQQ-NQNQNQNQNX-X 192 Q-XQNQNQNNNN-NQNQXQNXNQ 193 XQNQNQNQQQNQNQNQNQNX-X 194 Q-XQNQNQNNNN-NQNQNXXQNQ 195 XQNQNQNQQQ-NQNQNQNQNX-X 196 Q-XQNQNQNNNN-NQNXNQXQNQ 197 XQNQNQNQQQ-NQNQNQNQNX-X 198 Q-XQNQNQNNNN-NQNQXXNQNQ

[0193] Examples of UNA oligomers containing four UNA monomers and additional Q monomers are shown in Table 11.

TABLE-US-00012 TABLE 11 Oligomeric compounds containing four UNA monomers and additional Q monomers SEQ ID NO: OLIGOMER 199 XQNQNQNQQQ-NQNQNQNQNX-Q 200 Q-XQNQNQNNNN-NQNQNQNQXQ 201 XQNQNQNQQQ-NQNQNQNQNX-Q 202 Q-XQNQNQNNNN-NQNQNQNXNQ 203 XQNQNQNQQQ-NQNQNQNQNX-Q 204 Q-XQNQNQNNNN-NQNQNQXQNQ 205 XQNQNQNQQQ-NQNQNQNQNX-Q 206 Q-XQNQNQNNNN-NQNQNXNQNQ 207 XQNQNQNQQQ-NQNQNQNQNX-Q 208 Q-XQNQNQNNNN-NQNQXQNQNQ 209 XQNQNQNQQQNQNQNQNQNX-Q 210 Q-XQNQNQNNNN-NQNXNQNQNQ 211 XQNQNQNQQQ-NQNQNQNQNX-Q 212 Q-XQNQNQNNNN-NQXQNQNQNQ

[0194] Examples of UNA oligomers containing five UNA monomers and additional Q monomers are shown in Table 12.

TABLE-US-00013 TABLE 12 Oligomeric compounds containing five UNA monomers and additional Q monomers SEQ ID NO: OLIGOMER 213 XQNQNQNQQQ-NQNQNQNQNX-Q 214 Q-XQNQNQNNNN-NQNQNQNXXQ 215 XQNQNQNQQQ-NQNQNQNQNX-Q 216 Q-XQNQNQNNNN-NQNQNQXQXQ 217 XQNQNQNQQQ-NQNQNQNQNX-Q 218 Q-XQNQNQNNNN-NQNQNXNQXQ 219 XQNQNQNQQQ-NQNQNQNQNX-Q 220 Q-XQNQNQNNNN-NQNQXQNXNQ 221 XQNQNQNQQQ-NQNQNQNQNX-Q 222 Q-XQNQNQNNNN-NQNQNXXQNQ 223 XQNQNQNQQQNQNQNQNQNX-Q 224 Q-XQNQNQNNNN-NQNXNQXQNQ 225 XQNQNQNQQQ-NQNQNQNQNX-Q 226 Q-XQNQNQNNNN-NQNQXXNQNQ

[0195] Examples of UNA oligomers containing seven or more UNA monomers and additional Q monomers are shown in Table 13.

TABLE-US-00014 TABLE 13 Oligomeric compounds containing seven or more UNA monomers and additional Q monomers SEQ ID NO: OLIGOMER 227 XQNQNQNQQQ-NQNQNQNQNX-X 228 X-XQNQNQNNNN-NQNQXQXQXQ 229 XQNQNQNQQQ-NQNQNQNQNX-Q 230 X-XQNQNQNNNN-NQNQNQXXXQ 231 XQNQNQNQQQ-NQNQNQNQNX-X 232 Q-XQNQNQNNNN-NQNXXXNQNQ 233 XQNQNQNQQQ-NQNQNQNQNX-Q 234 Q-XQNQNQNNNN-NQNXXXXXXQ 235 XQNQNQNQQQ-NQNQNQNQNX-X 236 X-XQNQNQNNNN-NQNXXXXXXQ

[0196] An oligomeric compound of this invention may have any one of the structures shown in Tables 1 to 13.

[0197] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a Q monomer.

[0198] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a Q monomer, and where the number of Q monomers is less than twenty.

[0199] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a Q monomer, and where the number of Q monomers is less than twelve.

[0200] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a Q monomer, and where the number of Q monomers is less than ten.

[0201] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a Q monomer, and where the number of Q monomers is less than eight.

[0202] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a Q monomer, and where the number of Q monomers is from 1 to 20.

[0203] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a Q monomer, and where the number of Q monomers is from 1 to 15.

[0204] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a Q monomer, and where the number of Q monomers is from 1 to 9.

[0205] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a 2'-O-Methyl modified ribonucleotide.

[0206] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a 2'-O-Methyl modified ribonucleotide, and where the number of 2'-O-Methyl modified ribonucleotides is less than twenty.

[0207] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a 2'-O-Methyl modified ribonucleotide, and where the number of 2'-O-Methyl modified ribonucleotides is less than twelve.

[0208] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a 2'-O-Methyl modified ribonucleotide, and where the number of 2'-O-Methyl modified ribonucleotides is less than ten.

[0209] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a 2'-O-Methyl modified ribonucleotide, and where the number of 2'-O-Methyl modified ribonucleotides is less than eight.

[0210] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a 2'-O-Methyl modified ribonucleotide, and where the number of 2'-O-Methyl modified ribonucleotides is from 1 to 20.

[0211] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a 2'-O-Methyl modified ribonucleotide, and where the number of 2'-O-Methyl modified ribonucleotides is from 1 to 15.

[0212] In some embodiments, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a 2'-O-Methyl modified ribonucleotide, and where the number of 2'-O-Methyl modified ribonucleotides is from 1 to 9.

[0213] In further aspects, an oligomeric compound of this invention may have a first strand and a second strand, each of the strands independently being 19-23 monomers in length, where any monomer that is not a UNA monomer can be a Q monomer, and where the oligomeric compound does not contain fluorine.

[0214] Embodiments of this invention advantageously provide oligomeric compounds, which are active agents against HBV and do not contain fluorine.

[0215] Methods of this invention include the treatment and/or prevention of HBV disease in a subject. A subject can be a mammalian subject, including a human subject.

HBV Component Target Sequences

[0216] As used herein, "Ref Pos" refers to reference position, which is the numerical position of a reference nucleotide in an HBV genome. The reference position is the position that corresponds target-wise to the 5' end of the sense strand of the oligomeric compound of this invention. The reference positions are numerical nucleotide positions based on a reference genome, which as used herein is HBV Genotype A2, Accession No. HE974376. Thus, a reference position number by itself refers to one sequence from the reference genome, and each sequence can be used in an oligomeric compound of this invention. Table 14 shows genomic positions for the HBV reference genome.

TABLE-US-00015 TABLE 14 HBV genomic positions Start End Gene 1 835 S 1 1623 Pol 1374 1838 X 1901 2458 C 2307 3221 Pol 2854 3221 S

[0217] In FIG. 1 is shown a map of HBV protein coding regions and selected transcripts for the reference genome HE974376. Nucleotide position 1/3221 is designated at the top. Further designations are as follows: pre-S1, large HBsAg; pre-S2, medium HBsAg; S, HBsAg; P, polymerase; X, HBx protein; pre-C, pre-core/HBeAg; C, HB core Ag. The 2.4 kb, 2.1 kb, and 0.7 kb transcripts coding for the pre-S1/pre-S2/S, as well as the transcript coding the X protein are shown. The pre-Core/HBeAg protein is generated from a long, 3.5 kb transcript (not shown) originating at position .about.1700, while the core and polymerase proteins and the pre-genomic RNA used as a template for viral replication are generated from a .about.200 nt shorter transcript.

[0218] The ranges of reference positions for certain UNA oligomers, designated UNA oligomer 1, UNA oligomer 2, and UNA oligomer 3, are shown in FIG. 1.

[0219] In some aspects, the inventive oligomers of this disclosure may target the long transcript coding for HBV core and polymerase proteins.

[0220] UNA Oligomers Targeting HBV

[0221] Examples of base sequences of this invention targeted to an HBV component are shown in Table 15.

[0222] An oligomeric compound of this invention can be formed having a first strand and a second strand each being 21 monomers in length. The first strand can have 19 contiguous monomers with a sequence of attached bases shown in Table 15 (sense), and two additional overhang monomers on the 3' end. The second strand can have 19 contiguous monomers with a sequence of attached bases shown in Table 15 (antisense), and two additional overhang monomers on the 3' end. The overhang monomers can be any of NN, QQ, XX, NX, NQ, XN, XQ, QN, and QX. For example, XQ can be UNA-U/mU, or UNA-U/*/dT.

[0223] An oligomeric compound of this invention can be composed of monomers. The monomers can have attached bases. An oligomeric compound of this invention can have a sequence of attached bases. The sequences of bases shown in Table 15 do not indicate to which monomer each of the bases in the sequence is attached. Thus, each sequence shown in Table 15 refers to a large number of small molecules, each of which is composed of UNA monomers, as well as nucleic acid monomers.

[0224] In some aspects, an oligomeric compound of this invention can be described by a sequence of attached bases, for example as shown in Table 15, and being substituted forms thereof. As used herein, substituted forms include differently substituted UNA monomers, as well as differently substituted or modified nucleic acid monomers, as are further described herein.

[0225] In some embodiments, one or more of three monomers at each end of each strand can be connected by a phosphorothioate, a chiral phosphorothioate, or a phosphorodithioate linkage.

[0226] For example, a compound may have one phosphorothioate linkage between two monomers at the 5' end of the first strand, one phosphorothioate linkage between two monomers at the 3' end of the first strand, one phosphorothioate linkage between monomers at the second and third positions from the 3' end of the first strand, and one phosphorothioate linkage between two monomers at the 3' end of the second strand.

[0227] In certain embodiments, a compound may have two or three phosphorothioate linkages at the 5' end of the first strand, two or three phosphorothioate linkages at the 3' end of the first strand, and one phosphorothioate linkage at the 3' end of the second strand.

[0228] In additional embodiments, a compound may have one to three phosphorothioate linkages at the 5' end of the first strand, two or three phosphorothioate linkages at the 3' end of the first strand, two phosphorothioate linkages at the 5' end of the second strand, and two phosphorothioate linkages at the 3' end of the second strand.

[0229] In some examples, a compound may have a deoxythymidine nucleotide at the 3' end of the first strand, at the 3' end of the second strand, or at both the 3' end of the first strand and the 3' end of the second strand.

[0230] In some aspects, a compound may contain one to five UNA monomers.

[0231] In certain aspects, a compound may contain three UNA monomers.

[0232] In some embodiments, a compound may contain a UNA monomer at the 1-end of the first strand (5' end), a UNA monomer at the 3-end of the first strand (3' end), and a UNA monomer at the second position from the 3' end of the second strand.

[0233] In certain embodiments, a compound may contain a UNA monomer at any one or more of positions 2 to 8 from the 5' end of the second strand (seed region).

TABLE-US-00016 TABLE 15 HBV sense and antisense sequences SEQ REF SEQ Sense (5'-3') ID Antisense (5'-3') POS ID NO SEQ ID NOS: 237 to 548 NO SEQ ID NOS: 549 to 860 1525 237 CGCACCUCUCUUUACGCGG 549 CCGCGUAAAGAGAGGUGCG 251 238 GACUCGUGGUGGACUUCUC 550 GAGAAGUCCACCACGAGUC 254 239 UCGUGGUGGACUUCUCUCA 551 UGAGAGAAGUCCACCACGA 374 240 UGGAUGUGUCUGCGGCGUU 552 AACGCCGCAGACACAUCCA 1575 241 CCGUGUGCACUUCGCUUCA 553 UGAAGCGAAGUGCACACGG 1577 242 GUGUGCACUUCGCUUCACC 554 GGUGAAGCGAAGUGCACAC 1578 243 UGUGCACUUCGCUUCACCU 555 AGGUGAAGCGAAGUGCACA 1579 244 GUGCACUUCGCUUCACCUC 556 GAGGUGAAGCGAAGUGCAC 1581 245 GCACUUCGCUUCACCUCUG 557 CAGAGGUGAAGCGAAGUGC 1863 246 UUCAAGCCUCCAAGCUGUG 558 CACAGCUUGGAGGCUUGAA 1864 247 UCAAGCCUCCAAGCUGUGC 559 GCACAGCUUGGAGGCUUGA 1865 248 CAAGCCUCCAAGCUGUGCC 560 GGCACAGCUUGGAGGCUUG 1866 249 AAGCCUCCAAGCUGUGCCU 561 AGGCACAGCUUGGAGGCUU 247 250 UCUAGACUCGUGGUGGACU 562 AGUCCACCACGAGUCUAGA 248 251 CUAGACUCGUGGUGGACUU 563 AAGUCCACCACGAGUCUAG 249 252 UAGACUCGUGGUGGACUUC 564 GAAGUCCACCACGAGUCUA 250 253 AGACUCGUGGUGGACUUCU 565 AGAAGUCCACCACGAGUCU 376 254 GAUGUGUCUGCGGCGUUUU 566 AAAACGCCGCAGACACAUC 378 255 UGUGUCUGCGGCGUUUUAU 567 AUAAAACGCCGCAGACACA 380 256 UGUCUGCGGCGUUUUAUCA 568 UGAUAAAACGCCGCAGACA 1776 257 GGAGGCUGUAGGCAUAAAU 569 AUUUAUGCCUACAGCCUCC 1777 258 GAGGCUGUAGGCAUAAAUU 570 AAUUUAUGCCUACAGCCUC 1779 259 GGCUGUAGGCAUAAAUUGG 571 CCAAUUUAUGCCUACAGCC 1780 260 GCUGUAGGCAUAAAUUGGU 572 ACCAAUUUAUGCCUACAGC 1818 261 AACUUUUUCACCUCUGCCU 573 AGGCAGAGGUGAAAAAGUU 244 262 GAGUCUAGACUCGUGGUGG 574 CCACCACGAGUCUAGACUC 245 263 AGUCUAGACUCGUGGUGGA 575 UCCACCACGAGUCUAGACU 246 264 GUCUAGACUCGUGGUGGAC 576 GUCCACCACGAGUCUAGAC 409 265 CAUCCUGCUGCUAUGCCUC 577 GAGGCAUAGCAGCAGGAUG 411 266 UCCUGCUGCUAUGCCUCAU 578 AUGAGGCAUAGCAGCAGGA 412 267 CCUGCUGCUAUGCCUCAUC 579 GAUGAGGCAUAGCAGCAGG 413 268 CUGCUGCUAUGCCUCAUCU 580 AGAUGAGGCAUAGCAGCAG 414 269 UGCUGCUAUGCCUCAUCUU 581 AAGAUGAGGCAUAGCAGCA 1781 270 CUGUAGGCAUAAAUUGGUC 582 GACCAAUUUAUGCCUACAG 1782 271 UGUAGGCAUAAAUUGGUCU 583 AGACCAAUUUAUGCCUACA 252 272 ACUCGUGGUGGACUUCUCU 584 AGAGAAGUCCACCACGAGU 253 273 CUCGUGGUGGACUUCUCUC 585 GAGAGAAGUCCACCACGAG 1576 274 CGUGUGCACUUCGCUUCAC 586 GUGAAGCGAAGUGCACACG 1580 275 UGCACUUCGCUUCACCUCU 587 AGAGGUGAAGCGAAGUGCA 1582 276 CACUUCGCUUCACCUCUGC 588 GCAGAGGUGAAGCGAAGUG 1583 277 ACUUCGCUUCACCUCUGCA 589 UGCAGAGGUGAAGCGAAGU 1867 278 AGCCUCCAAGCUGUGCCUU 590 AAGGCACAGCUUGGAGGCU 1868 279 GCCUCCAAGCUGUGCCUUG 591 CAAGGCACAGCUUGGAGGC 2382 280 GAACUCCCUCGCCUCGCAG 592 CUGCGAGGCGAGGGAGUUC 2383 281 AACUCCCUCGCCUCGCAGA 593 UCUGCGAGGCGAGGGAGUU 2384 282 ACUCCCUCGCCUCGCAGAC 594 GUCUGCGAGGCGAGGGAGU 2385 283 CUCCCUCGCCUCGCAGACG 595 CGUCUGCGAGGCGAGGGAG 56 284 CCUGCUGGUGGCUCCAGUU 596 AACUGGAGCCACCAGCAGG 57 285 CUGCUGGUGGCUCCAGUUC 597 GAACUGGAGCCACCAGCAG 375 286 GGAUGUGUCUGCGGCGUUU 598 AAACGCCGCAGACACAUCC 377 287 AUGUGUCUGCGGCGUUUUA 599 UAAAACGCCGCAGACACAU 379 288 GUGUCUGCGGCGUUUUAUC 600 GAUAAAACGCCGCAGACAC 381 289 GUCUGCGGCGUUUUAUCAU 601 AUGAUAAAACGCCGCAGAC 637 290 CCUAUGGGAGUGGGCCUCA 602 UGAGGCCCACUCCCAUAGG 638 291 CUAUGGGAGUGGGCCUCAG 603 CUGAGGCCCACUCCCAUAG 1584 292 CUUCGCUUCACCUCUGCAC 604 GUGCAGAGGUGAAGCGAAG 1585 293 UUCGCUUCACCUCUGCACG 605 CGUGCAGAGGUGAAGCGAA 1586 294 UCGCUUCACCUCUGCACGU 606 ACGUGCAGAGGUGAAGCGA 1778 295 AGGCUGUAGGCAUAAAUUG 607 CAAUUUAUGCCUACAGCCU 1819 296 ACUUUUUCACCUCUGCCUA 608 UAGGCAGAGGUGAAAAAGU 410 297 AUCCUGCUGCUAUGCCUCA 609 UGAGGCAUAGCAGCAGGAU 415 298 GCUGCUAUGCCUCAUCUUC 610 GAAGAUGAGGCAUAGCAGC 416 299 CUGCUAUGCCUCAUCUUCU 611 AGAAGAUGAGGCAUAGCAG 417 300 UGCUAUGCCUCAUCUUCUU 612 AAGAAGAUGAGGCAUAGCA 1783 301 GUAGGCAUAAAUUGGUCUG 613 CAGACCAAUUUAUGCCUAC 1869 302 CCUCCAAGCUGUGCCUUGG 614 CCAAGGCACAGCUUGGAGG 255 303 CGUGGUGGACUUCUCUCAA 615 UUGAGAGAAGUCCACCACG 256 304 GUGGUGGACUUCUCUCAAU 616 AUUGAGAGAAGUCCACCAC 257 305 UGGUGGACUUCUCUCAAUU 617 AAUUGAGAGAAGUCCACCA 258 306 GGUGGACUUCUCUCAAUUU 618 AAAUUGAGAGAAGUCCACC 259 307 GUGGACUUCUCUCAAUUUU 619 AAAAUUGAGAGAAGUCCAC 260 308 UGGACUUCUCUCAAUUUUC 620 GAAAAUUGAGAGAAGUCCA 262 309 GACUUCUCUCAAUUUUCUA 621 UAGAAAAUUGAGAGAAGUC 263 310 ACUUCUCUCAAUUUUCUAG 622 CUAGAAAAUUGAGAGAAGU 264 311 CUUCUCUCAAUUUUCUAGG 623 CCUAGAAAAUUGAGAGAAG 265 312 UUCUCUCAAUUUUCUAGGG 624 ccCUAGAAAAUUGAGAGAA 266 313 UCUCUCAAUUUUCUAGGGG 625 ccCCUAGAAAAUUGAGAGA 1264 314 AUCCAUACUGCGGAACUCC 626 GGAGUUCCGCAGUAUGGAU 1265 315 UCCAUACUGCGGAACUCCU 627 AGGAGUUCCGCAGUAUGGA 2376 316 GAAGAAGAACUCCCUCGCC 628 GGCGAGGGAGUUCUUCUUC 2377 317 AAGAAGAACUCCCUCGCCU 629 AGGCGAGGGAGUUCUUCUU 2378 318 AGAAGAACUCCCUCGCCUC 630 GAGGCGAGGGAGUUCUUCU 2379 319 GAAGAACUCCCUCGCCUCG 631 CGAGGCGAGGGAGUUCUUC 2380 320 AAGAACUCCCUCGCCUCGC 632 GCGAGGCGAGGGAGUUCUU 2381 321 AGAACUCCCUCGCCUCGCA 633 UGCGAGGCGAGGGAGUUCU 243 322 AGAGUCUAGACUCGUGGUG 634 CACCACGAGUCUAGACUCU 261 323 GGACUUCUCUCAAUUUUCU 635 AGAAAAUUGAGAGAAGUCC 1263 324 GAUCCAUACUGCGGAACUC 636 GAGUUCCGCAGUAUGGAUC 1815 325 UGCAACUUUUUCACCUCUG 637 CAGAGGUGAAAAAGUUGCA 1816 326 GCAACUUUUUCACCUCUGC 638 GCAGAGGUGAAAAAGUUGC 1817 327 CAACUUUUUCACCUCUGCC 639 GGCAGAGGUGAAAAAGUUG 301 328 UGGCCAAAAUUCGCAGUCC 640 GGACUGCGAAUUUUGGCCA 302 329 GGCCAAAAUUCGCAGUCCC 641 GGGACUGCGAAUUUUGGCC 1261 330 CCGAUCCAUACUGCGGAAC 642 GUUCCGCAGUAUGGAUCGG 1262 331 CGAUCCAUACUGCGGAACU 643 AGUUCCGCAGUAUGGAUCG 1820 332 CUUUUUCACCUCUGCCUAA 644 UUAGGCAGAGGUGAAAAAG 1821 333 UUUUUCACCUCUGCCUAAU 645 AUUAGGCAGAGGUGAAAAA 1822 334 UUUUCACCUCUGCCUAAUC 646 GAUUAGGCAGAGGUGAAAA 1823 335 UUUCACCUCUGCCUAAUCA 647 UGAUUAGGCAGAGGUGAAA 1874 336 AAGCUGUGCCUUGGGUGGC 648 GCCACCCAAGGCACAGCUU 1875 337 AGCUGUGCCUUGGGUGGCU 649 AGCCACCCAAGGCACAGCU 1876 338 GCUGUGCCUUGGGUGGCUU 650 AAGCCACCCAAGGCACAGC 1877 339 CUGUGCCUUGGGUGGCUUU 651 AAAGCCACCCAAGGCACAG 2267 340 GGAGUGUGGAUUCGCACUC 652 GAGUGCGAAUCCACACUCC 2268 341 GAGUGUGGAUUCGCACUCC 653 GGAGUGCGAAUCCACACUC 242 342 CAGAGUCUAGACUCGUGGU 654 ACCACGAGUCUAGACUCUG 1654 343 AUAAGAGGACUCUUGGACU 655 AGUCCAAGAGUCCUCUUAU 1774 344 UAGGAGGCUGUAGGCAUAA 656 UUAUGCCUACAGCCUCCUA 1775 345 AGGAGGCUGUAGGCAUAAA 657 UUUAUGCCUACAGCCUCCU 1813 346 CAUGCAACUUUUUCACCUC 658 GAGGUGAAAAAGUUGCAUG 1814 347 AUGCAACUUUUUCACCUCU 659 AGAGGUGAAAAAGUUGCAU 1824 348 UUCACCUCUGCCUAAUCAU 660 AUGAUUAGGCAGAGGUGAA 1825 349 UCACCUCUGCCUAAUCAUC 661 GAUGAUUAGGCAGAGGUGA 1826 350 CACCUCUGCCUAAUCAUCU 662 AGAUGAUUAGGCAGAGGUG 1870 351 CUCCAAGCUGUGCCUUGGG 663 CCCAAGGCACAGCUUGGAG 1871 352 UCCAAGCUGUGCCUUGGGU 664 ACCCAAGGCACAGCUUGGA 1872 353 CCAAGCUGUGCCUUGGGUG 665 CACCCAAGGCACAGCUUGG 1873 354 CAAGCUGUGCCUUGGGUGG 666 CCACCCAAGGCACAGCUUG 2373 355 CUAGAAGAAGAACUCCCUC 667 GAGGGAGUUCUUCUUCUAG 2374 356 UAGAAGAAGAACUCCCUCG 668 CGAGGGAGUUCUUCUUCUA 2375 357 AGAAGAAGAACUCCCUCGC 669 GCGAGGGAGUUCUUCUUCU 1862 358 GUUCAAGCCUCCAAGCUGU 670 ACAGCUUGGAGGCUUGAAC

2297 359 AGACCACCAAAUGCCCCUA 671 UAGGGGCAUUUGGUGGUCU 2298 360 GACCACCAAAUGCCCCUAU 672 AUAGGGGCAUUUGGUGGUC 2299 361 ACCACCAAAUGCCCCUAUC 673 GAUAGGGGCAUUUGGUGGU 599 362 UGUAUUCCCAUCCCAUCAU 674 AUGAUGGGAUGGGAAUACA 600 363 GUAUUCCCAUCCCAUCAUC 675 GAUGAUGGGAUGGGAAUAC 703 364 CGUAGGGCUUUCCCCCACU 676 AGUGGGGGAAAGCCCUACG 704 365 GUAGGGCUUUCCCCCACUG 677 CAGUGGGGGAAAGCCCUAC 705 366 UAGGGCUUUCCCCCACUGU 678 ACAGUGGGGGAAAGCCCUA 1259 367 UGCCGAUCCAUACUGCGGA 679 UCCGCAGUAUGGAUCGGCA 1260 368 GCCGAUCCAUACUGCGGAA 680 UUCCGCAGUAUGGAUCGGC 1518 369 CACGGGGCGCACCUCUCUU 681 AAGAGAGGUGCGCCCCGUG 1519 370 ACGGGGCGCACCUCUCUUU 682 AAAGAGAGGUGCGCCCCGU 1520 371 CGGGGCGCACCUCUCUUUA 683 UAAAGAGAGGUGCGCCCCG 1521 372 GGGGCGCACCUCUCUUUAC 684 GUAAAGAGAGGUGCGCCCC 1522 373 GGGCGCACCUCUCUUUACG 685 CGUAAAGAGAGGUGCGCCC 1523 374 GGCGCACCUCUCUUUACGC 686 GCGUAAAGAGAGGUGCGCC 1524 375 GCGCACCUCUCUUUACGCG 687 CGCGUAAAGAGAGGUGCGC 1859 376 ACUGUUCAAGCCUCCAAGC 688 GCUUGGAGGCUUGAACAGU 1860 377 CUGUUCAAGCCUCCAAGCU 689 AGCUUGGAGGCUUGAACAG 1861 378 UGUUCAAGCCUCCAAGCUG 690 CAGCUUGGAGGCUUGAACA 459 379 GUAUGUUGCCCGUUUGUCC 691 GGACAAACGGGCAACAUAC 460 380 UAUGUUGCCCGUUUGUCCU 692 AGGACAAACGGGCAACAUA 462 381 UGUUGCCCGUUUGUCCUCU 693 AGAGGACAAACGGGCAACA 1136 382 UGAACCUUUACCCCGUUGC 694 GCAACGGGGUAAAGGUUCA 1266 383 CCAUACUGCGGAACUCCUA 695 UAGGAGUUCCGCAGUAUGG 1267 384 CAUACUGCGGAACUCCUAG 696 CUAGGAGUUCCGCAGUAUG 1268 385 AUACUGCGGAACUCCUAGC 697 GCUAGGAGUUCCGCAGUAU 1517 386 CCACGGGGCGCACCUCUCU 698 AGAGAGGUGCGCCCCGUGG 2371 387 CCCUAGAAGAAGAACUCCC 699 GGGAGUUCUUCUUCUAGGG 2372 388 CCUAGAAGAAGAACUCCCU 700 AGGGAGUUCUUCUUCUAGG 2380 389 UCCCUCGCCUCGCAGACGA 701 UCGUCUGCGAGGCGAGGGA 401 390 UUCCUCUUCAUCCUGCUGC 702 GCAGCAGGAUGAAGAGGAA 402 391 UCCUCUUCAUCCUGCUGCU 703 AGCAGCAGGAUGAAGAGGA 403 392 CCUCUUCAUCCUGCUGCUA 704 UAGCAGCAGGAUGAAGAGG 404 393 CUCUUCAUCCUGCUGCUAU 705 AUAGCAGCAGGAUGAAGAG 405 394 UCUUCAUCCUGCUGCUAUG 706 CAUAGCAGCAGGAUGAAGA 406 395 CUUCAUCCUGCUGCUAUGC 707 GCAUAGCAGCAGGAUGAAG 407 396 UUCAUCCUGCUGCUAUGCC 708 GGCAUAGCAGCAGGAUGAA 408 397 UCAUCCUGCUGCUAUGCCU 709 AGGCAUAGCAGCAGGAUGA 458 398 GGUAUGUUGCCCGUUUGUC 710 GACAAACGGGCAACAUACC 461 399 AUGUUGCCCGUUUGUCCUC 711 GAGGACAAACGGGCAACAU 1426 400 UACGUCCCGUCGGCGCUGA 712 UCAGCGCCGACGGGACGUA 1427 401 ACGUCCCGUCGGCGCUGAA 713 UUCAGCGCCGACGGGACGU 1428 402 CGUCCCGUCGGCGCUGAAU 714 AUUCAGCGCCGACGGGACG 1429 403 GUCCCGUCGGCGCUGAAUC 715 GAUUCAGCGCCGACGGGAC 1430 404 UCCCGUCGGCGCUGAAUCC 716 GGAUUCAGCGCCGACGGGA 2269 405 AGUGUGGAUUCGCACUCCU 717 AGGAGUGCGAAUCCACACU 2370 406 cCCCUAGAAGAAGAACUCC 718 GGAGUUCUUCUUCUAGGGG 455 407 CAAGGUAUGUUGCCCGUUU 719 AAACGGGCAACAUACCUUG 456 408 AAGGUAUGUUGCCCGUUUG 720 CAAACGGGCAACAUACCUU 457 409 AGGUAUGUUGCCCGUUUGU 721 ACAAACGGGCAACAUACCU 1513 410 CCGACCACGGGGCGCACCU 722 AGGUGCGCCCCGUGGUCGG 1514 411 CGACCACGGGGCGCACCUC 723 GAGGUGCGCCCCGUGGUCG 1515 412 GACCACGGGGCGCACCUCU 724 AGAGGUGCGCCCCGUGGUC 1516 413 ACCACGGGGCGCACCUCUC 725 GAGAGGUGCGCCCCGUGGU 1545 414 CUCCCCGUCUGUGCCUUCU 726 AGAAGGCACAGACGGGGAG 1546 415 UCCCCGUCUGUGCCUUCUC 727 GAGAAGGCACAGACGGGGA 2417 416 CCGCGUCGCAGAAGAUCUC 728 GAGAUCUUCUGCGACGCGG 2418 417 CGCGUCGCAGAAGAUCUCA 729 UGAGAUCUUCUGCGACGCG 2419 418 GCGUCGCAGAAGAUCUCAA 730 UUGAGAUCUUCUGCGACGC 2420 419 CGUCGCAGAAGAUCUCAAU 731 AUUGAGAUCUUCUGCGACG 2421 420 GUCGCAGAAGAUCUCAAUC 732 GAUUGAGAUCUUCUGCGAC 2422 421 UCGCAGAAGAUCUCAAUCU 733 AGAUUGAGAUCUUCUGCGA 181 422 AGGACCCCUGCUCGUGUUA 734 UAACACGAGCAGGGGUCCU 182 423 GGACCCCUGCUCGUGUUAC 735 GUAACACGAGCAGGGGUCC 183 424 GACCCCUGCUCGUGUUACA 736 UGUAACACGAGCAGGGGUC 184 425 ACCCCUGCUCGUGUUACAG 737 CUGUAACACGAGCAGGGGU 185 426 CCCCUGCUCGUGUUACAGG 738 CCUGUAACACGAGCAGGGG 368 427 UAUCGCUGGAUGUGUCUGC 739 GCAGACACAUCCAGCGAUA 369 428 AUCGCUGGAUGUGUCUGCG 740 CGCAGACACAUCCAGCGAU 370 429 UCGCUGGAUGUGUCUGCGG 741 CCGCAGACACAUCCAGCGA 371 430 CGCUGGAUGUGUCUGCGGC 742 GCCGCAGACACAUCCAGCG 372 431 GCUGGAUGUGUCUGCGGCG 743 CGCCGCAGACACAUCCAGC 373 432 CUGGAUGUGUCUGCGGCGU 744 ACGCCGCAGACACAUCCAG 463 433 GUUGCCCGUUUGUCCUCUA 745 UAGAGGACAAACGGGCAAC 686 434 CCAUUUGUUCAGUGGUUCG 746 CGAACCACUGAACAAAUGG 800 435 UUACCAAUUUUCUUUUGUC 747 GACAAAAGAAAAUUGGUAA 1102 436 CCAACUUACAAGGCCUUUC 748 GAAAGGCCUUGUAAGUUGG 1103 437 CAACUUACAAGGCCUUUCU 749 AGAAAGGCCUUGUAAGUUG 1183 438 UUUGCUGACGCAACCCCCA 750 UGGGGGUUGCGUCAGCAAA 1184 439 UUGCUGACGCAACCCCCAC 751 GUGGGGGUUGCGUCAGCAA 1185 440 UGCUGACGCAACCCCCACU 752 AGUGGGGGUUGCGUCAGCA 1186 441 GCUGACGCAACCCCCACUG 753 CAGUGGGGGUUGCGUCAGC 1187 442 CUGACGCAACCCCCACUGG 754 CCAGUGGGGGUUGCGUCAG 1553 443 CUGUGCCUUCUCAUCUGCC 755 GGCAGAUGAGAAGGCACAG 1554 444 UGUGCCUUCUCAUCUGCCG 756 CGGCAGAUGAGAAGGCACA 1555 445 GUGCCUUCUCAUCUGCCGG 757 CCGGCAGAUGAGAAGGCAC 1805 446 ACCAGCACCAUGCAACUUU 758 AAAGUUGCAUGGUGCUGGU 1806 447 CCAGCACCAUGCAACUUUU 759 AAAAGUUGCAUGGUGCUGG 1807 448 CAGCACCAUGCAACUUUUU 760 AAAAAGUUGCAUGGUGCUG 1808 449 AGCACCAUGCAACUUUUUC 761 GAAAAAGUUGCAUGGUGCU 1809 450 GCACCAUGCAACUUUUUCA 762 UGAAAAAGUUGCAUGGUGC 1810 451 CACCAUGCAACUUUUUCAC 763 GUGAAAAAGUUGCAUGGUG 1811 452 ACCAUGCAACUUUUUCACC 764 GGUGAAAAAGUUGCAUGGU 1812 453 CCAUGCAACUUUUUCACCU 765 AGGUGAAAAAGUUGCAUGG 2423 454 CGCAGAAGAUCUCAAUCUC 766 GAGAUUGAGAUCUUCUGCG 177 455 UCCUAGGACCCCUGCUCGU 767 ACGAGCAGGGGUCCUAGGA 178 456 CCUAGGACCCCUGCUCGUG 768 CACGAGCAGGGGUCCUAGG 179 457 CUAGGACCCCUGCUCGUGU 769 ACACGAGCAGGGGUCCUAG 180 458 UAGGACCCCUGCUCGUGUU 770 AACACGAGCAGGGGUCCUA 186 459 CCCUGCUCGUGUUACAGGC 771 GCCUGUAACACGAGCAGGG 187 460 CCUGCUCGUGUUACAGGCG 772 CGCCUGUAACACGAGCAGG 188 461 CUGCUCGUGUUACAGGCGG 773 CCGCCUGUAACACGAGCAG 685 462 GCCAUUUGUUCAGUGGUUC 774 GAACCACUGAACAAAUGGC 1099 463 UCGCCAACUUACAAGGCCU 775 AGGCCUUGUAAGUUGGCGA 1100 464 CGCCAACUUACAAGGCCUU 776 AAGGCCUUGUAAGUUGGCG 1101 465 GCCAACUUACAAGGCCUUU 777 AAAGGCCUUGUAAGUUGGC 1230 466 GCGCAUGCGUGGAACCUUU 778 AAAGGUUCCACGCAUGCGC 1258 467 CUGCCGAUCCAUACUGCGG 779 CCGCAGUAUGGAUCGGCAG 1606 468 GCAUGGAGACCACCGUGAA 780 UUCACGGUGGUCUCCAUGC 1607 469 CAUGGAGACCACCGUGAAC 781 GUUCACGGUGGUCUCCAUG 1608 470 AUGGAGACCACCGUGAACG 782 CGUUCACGGUGGUCUCCAU 1609 471 UGGAGACCACCGUGAACGC 783 GCGUUCACGGUGGUCUCCA 1610 472 GGAGACCACCGUGAACGCC 784 GGCGUUCACGGUGGUCUCC 1611 473 GAGACCACCGUGAACGCCC 785 GGGCGUUCACGGUGGUCUC 1804 474 CACCAGCACCAUGCAACUU 786 AAGUUGCAUGGUGCUGGUG 2381 475 CCCUCGCCUCGCAGACGAA 787 UUCGUCUGCGAGGCGAGGG 3077 476 UGGGGUGGAGCCCUCAGGC 788 GCCUGAGGGCUCCACCCCA 303 477 GCCAAAAUUCGCAGUCCCC 789 GGGGACUGCGAAUUUUGGC 304 478 CCAAAAUUCGCAGUCCCCA 790 UGGGGACUGCGAAUUUUGG 305 479 CAAAAUUCGCAGUCCCCAA 791 UUGGGGACUGCGAAUUUUG 801 480 UACCAAUUUUCUUUUGUCU 792 AGACAAAAGAAAAUUGGUA 1174 481 UGCCAAGUGUUUGCUGACG 793 CGUCAGCAAACACUUGGCA 1175 482 GCCAAGUGUUUGCUGACGC 794 GCGUCAGCAAACACUUGGC 1176 483 CCAAGUGUUUGCUGACGCA 795 UGCGUCAGCAAACACUUGG

2382 484 CCUCGCCUCGCAGACGAAG 796 CUUCGUCUGCGAGGCGAGG 2408 485 UCUCAAUCGCCGCGUCGCA 797 UGCGACGCGGCGAUUGAGA 2409 486 CUCAAUCGCCGCGUCGCAG 798 CUGCGACGCGGCGAUUGAG 2410 487 UCAAUCGCCGCGUCGCAGA 799 UCUGCGACGCGGCGAUUGA 2463 488 CCUUGGACUCAUAAGGUGG 800 CCACCUUAUGAGUCCAAGG 2464 489 CUUGGACUCAUAAGGUGGG 801 CCCACCUUAUGAGUCCAAG 55 490 UCCUGCUGGUGGCUCCAGU 802 ACUGGAGCCACCAGCAGGA 668 491 UGGCUCAGUUUACUAGUGC 803 GCACUAGUAAACUGAGCCA 701 492 UUCGUAGGGCUUUCCCCCA 804 UGGGGGAAAGCCCUACGAA 1177 493 CAAGUGUUUGCUGACGCAA 805 UUGCGUCAGCAAACACUUG 1178 494 AAGUGUUUGCUGACGCAAC 806 GUUGCGUCAGCAAACACUU 1179 495 AGUGUUUGCUGACGCAACC 807 GGUUGCGUCAGCAAACACU 1180 496 GUGUUUGCUGACGCAACCC 808 GGGUUGCGUCAGCAAACAC 1181 497 UGUUUGCUGACGCAACCCC 809 GGGGUUGCGUCAGCAAACA 1182 498 GUUUGCUGACGCAACCCCC 810 GGGGGUUGCGUCAGCAAAC 1680 499 AUGUCAACGACCGACCUUG 811 CAAGGUCGGUCGUUGACAU 1681 500 UGUCAACGACCGACCUUGA 812 UCAAGGUCGGUCGUUGACA 1682 501 GUCAACGACCGACCUUGAG 813 CUCAAGGUCGGUCGUUGAC 1683 502 UCAACGACCGACCUUGAGG 814 CCUCAAGGUCGGUCGUUGA 1684 503 CAACGACCGACCUUGAGGC 815 GCCUCAAGGUCGGUCGUUG 2411 504 CAAUCGCCGCGUCGCAGAA 816 UUCUGCGACGCGGCGAUUG 2412 505 AAUCGCCGCGUCGCAGAAG 817 CUUCUGCGACGCGGCGAUU 2413 506 AUCGCCGCGUCGCAGAAGA 818 UCUUCUGCGACGCGGCGAU 2414 507 UCGCCGCGUCGCAGAAGAU 819 AUCUUCUGCGACGCGGCGA 2415 508 CGCCGCGUCGCAGAAGAUC 820 GAUCUUCUGCGACGCGGCG 2416 509 GCCGCGUCGCAGAAGAUCU 821 AGAUCUUCUGCGACGCGGC 54 510 UUCCUGCUGGUGGCUCCAG 822 CUGGAGCCACCAGCAGGAA 700 511 GUUCGUAGGGCUUUCCCCC 823 GGGGGAAAGCCCUACGAAC 702 512 UCGUAGGGCUUUCCCCCAC 824 GUGGGGGAAAGCCCUACGA 1253 513 CUCCUCUGCCGAUCCAUAC 825 GUAUGGAUCGGCAGAGGAG 1254 514 UCCUCUGCCGAUCCAUACU 826 AGUAUGGAUCGGCAGAGGA 1255 515 CCUCUGCCGAUCCAUACUG 827 CAGUAUGGAUCGGCAGAGG 1439 516 CGCUGAAUCCCGCGGACGA 828 UCGUCCGCGGGAUUCAGCG 1547 517 CCCCGUCUGUGCCUUCUCA 829 UGAGAAGGCACAGACGGGG 1548 518 CCCGUCUGUGCCUUCUCAU 830 AUGAGAAGGCACAGACGGG 1549 519 CCGUCUGUGCCUUCUCAUC 831 GAUGAGAAGGCACAGACGG 1550 520 CGUCUGUGCCUUCUCAUCU 832 AGAUGAGAAGGCACAGACG 1653 521 CAUAAGAGGACUCUUGGAC 833 GUCCAAGAGUCCUCUUAUG 1910 522 GACCCUUAUAAAGAAUUUG 834 CAAAUUCUUUAUAAGGGUC 2270 523 GUGUGGAUUCGCACUCCUC 835 GAGGAGUGCGAAUCCACAC 2361 524 GAGGCAGGUCCCCUAGAAG 836 CUUCUAGGGGACCUGCCUC 2362 525 AGGCAGGUCCCCUAGAAGA 837 UCUUCUAGGGGACCUGCCU 316 526 GUCCCCAACCUCCAAUCAC 838 GUGAUUGGAGGUUGGGGAC 317 527 UCCCCAACCUCCAAUCACU 839 AGUGAUUGGAGGUUGGGGA 452 528 UAUCAAGGUAUGUUGCCCG 840 CGGGCAACAUACCUUGAUA 453 529 AUCAAGGUAUGUUGCCCGU 841 ACGGGCAACAUACCUUGAU 687 530 CAUUUGUUCAGUGGUUCGU 842 ACGAACCACUGAACAAAUG 689 531 UUUGUUCAGUGGUUCGUAG 843 CUACGAACCACUGAACAAA 690 532 UUGUUCAGUGGUUCGUAGG 844 CCUACGAACCACUGAACAA 691 533 UGUUCAGUGGUUCGUAGGG 845 CCCUACGAACCACUGAACA 692 534 GUUCAGUGGUUCGUAGGGC 846 GCCCUACGAACCACUGAAC 693 535 UUCAGUGGUUCGUAGGGCU 847 AGCCCUACGAACCACUGAA 694 536 UCAGUGGUUCGUAGGGCUU 848 AAGCCCUACGAACCACUGA 695 537 CAGUGGUUCGUAGGGCUUU 849 AAAGCCCUACGAACCACUG 696 538 AGUGGUUCGUAGGGCUUUC 850 GAAAGCCCUACGAACCACU 697 539 GUGGUUCGUAGGGCUUUCC 851 GGAAAGCCCUACGAACCAC 698 540 UGGUUCGUAGGGCUUUCCC 852 GGGAAAGCCCUACGAACCA 699 541 GGUUCGUAGGGCUUUCCCC 853 GGGGAAAGCCCUACGAACC 1228 542 CAGCGCAUGCGUGGAACCU 854 AGGUUCCACGCAUGCGCUG 1229 543 AGCGCAUGCGUGGAACCUU 855 AAGGUUCCACGCAUGCGCU 1231 544 CGCAUGCGUGGAACCUUUG 856 CAAAGGUUCCACGCAUGCG 1256 545 CUCUGCCGAUCCAUACUGC 857 GCAGUAUGGAUCGGCAGAG 1257 546 UCUGCCGAUCCAUACUGCG 858 CGCAGUAUGGAUCGGCAGA 1438 547 GCGCUGAAUCCCGCGGACG 859 CGUCCGCGGGAUUCAGCGC 1827 548 ACCUCUGCCUAAUCAUCUC 860 GAGAUGAUUAGGCAGAGGU

[0234] UNA Oligomers Targeting HBV

[0235] Examples of base sequences of this invention targeted to an HBV component are shown in Table 16.

[0236] An oligomeric compound of this invention can be formed having a first strand and a second strand each being 21 monomers in length. The first strand can have 19 contiguous monomers with a sequence of attached bases shown in Table 16 (sense), and two additional overhang monomers on the 3' end. The second strand can have 19 contiguous monomers with a sequence of attached bases shown in Table 16 (antisense), and two additional overhang monomers on the 3' end. The overhang monomers can be any of NN, QQ, XX, NX, NQ, XN, XQ, QN, and QX. For example, XQ can be UNA-U/mU, or UNA-U/*/dT.

TABLE-US-00017 TABLE 16 HBV sense and antisense sequences SEQ Sense (5'-3') SEQ Antisense (5'-3') REF ID SEQ ID NOS: ID SEQ ID NOS: POS NO 861 to 901 NO 902 to 942 1525 861 CGCACCUCUCUUUACGCGG 902 CCGCGUAAAGAGAGGUGCG 251 862 GACUCGUGGUGGACUUCUC 903 GAGAAGUCCACCACGAGUC 254 863 UCGUGGUGGACUUCUCUCA 904 UGAGAGAAGUCCACCACGA 374 864 UGGAUGUGUCUGCGGCGUU 905 AACGCCGCAGACACAUCCA 1575 865 CCGUGUGCACUUCGCUUCA 906 UGAAGCGAAGUGCACACGG 1577 866 GUGUGCACUUCGCUUCACC 907 GGUGAAGCGAAGUGCACAC 1578 867 UGUGCACUUCGCUUCACCU 908 AGGUGAAGCGAAGUGCACA 1579 868 GUGCACUUCGCUUCACCUC 909 GAGGUGAAGCGAAGUGCAC 1581 869 GCACUUCGCUUCACCUCUG 910 CAGAGGUGAAGCGAAGUGC 247 870 UCUAGACUCGUGGUGGACU 911 AGUCCACCACGAGUCUAGA 248 871 CUAGACUCGUGGUGGACUU 912 AAGUCCACCACGAGUCUAG 249 872 UAGACUCGUGGUGGACUUC 913 GAAGUCCACCACGAGUCUA 250 873 AGACUCGUGGUGGACUUCU 914 AGAAGUCCACCACGAGUCU 1776 874 GGAGGCUGUAGGCAUAAAU 915 AUUUAUGCCUACAGCCUCC 1777 875 GAGGCUGUAGGCAUAAAUU 916 AAUUUAUGCCUACAGCCUC 1779 876 GGCUGUAGGCAUAAAUUGG 917 CCAAUUUAUGCCUACAGCC 1780 877 GCUGUAGGCAUAAAUUGGU 918 ACCAAUUUAUGCCUACAGC 1781 878 CUGUAGGCAUAAAUUGGUC 919 GACCAAUUUAUGCCUACAG 1782 879 UGUAGGCAUAAAUUGGUCU 920 AGACCAAUUUAUGCCUACA 256 880 GUGGUGGACUUCUCUCAAU 921 AUUGAGAGAAGUCCACCAC 1863 881 UUCAAGCCUCCAAGCUGUG 922 CACAGCUUGGAGGCUUGAA 1864 882 UCAAGCCUCCAAGCUGUGC 923 GCACAGCUUGGAGGCUUGA 1865 883 CAAGCCUCCAAGCUGUGCC 924 GGCACAGCUUGGAGGCUUG 1866 884 AAGCCUCCAAGCUGUGCCU 925 AGGCACAGCUUGGAGGCUU 376 885 GAUGUGUCUGCGGCGUUUU 926 AAAACGCCGCAGACACAUC 378 886 UGUGUCUGCGGCGUUUUAU 927 AUAAAACGCCGCAGACACA 380 887 UGUCUGCGGCGUUUUAUCA 928 UGAUAAAACGCCGCAGACA 1818 888 AACUUUUUCACCUCUGCCU 929 AGGCAGAGGUGAAAAAGUU 244 889 GAGUCUAGACUCGUGGUGG 930 CCACCACGAGUCUAGACUC 245 890 AGUCUAGACUCGUGGUGGA 931 UCCACCACGAGUCUAGACU 246 891 GUCUAGACUCGUGGUGGAC 932 GUCCACCACGAGUCUAGAC 409 892 CAUCCUGCUGCUAUGCCUC 933 GAGGCAUAGCAGCAGGAUG 411 893 UCCUGCUGCUAUGCCUCAU 934 AUGAGGCAUAGCAGCAGGA 412 894 CCUGCUGCUAUGCCUCAUC 935 GAUGAGGCAUAGCAGCAGG 413 895 CUGCUGCUAUGCCUCAUCU 936 AGAUGAGGCAUAGCAGCAG 414 896 UGCUGCUAUGCCUCAUCUU 937 AAGAUGAGGCAUAGCAGCA 252 897 ACUCGUGGUGGACUUCUCU 938 AGAGAAGUCCACCACGAGU 253 898 CUCGUGGUGGACUUCUCUC 939 GAGAGAAGUCCACCACGAG 1576 899 CGUGUGCACUUCGCUUCAC 940 GUGAAGCGAAGUGCACACG 1580 900 UGCACUUCGCUUCACCUCU 941 AGAGGUGAAGCGAAGUGCA 1582 901 CACUUCGCUUCACCUCUGC 942 GCAGAGGUGAAGCGAAGUG

UNA Oligomers Targeting HBV

[0237] Embodiments of this invention can provide oligomeric molecules that are active agents targeted to HBV.

[0238] Examples of UNA oligomers of this invention that are targeted to an HBV component are shown in Table 17. Table 17 shows "sense" and "antisense" pairs.

TABLE-US-00018 TABLE 17 UNA oligomers targeted to HBV (Sense (S)- Antisense (AS)) SEQ REF ID HBV (Sense (S)-Antisense (AS)) POS NO S/AS (5'-3') 244 943 S UNA-G/mAGmUCmUAmGACUmCGmUGmGUm GG/UNA-U/mU 244 944 AS mCCmACmCAmCGmAGmUmCmUAmGAmCUm C/UNA-U/mU 245 945 S UNA-A/mGUmCUmAGmACUCmGUmGGmUGm GA/UNA-U/mU 245 946 AS mUCmCAmCCmACmGAmGmUmCUmAGmACm U/UNA-U/mU 246 947 S UNA-G/mUCmUAmGAmCUCGmUGmGUmGGm AC/UNA-U/mU 246 948 AS mGUmCCmACmCAmCGmAmGmUCmUAmGAm C/UNA-U/mU 247 949 S UNA-U/mCUmAGmACmUCGUmGGmUGmGAm CU/UNA-U/mU 247 950 AS mAGmUCmCAmCCmACmGmAmGUmCUmAGm A/UNA-U/mU 248 951 S UNA-C/mUAmGAmCUmCGUGmGUmGGmACm UU/UNA-U/mU 248 952 AS mAAmGUmCCmACmCAmCmGmAGmUCmUAm G/UNA-U/mU 249 953 S UNA-U/mAGmACmUCmGUGGmUGmGAmCUm UC/UNA-U/mU 249 954 AS mGAmAGmUCmCAmCCmAmCmGAmGUmCUm A/UNA-U/mU 250 955 S UNA-A/mGAmCUmCGmUGGUmGGmACmUUm CU/UNA-U/mU 250 956 AS mAGmAAmGUmCCmACmCmAmCGmAGmUCm U/UNA-U/mU 251 957 S UNA-G/mACmUCmGUmGGUGmGAmCUmUCm UC/UNA-U/mU 251 958 AS mGAmGAmAGmUCmCAmCmCmACmGAmGUm C/UNA-U/mU 252 959 S UNA-A/mCUmCGmUGmGUGGmACmUUmCUm CU/UNA-U/mU 252 960 AS mAGmAGmAAmGUmCCmAmCmCAmCGmAGm U/UNA-U/mU 253 961 S UNA-C/mUCmGUmGGmUGGAmCUmUCmUCm UC/UNA-U/mU 253 962 AS mGAmGAmGAmAGmUCmCmAmCCmACmGAm G/UNA-U/mU 254 963 S UNA-U/mCGmUGmGUmGGACmUUmCUmCUm CA/UNA-U/mU 254 964 AS mUGmAGmAGmAAmGUmCmCmACmCAmCGm A/UNA-U/mU 256 965 S UNA-G/mUGmGUmGGmACUUmCUmCUmCAm AU/UNA-U/mU 256 966 AS mAUmUGmAGmAGmAAmGmUmCCmACmCAm C/UNA-U/mU 374 967 5 UNA-U/mGGmAUmGUmGUCUmGCmGGmCGm UU/UNA-U/mU 374 968 AS mAAmCGmCCmGCmAGmAmCmACmAUmCCm A/UNA-U/mU 376 969 S UNA-G/mAUmGUmGUmCUGCmGGmCGmUUm UU/UNA-U/mU 376 970 AS mAAmAAmCGmCCmGCmAmGmACmACmAUm C/UNA-U/mU 378 971 S UNA-U/mGUmGUmCUmGCGGmCGmUUmUUm AU/UNA-U/mU 378 972 AS mAUmAAmAAmCGmCCmGmCmAGmACmACm A/UNA-U/mU 380 973 S UNA-U/mGUmCUmGCmGGCGmUUmUUmAUm CA/UNA-U/mU 380 974 AS mUGmAUmAAmAAmCGmCmCmGCmAGmACm A/UNA-U/mU 409 975 S UNA-C/mAUmCCmUGmCUGCmUAmUGmCCm UC/UNA-U/mU 409 976 AS mGAmGGmCAmUAmGCmAmGmCAmGGmAUm G/UNA-U/mU 411 977 S UNA-U/mCCmUGmCUmGCUAmUGmCCmUCm AU/UNA-U/mU 411 978 AS mAUmGAmGGmCAmUAmGmCmAGmCAmGGm A/UNA-U/mU 412 979 S UNA-C/mCUmGCmUGmCUAUmGCmCUmCAm UC/UNA-U/mU 412 980 AS mGAmUGmAGmGCmAUmAmGmCAmGCmAGm G/UNA-U/mU 413 981 S UNA-C/mUGmCUmGCmUAUGmCCmUCmAUm CU/UNA-U/mU 413 982 AS mAGmAUmGAmGGmCAmUmAmGCmAGmCAm G/UNA-U/mU 414 983 S UNA-U/mGCmUGmCUmAUGCmCUmCAmUCm UU/UNA-U/mU 414 984 AS mAAmGAmUGmAGmGCmAmUmAGmCAmGCm A/UNA-U/mU 1525 985 S UNA-C/mGCmACmCUmCUCUmUUmACmGCm GG/UNA-U/mU 1525 986 AS mCCmGCmGUmAAmAGmAmGmAGmGUmGCm G/UNA-U/mU 1575 987 S UNA-C/mCGmUGmUGmCACUmUCmGCmUUm CA/UNA-U/mU 1575 988 AS mUGmAAmGCmGAmAGmUmGmCAmCAmCGm G/UNA-U/mU 1576 989 S UNA-C/mGUmGUmGCmACUUmCGmCUmUCm AC/UNA-U/mU 1576 990 AS mGUmGAmAGmCGmAAmGmUmGCmACmACm G/UNA-U/mU 1577 991 S UNA-G/mUGmUGmCAmCUUCmGCmUUmCAm CC/UNA-U/mU 1577 992 AS mGGmUGmAAmGCmGAmAmGmUGmCAmCAm C/UNA-U/mU 1578 993 S UNA-U/mGUmGCmACmUUCGmCUmUCmACm CU/UNA-U/mU 1578 994 AS mAGmGUmGAmAGmCGmAmAmGUmGCmACm A/UNA-U/mU 1579 995 S UNA-G/mUGmCAmCUmUCGCmUUmCAmCCm UC/UNA-U/mU 1579 996 AS mGAmGGmUGmAAmGCmGmAmAGmUGmCAm C/UNA-U/mU 1580 997 5 UNA-U/mGCmACmUUmCGCUmUCmACmCUm CU/UNA-U/mU 1580 998 AS mAGmAGmGUmGAmAGmCmGmAAmGUmGCm A/UNA-U/mU 1581 999 S UNA-G/mCAmCUmUCmGCUUmCAmCCmUCm UG/UNA-U/mU 1581 1000 AS mCAmGAmGGmUGmAAmGmCmGAmAGmUGm C/UNA-U/mU 1582 1001 S UNA-C/mACmUUmCGmCUUCmACmCUmCUm GC/UNA-U/mU 1582 1002 AS mGCmAGmAGmGUmGAmAmGmCGmAAmGUm G/UNA-U/mU 1776 1003 S UNA-G/mGAmGGmCUmGUAGmGCmAUmAAm AU/UNA-U/mU 1776 1004 AS mAUmUUmAUmGCmCUmAmCmAGmCCmUCm C/UNA-U/mU 1777 1005 S UNA-G/mAGmGCmUGmUAGGmCAmUAmAAm UU/UNA-U/mU 1777 1006 AS mAAmUUmUAmUGmCCmUmAmCAmGCmCUm C/UNA-U/mU 1779 1007 S UNA-G/mGCmUGmUAmGGCAmUAmAAmUUm GG/UNA-U/mU 1779 1008 AS mCCmAAmUUmUAmUGmCmCmUAmCAmGCm C/UNA-U/mU 1780 1009 S UNA-G/mCUmGUmAGmGCAUmAAmAUmUGm GU/UNA-U/mU 1780 1010 AS mACmCAmAUmUUmAUmGmCmCUmACmAGm C/UNA-U/mU 1781 1011 S UNA-C/mUGmUAmGGmCAUAmAAmUUmGGm UC/UNA-U/mU 1781 1012 AS mGAmCCmAAmUUmUAmUmGmCCmUAmCAm G/UNA-U/mU 1782 1013 S UNA-U/mGUmAGmGCmAUAAmAUmUGmGUm CU/UNA-U/mU 1782 1014 AS mAGmACmCAmAUmUUmAmUmGCmCUmACm A/UNA-U/mU 1818 1015 S UNA-A/mACmUUmUUmUCACmCUmCUmGCm CU/UNA-U/mU 1818 1016 AS mAGmGCmAGmAGmGUmGmAmAAmAAmGUm U/UNA-U/mU 1863 1017 S UNA-U/mUCmAAmGCmCUCCmAAmGCmUGm UG/UNA-U/mU 1863 1018 AS mCAmCAmGCmUUmGGmAmGmGCmUUmGAm A/UNA-U/mU 1864 1019 S UNA-U/mCAmAGmCCmUCCAmAGmCUmGUm GC/UNA-U/mU 1864 1020 AS mGCmACmAGmCUmUGmGmAmGGmCUmUGm A/UNA-U/mU 1865 1021 S UNA-C/mAAmGCmCUmCCAAmGCmUGmUGm CC/UNA-U/mU 1865 1022 AS mGGmCAmCAmGCmUUmGmGmAGmGCmUUm G/UNA-U/mU 1866 1023 S UNA-A/mAGmCCmUCmCAAGmCUmGUmGCm CU/UNA-U/mU

1866 1024 AS mAGmGCmACmAGmCUmUmGmGAmGGmCUm U/UNA-U/mU

UNA Oligomers Targeting HBV

[0239] Embodiments of this invention can provide oligomeric molecules that are active agents targeted to HBV.

[0240] Examples of UNA oligomers of this invention that are targeted to an HBV component are shown in Table 18. Table 18 shows "sense" and "antisense" pairs.

TABLE-US-00019 TABLE 18 UNA oligomers targeted to HBV (Sense (S)- Antisense (AS)) SEQ REF ID HBV (Sense (S)-Antisense (AS)) POS NO S/AS (5'-3') 1576 1025 S UNA-C/mGrUmGrUmGrCmArCrUrUm CrGmCrUmUrCmArC/UNA-U/mU 1576 1026 AS mGrUmGrAmArGmC/UNA-G/mArAm GmUmGrCmArCmArCmG/UNA-U/mU 1576 1027 S UNA-C*/mGrUmGrUmGrCmArCrUrUm CrGmCrUmUrCmArC*/UNA-U*/mU 1576 1028 AS mGrUmGrAmArGmC/UNA-G/mArAmGm UmGrCmArCmArCmG/UNA-U*/mU 1576 1029 S UNA-C*/mG*rU*mGrUmGrCmArCrUr UmCrGmCrUmUrCmArC*/UNA-U*/mU 1576 1030 AS mGrUmGrAmArGmC/UNA-G/mArAmGm UmGrCmArCmArCmG/UNA-U*/mU 1576 1031 S UNA-C*/mG*rU*mGrUmGrCmArCrUr UmCrGmCrUmUrCmA*rC*/UNA-U*/mU 1576 1032 AS mGrUmGrAmArGmC/UNA-G/mArAmGm UmGrCmArCmArCmG/UNA-U*/mU 1576 1033 S UNA-C*/mGrUmGrUmGrCmArCrUrUm CrGmCrUmUrCmArC*/UNA-U*/mU 1576 1034 AS mG*rU*mGrAmArGmC/UNA-G/mArAm GmUmGrCmArCmArCmG*/UNA-U*/mU 1576 1035 S UNA-C*/mG*rUmGrUmGrCmArCrUrUm CrGmCrUmUrCmArC*/UNA-U*/mU 1576 1036 AS mG*rU*mGrAmArGmC/UNA-G/mArAm GmUmGrCmArCmArCmG*/UNA-U*/mU 1576 1037 S UNA-C*/mG*rU*mGrUmGrCmArCrUr UmCrGmCrUmUrCmArC*/UNA-U*/mU 1576 1038 AS mG*rU*mGrAmArGmC/UNA-G/mArAm GmUmGrCmArCmArCmG*/UNA-U*/mU 1576 1039 S UNA-C*/mG*rU*mGrUmGrCmArCrUr UmCrGmCrUmUrCmA*rC*/UNA-U*/mU 1576 1040 AS mG*rU*mGrAmArGmC/UNA-G/mArAm GmUmGrCmArCmArCmG*/UNA-U*/mU 1575 1041 S UNA-C*/mC*rGmUrGmUrGmCrArCrUm UrCmGrCmUrUmCrA*/UNA-U*/mU 1575 1042 AS mUrGmArA/UNA-G/rCmGrAmArGmUm GmCrAmCrAmCrGmG/UNA-U*/mU 1575 1043 S UNA-C*/mC*rGmUrGmUrGmCrArCrUm UrCmGrCmUrUmCrA*/UNA-U*/mU 1575 1044 AS mUrGmArAmGrC/UNA-G/rAmArGmUm GmCrAmCrAmCrGmG/UNA-U*/mU 1575 1045 S UNA-C*/mC*rGmUrGmUrGmCrArCr UmUrCmGrCmUrUmCrA*/UNA-U*/mU 1575 1046 AS mUrGmArAmGrCmG/UNA-A/mArGmUm GmCrAmCrAmCrGmG/UNA-U*/mU 1578 1047 S UNA-U*/mG*rU*mGrCmArCmUrUrCr GmCrUmUrCmArCmC*rU*/UNA-U*/mU 1578 1048 AS mArGmGrU/UNA-G/rAmArGmCrGmAm AmGrUmGrCmArCmA/UNA-U*/mu 1578 1049 S UNA-U*/mG*rU*mGrCmArCmUrUrCr GmCrUmUrCmArCmC*rU*/UNA-U*/mU 1578 1050 AS mArGmGrUmG/UNA-A/mArGmCrGmAm AmGrUmGrCmArCmA/UNA-U*/mu 1578 1051 S UNA-U*/mG*rU*mGrCmArCmUrUrCr GmCrUmUrCmArCmC*rU*/UNA-U*/mU 1578 1052 AS mArGmGrUmGrAmA/UNA-G/mCrGmAm AmGrUmGrCmArCmA/UNA-U*/mu 1818 1053 S UNA-A/mArCmUrUmUrUmUrCrArCm CrUmCrUmGrCmCrU/UNA-U/mU 1818 1054 AS mArGmGrC/UNA-A/rGmArGmGrUm GmAmArAmArAmGrUmU/UNA-U/mU 1818 1055 S UNA-A/mArCmUrUmUrUmUrCrArCm CrUmCrUmGrCmCrU/UNA-U/mU 1818 1056 AS mArGmGrCmA/UNA-G/mArGmGrUm GmAmArAmArAmGrUmU/UNA-U/mU 1818 1057 S UNA-A/mArCmUrUmUrUmUrCrArCm CrUmCrUmGrCmCrU/UNA-U/mU 1818 1058 AS mArGmGrCmArG/UNA-A/rGmGrUm GmAmArAmArAmGrUmU/UNA-U/mU 245 1059 S UNA-A/mGrUmCrUmArGmArCrUrCm GrUmGrGmUrGmGrA/UNA-U/mU 245 1060 AS mUrCmCrAmCrC/-UNA-A/rCmGrAm GmUmCrUmArGmArCmU/UNA-U/mU 1580 1061 S UNA-U/mGrCmArCmUrUmCrGrCrUm UrCmArCmCrUmCrU/UNA-U/mU 1580 1062 AS mArGmArG/UNA-G/rUmGrAmArGm CmGmArAmGrUmGrCmA/UNA-U/mU 1580 1063 S UNA-U/mGrCmArCmUrUmCrGrCrUm UrCmArCmCrUmCrU/UNA-U/mU 1580 1064 AS mArGmArGmG/UNA-U/mGrAmArGm CmGmArAmGrUmGrCmA/UNA-U/mU 1580 1065 S UNA-U/mGrCmArCmUrUmCrGrCrUm UrCmArCmCrUmCrU/UNA-U/mU 1580 1066 AS mArGmArGmGrU/UNA-G/rAmArGm CmGmArAmGrUmGrCmA/UNA-U/mU 1580 1067 S UNA-U/mGrCmArCmUrUmCrGrCrUm UrCmArCmCrUmCrU/UNA-U/mU 1580 1068 AS mArGmArGmGrUmG/UNA-A/mArGm CmGmArAmGrUmGrCmA/UNA-U/mU

UNA Oligomers Targeting HBV

[0241] Embodiments of this invention can provide oligomeric molecules that are active agents targeted to HBV.

[0242] Examples of UNA oligomers of this invention that are targeted to an HBV component are shown in Table 19. Table 19 shows "sense" and "antisense" pairs.

TABLE-US-00020 TABLE 19 UNA oligomers targeted to HBV(Sense (S)- Antisense (AS)) SEQ REF ID HBV (Sense (S)-Antisense (AS)) POS NO S/AS (5'-3') 1578 1069 S UNA-U*/mGrUmGrCmArCmUrUrCrGmCr UmUrCmArCmCrU*/UNA-U*/mU 1578 1070 AS mArGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U*/mu 1578 1071 S UNA-U*/mG*rUmGrCmArCmUrUrCrGm CrUmUrCmArCmCrU*/UNA-U*/mU 1578 1072 AS mArGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U*/mu 1578 1073 S UNA-U*/mG*rU*mGrCmArCmUrUrCr GmCrUmUrCmArCmCrU*/UNA-U*/mU 1578 1074 AS mArGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U*/mu 1578 1075 S UNA-U*/mG*rU*mGrCmArCmUrUrCrGm CrUmUrCmArCmC*rU*/UNA-U*/mU 1578 1076 AS mArGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U*/mu 1578 1077 S UNA-U*/mGrUmGrCmArCmUrUrCrGmCr UmUrCmArCmCrU*/UNA-U*/mU 1578 1078 AS mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U*/mu 1578 1079 S UNA-U*/mG*rUmGrCmArCmUrUrCrGmCr UmUrCmArCmCrU*/UNA-U*/mU 1578 1080 AS mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U*/mu 1578 1081 S UNA-U*/mG*rU*mGrCmArCmUrUrCrGm CrUmUrCmArCmCrU*/UNA-U*/mU 1578 1082 AS mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U*/mu 1578 1083 S UNA-U*/mG*rU*mGrCmArCmUrUrCrGm CrUmUrCmArCmC*rU*/UNA-U*/mU 1578 1084 AS mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U*/mu 1578 1085 S UNA-U*/mGrUmGrCmArCmUrUrCrGmCr UmUrCmArCmCrU*/UNA-U*/mU 1578 1086 AS mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA*/UNA-U*/mu 1578 1087 S UNA-U*/mG*rUmGrCmArCmUrUrCrGm CrUmUrCmArCmCrU*/UNA-U*/mU 1578 1088 AS mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA*/UNA-U*/mu 1578 1089 S UNA-U*/mG*rU*mGrCmArCmUrUrCrGm CrUmUrCmArCmCrU*/UNA-U*/mU 1578 1090 AS mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA*/UNA-U*/mu 1578 1091 S UNA-U*/mG*rU*mGrCmArCmUrUrCrGm CrUmUrCmArCmC*rU*/UNA-U*/mU 1578 1092 AS mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA*/UNA-U*/mu 1578 1093 S UNA-U*/mGrUmGrCmArCmUrUrCrGmCr UmUrCmArCmCrU*/UNA-U*/mU 1578 1094 AS mA*rG*mGrUmGrAmArGmCrGmAmAmGr UmGrCmArCmA*/UNA-U*/mu 1578 1095 S UNA-U*/mG*rUmGrCmArCmUrUrCrGm CrUmUrCmArCmCrU*/UNA-U*/mU 1578 1096 AS mA*rG*mGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA*/UNA-U*/mu 1578 1097 S UNA-U*/mG*rU*mGrCmArCmUrUrCrGm CrUmUrCmArCmCrU*/UNA-U*/mU 1578 1098 AS mA*rG*mGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA*/UNA-U*/mu 1578 1099 S UNA-U*/mG*rU*mGrCmArCmUrUrCrGm CrUmUrCmArCmC*rU*/UNA-U*/mU 1578 1100 AS mA*rG*mGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA*/UNA-U*/mu 1777 1101 S UNA-G*/mArGmGrCmUrGmUrArGrGmCr AmUrAmArAmUrU*/UNA-U*/mU 1777 1102 AS mArAmUrUmUrAmUrGmCrCmUmAmCrAmGr CmCrUmC/UNA-U*/mU 1777 1103 S UNA-G*/mA*rGmGrCmUrGmUrArGrGmCr AmUrAmArAmUrU*/UNA-U*/mU 1777 1104 AS mArAmUrUmUrAmUrGmCrCmUmAmCrAmGr CmCrUmC*/UNA-U*/mU 1777 1105 S UNA-G*/mA*rG*mGrCmUrGmUrArGrGmCr AmUrAmArAmUrU*/UNA-U*/mU 1777 1106 AS mArAmUrUmUrAmUrGmCrCmUmAmCrAmGr CmCrU*mC*/UNA-U*/mU 380 1107 S UNA-U*/mGrUmCrUmGrCmGrGrCrGmUrUm UrUmArUmCrA*/UNA-U*/mU 380 1108 AS mUrGmArUmArAmArAmCrGmCmCmGrCmAr GmArCmA/UNA-U*/mU 380 1109 S UNA-U*/mG*rUmCrUmGrCmGrGrCrGmUr UmUrUmArUmCrA*/UNA-U*/mU 380 1110 AS mUrGmArUmArAmArAmCrGmCmCmGrCmAr GmArCmA/UNA-U*/mU 380 1111 S UNA-U*/mGrUmCrUmGrCmGrGrCrGmUr UmUrUmArUmCrA*/UNA-U*/mU 380 1112 AS mU*rGmArUmArAmArAmCrGmCmCmGrCm ArGmArCmA/UNA-U*/mU 380 1113 S UNA-U*/mG*rU*mCrUmGrCmGrGrCrGm UrUmUrUmArUmC*rA*/UNA-U*/mU 380 1114 AS mU*rGmArUmArAmArAmCrGmCmCmGrCm ArGmArCmA/UNA-U*/mU 1576 1115 S UNA-C*/mGrUmGrUmGrCmArCrUrUmCr GmCrUmUrCmArC*/UNA-U*/mU 1576 1116 AS mGrUmGrAmArGmCrGmArAmGmUmGrCm ArCmArCmG/UNA-U*/mU 1575 1117 S UNA-C*/mC*rGmUrGmUrGmCrArCrUm UrCmGrCmUrUmCrA*/UNA-U*/mU 1575 1118 AS mUrGmArAmGrCmGrAmArGmUmGmCrAm CrAmCrGmG/UNA-U*/mU 1580 1119 S UNA-U*/mG*rC*mArCmUrUmCrGrCrUm UrCmArCmCrUmCrU*/UNA-U*/mU 1580 1120 AS mArGmArGmGrUmGrAmArGmCmGmArAm GrUmGrCmA*/UNA-U*/mU

[0243] UNA Oligomers Targeting HBV

[0244] Embodiments of this invention can provide oligomeric molecules that are active agents targeted to HBV.

[0245] Examples of UNA oligomers of this invention that are targeted to an HBV component are shown in Table 20. Table 20 shows "sense" and "antisense" pairs.

TABLE-US-00021 TABLE 20 UNA oligomers targeted to HBV (Sense (S)- Antisense (AS)) SEQ REF ID HBV (Sense (S)-Antisense (AS)) POS NO S/AS (5'-3') 1578 1121 S UNA-U/*/mGrUmGrCmArCmUrUrCrGm CrUmUrCmArCmCrU/*/UNA-U/*/T 1578 1122 AS mArGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U/*/T 1578 1123 S UNA-U/*/fGrUfGrCfArCfUrUrCrGf CrUfUrCfArCfCrU/*/UNA-U/*/dT 1578 1124 AS fArGfGrUfGrAfArGfCrGfAfAfGrUf GrCfArCfA/UNA-U/*/dT 1578 1125 S UNA-U/*/rGfUrGfCrAfCfUfUfCrGf CfUfUfCrAfCfCfU/*/UNA-U/*/dT 1578 1126 AS rArGrGfUrGrArArGfCrGrArArGfUr GfCrAfCrA/UNA-U/*/dT 1578 1127 S UNA-U/*/mGfUmGfCmAfCmUfUfCfGm CfUmUfCmAfCmCfU/*/UNA-U/*/T 1578 1128 AS mAfGmGfUmGfAmAfGmCfGmAmAmGfUm GfCmAfCmA/UNA-U/*/T 1777 1129 S UNA-G/*/mArGmGrCmUrGmUrArGrGm CrAmUrAmArAmUrU/*/UNA-U/*/T 1777 1130 AS UNA-G/*/mArGmGrCmUrGmUrArGrGm CrAmUrAmArAmUrU/*/UNA-U/*/T 1777 1131 S UNA-G/*/fArGfGrCfUrGfUrArGrGf CrAfUrAfArAfUrU/*/UNA-U/*/T 1777 1132 AS fArAfUrUfUrAfUrGfCrCfUfAfCrAf GrCfCrUfC/UNA-U/*/T 1777 1133 S UNA-G/*/rArGrGfCfUrGfUrArGrGf CrAfUrArArAfUfU/*/UNA-U/*/T 1777 1134 AS rArAfUfUfUrAfUrGfCfCfUrAfCrAr GfCfCfUfC/UNA-U/*/T 1777 1135 S UNA-G/*/mAfGmGfCmUfGmUfAfGfGm CfAmUfAmAfAmUfU/*/UNA-U/*/T 1777 1136 AS UNA-G/*/mAfGmGfCmUfGmUfAfGfGm CfAmUfAmAfAmUfU/*/UNA-U/*/T 380 1137 S UNA-G/*/mAfGmGfCmUfGmUfAfGfGm CfAmUfAmAfAmUfU/*/UNA-U/*/T 380 1138 AS mUrGmArUmArAmArAmCrGmCmCmGrCm ArGmArCmA/UNA-U/*/mU 380 1139 S UNA-U/*/fGrUfCrUfGrCfGrGrCrGfU rUfUrUfArUfCrA/*/UNA-U/*/fU 380 1140 AS fUrGfArUfArAfArAfCrGfCfCfGrCfAr GfArCfA/UNA-U/*/fU 380 1141 S UNA-U/*/rGfUfCfUrGfCrGrGfCrGfUf UfUfUrAfUfCrA/*/UNA-U/*/fU 380 1142 AS fUrGrAfUrArArArAfCrGfCfCrGfCrAr GrAfCrA/UNA-U/*/fU 380 1143 S UNA-U/*/mGfUmCfUmGfCmGfGfCfGmUf UmUfUmAfUmCfA/*/UNA-U/*/mU 380 1144 AS UNA-U/*/mGfUmCfUmGfCmGfGfCfGmUf UmUfUmAfUmCfA/*/UNA-U/*/mU

[0246] In Tables herein, rN refers to N, which is a ribonucleotide, mN refers to a chemically-modified 2'-OMe ribonucleotide, an asterisk * between characters refers to a phosphorothioate linkage, dN refers to a deoxyribonucleotide, f refers to a 2'-deoxy-2'-fluoro ribonucleotide.

[0247] Additional compounds of this invention are shown in Table 21.

TABLE-US-00022 TABLE 21 UNA oligomers targeted to HBV (Sense (S)-Antisense (AS)) SEQ REF ID HBV (Sense (S)-Antisense (AS)) POS NO S/AS (5'-3') 1575 1145 S UNA-C*/mCrGmUrGmUrGmCrArCrUm UrCmGrCmUrUmCrA*/UNA-U*/dT 1575 1146 AS mUrGmArAmGrCmGrAmArGmUmGmCr AmCrAmCrGmG/UNA-U*/dT 1576 1147 S UNA-C*/mGrUmGrUmGrCmArCrUrUm CrGmCrUmUrCmArC*/UNA-U*/dT 1576 1148 AS mGrUmGrAmArGmCrGmArAmGmUmGr CmArCmArCmG/UNA-U*/dT 1581 1149 S UNA-G*/mCAmCUmUCmGCUUmCAmCC mUCmUG*/UNA-U*/dT 1581 1150 AS mCAmGAmGGmUGmAAmGmCmGAmAGmUG mC/UNA-U*/dT 1580 1151 S UNA-U*/mGrCmArCmUrUmCrGrCrUm UrCmArCmCrUmCrU*/UNA-U*/dT 1580 1152 AS mArGmArGmGrUmGrAmArGmCmGmAr AmGrUmGrCmA/UNA-U*/dT 376 1153 A UNA-G*/mAUmGUmGUmCUGCmGGmCG mUUmUU*/UNA-U*/dT 376 1154 AS mAAmAAmCGmCCmGCmAmGmACmAC mAUmC/UNA-U*/dT 378 1155 S UNA-U*/mGUmGUmCUmGCGGmCGm UUmUUmAU*/UNA-U*/dT 378 1156 AS mAUmAAmAAmCGmCCmGmCmAGmAC mACmA/UNA-U*/dT 380 1157 S UNA-U/*mGrUmCrUmGrCmGrGrCrG mUrUmUrUmArUmCrA/*UNA-U/*dT 380 1158 AS mUrGmArUmArAmArAmCrGmCmCmGr CmArGmArCmA/UNA-U/*dT 413 1159 S UNA-C/*mUGmCUmGCmUAUGmCCmUC mAUmCU/*UNA-U/*dT 413 1160 AS mAGmAUmGAmGGmCAmUmAmGCmAGm CAmG/UNA-U/*dT 411 1161 S UNA-U/*mCCmUGmCUmGCUAmUGm CCmUCmAU/*UNA-U/*dT 411 1162 AS mAUmGAmGGmCAmUAmGmCmAGmCA mGGmA/UNA-U/*dT 1777 1163 S UNA-G/*mArGmGrCmUrGmUrArGrGm CrAmUrAmArAmUrU/*UNA-U/*dT 1777 1164 AS mArAmUrUmUrAmUrGmCrCmUmAmCr AmGrCmCrUmC/UNA-U/*dT 1780 1165 S UNA-G/*mCUmGUmAGmGCAUmAAmA UmUGmGU/*UNA-U/*dT 1780 1166 AS mACmCAmAUmUUmAUmGmCmCUmAC mAGmC/UNA-U/*dT 1781 1167 S UNA-C/*mUGmUAmGGmCAUAmAAm UUmGGmUC/*UNA-U/*dT 1781 1168 AS mGAmCCmAAmUUmUAmUmGmCCmUA mCAmG/UNA-U/*dT 1782 1169 S UNA-U/*mGUmAGmGCmAUAAmAUm UGmGUmCU/*UNA-U/*dT 1782 1170 AS mAGmACmCAmAUmUUmAmUmGCm CUmACmA/UNA-U/*dT

[0248] Compositions for Use Against HBV

[0249] Embodiments of this invention can provide compositions of oligomeric molecules that are active agents targeted to HBV.

[0250] A composition for use against HBV viral infection can provide targeting for suppressing multiple viral gene products.

[0251] Without wishing to be bound by any one particular theory, certain open reading frames (ORF) encoding the P, S, C, and X genes of HBV can overlap.

[0252] In some embodiments, a composition of this invention may contain an oligomeric compound targeted to an HBV genomic transcript or ORF for HBsAg. For example, these embodiments can inhibit expression of HBsAg, regardless of the location of the HBV genomic DNA.

[0253] In additional embodiments, a composition may contain an oligomeric compound targeted to an HBV genomic transcript or ORF for HBeAg.

[0254] In further embodiments, a composition may contain an oligomeric compound targeted to an HBV genomic transcript or ORF for X protein.

[0255] In further embodiments, a composition may contain an oligomeric compound targeted to an HBV genomic transcript or ORF for DNA polymerase (P).

[0256] In certain embodiments, a composition may contain an oligomeric compound targeted to a conserved HBV genomic region of the transcripts or open reading frames from genes X, S, and C.

[0257] In certain embodiments, a composition may contain an oligomeric compound targeted to a conserved HBV genomic region of the transcripts or open reading frames from genes X, S, C and P.

[0258] In some aspects, a composition of this invention includes a dyad of oligomeric compounds as the active agents targeted to HBV.

[0259] Examples of dyad compositions include a composition containing a compound with a reference position in the range 1403 to 1623, and a compound with a reference position in the range 155 to 550.

[0260] Examples of dyad compositions include a composition containing a compound with a reference position in the range 1575 to 1581, and a compound with a reference position in the range 245 to 414.

[0261] Examples of dyad compositions include a composition containing a compound with a reference position in the range 1525 to 1604, and a compound with a reference position in the range 374 to 414.

[0262] Examples of dyad compositions include a composition containing a compound with a reference position in the range 1525 to 1604, and a compound with a reference position in the range 1776 to 1818.

[0263] Examples of dyad compositions include a composition containing a compound with a reference position in the range 374 to 414, and a compound with a reference position in the range 1776 to 1782.

[0264] Examples of dyad compositions include a composition containing a compound with the reference position 1578 and a compound with the reference position 380. Examples of dyad compositions include a composition containing a compound with the reference position 1578 and a compound with the reference position 376 or 411.

[0265] Examples of dyad compositions include compositions containing compounds with the reference positions 1575 and 376, 1575 and 380, 1575 and 511, 1581 and 376, 1581 and 380, as well as 1581 and 411.

[0266] Examples of dyad compositions include compositions containing a compound with the reference position 1578 and a compound with the reference position 1777.

[0267] Examples of dyad compositions include compositions containing compounds with the reference positions 1578 and 1780, or 1578 and 1782, or 1575 and 1777, or 1575 and 1780, or 1575 and 1782, or 1581 and 1777, or 1581 and 1780, or 1581 and 1782, or 1576 and 1777, or 1576 and 1780, or 1576 and 1782.

[0268] For example, a dyad composition may contain the compounds 1578 and 380 shown in Table 22.

TABLE-US-00023 TABLE 22 Dyad composition of UNA oligomers targeted to HBV (Sense (S)-Antisense (AS)) SEQ REF ID HBV (Sense (S)-Antisense (AS)) POS NO S/AS (5'-3') 1578 1171 S UNA-U/*mGrUmGrCmArCmUrUrCrGmCr UmUrCmArCmCrU/*UNA-U/*dT 1578 1172 AS mArGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U/*dT 380 1173 S UNA-U/*mGrUmCrUmGrCmGrGrCrGm UrUmUrUmArUmCrA/*UNA-U/*mU 380 1174 AS mUrGmArUmArAmArAmCrGmCmCmGr CmArGmArCmA/UNA-U/*mU

UNA Oligomer Triad Compositions for HBV

[0269] In some aspects, a composition of this invention includes triads of oligomeric compounds as the active agents targeted to HBV.

[0270] Examples of triad compositions include a composition containing a compound with a reference position in the range 1403 to 1623, a compound with a reference position in the range 155 to 550, and a compound with a reference position in the range 1624 to 1930.

[0271] Examples of triad compositions include a composition containing a compound with a reference position in the range 1525 to 1582, a compound with a reference position in the range 245 to 414, and a compound with a reference position in the range 1777 to 1818.

[0272] Examples of triad compositions include a composition containing a compound with a reference position in the range 1525 to 1604, a compound with a reference position in the range 374 to 414, and a compound with a reference position in the range 1776 to 1782.

[0273] Examples of triad compositions include a composition containing a compound with a reference position in the range 1525 to 1582, a compound with a reference position in the range 374 to 414, and a compound with a reference position in the range 1776 to 1782.

[0274] Examples of triad compositions include a composition containing a compound with the reference position 1578, a compound with the reference position 380, and a compound with the reference position 1777.

[0275] Examples of triad compositions include a composition containing a compound with the reference position 1576, a compound with the reference position 380, and a compound with the reference position 1777.

[0276] Examples of triad compositions include a composition containing a compound with the reference position 1575, a compound with the reference position 380, and a compound with the reference position 1777.

[0277] Examples of triad compositions include a composition containing a compound with the reference position 1578, a compound with the reference position 1777, and a compound with the reference position 376 or 411.

[0278] Examples of triad compositions include a composition containing a compound with the reference position 1578, a compound with the reference position 1780 or 1782, and a compound with the reference position 376 or 411.

[0279] Examples of triad compositions include compositions containing compounds with the reference positions:

1578, 1777 and 376; 1578, 1777 and 380; 1578, 1777 and 411; 1578, 1780 and 376; 1578, 1780 and 380; 1578, 1780 and 411; 1578, 1782 and 376; 1578, 1782 and 380; 1578, 1782 and 411; 1575, 1777 and 376; 1575, 1777 and 380; 1575, 1777 and 411; 1575, 1780 and 376; 1575, 1780 and 380; 1575, 1780 and 411; 1575, 1782 and 376; 1575, 1782 and 380; 1575, 1782 and 411; 1581, 1777 and 376; 1581, 1777 and 380; 1581, 1777 and 411; 1581, 1780 and 376; 1581, 1780 and 380; 1581, 1780 and 411; 1581, 1782 and 376; 1581, 1782 and 380; 1581, 1782 and 411; 1576, 1777 and 376; 1576, 1777 and 380; 1576, 1777 and 411; 1576, 1780 and 376; 1576, 1780 and 380; 1576, 1780 and 411; 1576, 1782 and 376; 1576, 1782 and 380; 1576, 1782 and 411; 1578, 1818 and 376; 1578, 1818 and 380; 1578, 1818 and 411; 1575, 1818 and 376; 1575, 1818 and 380; 1575, 1818 and 411.

[0280] For example, a triad composition may contain the compounds 1578, 380 and 1777 shown in Table 23.

TABLE-US-00024 TABLE 23 Triad composition of UNA oligomers targeted to HBV (Sense (5)-Antisense (AS)) SEQ REF ID HBV (Sense (S)-Antisense (AS)) POS NO S/AS (5'-3') 1578 1175 S UNA-U/*mGrUmGrCmArCmUrUrCrGmCr UmUrCmArCmCrU/*UNA-U/*dT 1578 1176 AS mArGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U/*dT 380 1177 S UNA-U/*mGrUmCrUmGrCmGrGrCrGm UrUmUrUmArUmCrA/*UNA-U/*dT 380 1178 AS mUrGmArUmArAmArAmCrGmCmCmGrCm ArGmArCmA/UNA-U/*dT 1777 1179 S UNA-G/*mArGmGrCmUrGmUrArGrGmCr AmUrAmArAmUrU/*UNA-U/*dT 1777 1180 AS mArAmUrUmUrAmUrGmCrCmUmAmCrAm GrCmCrUmC/UNA-U/*dT

[0281] In Tables herein, rN refers to N, which is a ribonucleotide, mN refers to a chemically-modified 2'-OMe ribonucleotide, an * between characters refers to a phosphorothioate linkage, and dN refers to a deoxyribonucleotide.

[0282] HBV Sequences

[0283] Some examples of known sequences for HBV are shown in Table 24.

TABLE-US-00025 TABLE 24 Sequences for HBV ACC # Genotype Description HE974383.1 A HBV genotype A2 complete genome, isolate Mart-B74 HE974381.1 A HBV genotype A1 complete genome, isolate Mart-B64 HE974376.1 A HBV genotype A2 complete genome, isolate Mart-B45 HE974375.1 A HBV genotype A1 complete genome, isolate Mart-B43 HE974374.1 A HBV genotype A2 complete genome, isolate Mart-B42 HE974371.1 A HBV genotype A2 complete genome, isolate Mart-B34 HE974370.1 A HBV genotype A1 complete genome, isolate Mart-B27 HE974367.1 A HBV genotype A2 complete genome, isolate Mart-B22 HE974365.1 A HBV genotype A1 complete genome, isolate Mart-B16 HE974364.1 A HBV genotype A2 complete genome, isolate Mart-B15 HE974363.1 A HBV genotype A1 complete genome, isolate Mart-B06 HE974362.1 A HBV genotype A1 complete genome, isolate Mart-B01 AB778116.1 A HBV genotype A gene for polymerase, complete cds, strain: OCU01 AB299858.1 adr Hepatitis B virus subtype adr DNA, complete genome, clone: HBVFH0204 AB176642.1 adr Hepatitis B virus subtype ADR DNA, complete genome, isolate: HBV-115 HW390268.1 adw JP 2013537423-A/508: RNA Interference Mediated Inhibition of Hepatitis B Virus (HBV) AM282986.1 adw Hepatitis B virus (SUBTYPE ADW2), genotype A, complete genome D00331.1 adw HPBADW3 Hepatitis B virus subtype ADW genomic DNA, complete genome, clone: pIDW420 D00330.1 adw HPBADW2 Hepatitis B virus subtype ADW genomic DNA, complete genome, clone: pODW282 D00329.1 adw HPBADW1 Hepatitis B virus subtype ADW genomic DNA, complete genome, clone: pJDW233 AB540582.1 B HBV genotype B DNA, complete genome, strain: B0901189(NT15) AB554017.1 B HBV genotype B DNA, complete genome, isolate: NMB09010 AB602818.1 B HBV genotype B DNA, complete genome, isolate: AH-2 AB644287.1 C HBV genotype C DNA, complete genome, isolate: NAB52 AB644286.1 C HBV genotype C DNA, complete genome, isolate: NAB47 AB644284.1 C HBV genotype C DNA, complete genome, isolate: NAB32 AB644283.1 C HBV genotype C DNA, complete genome, isolate: NAB28 AB644281.1 C HBV genotype C DNA, complete genome, isolate: NAB9 AB644280.1 C HBV genotype C DNA, complete genome, isolate: NAB1 AB560662.1 C HBV genotype C DNA, complete genome, isolate: 60PU AB560661.1 C HBV genotype C DNA, complete genome, isolate: 58PU AB554025.1 C HBV genotype C DNA, complete genome, isolate: MRK89073 AB554022.1 C HBV genotype C DNA, complete genome, isolate: GRS08325 AB554021.1 C HBV genotype C DNA, complete genome, isolate: GRS08298 AB554020.1 C HBV genotype C DNA, complete genome, isolate: NMB09124 AB554019.1 C HBV genotype C DNA, complete genome, isolate: NMB09122 AB554018.1 C HBV genotype C DNA, complete genome, isolate: NMB09075 AB554015.1 C HBV genotype C DNA, complete genome, isolate: TRF08111 AB554014.1 C HBV genotype C DNA, complete genome, isolate: TRF08029 AB540585.1 C HBV genotype C DNA, complete genome, strain: C0901192(NT18) AB540584.1 C HBV genotype C DNA, complete genome, strain: C0901190(NT16) AB540583.1 C HBV genotype C DNA, complete genome, strain: C0901177(NT3) HE974382.1 D HBV genotype D4 complete genome, isolate Mart-B70 HE974379.1 D HBV genotype D3 complete genome, isolate Mart-B58 HE974378.1 D HBV genotype D4 complete genome, isolate Mart-B50 HE974377.1 D HBV genotype D3 complete genome, isolate Mart-B47 HE974373.1 D HBV genotype D4 complete genome, isolate Mart-B37 HE974372.1 D HBV genotype D4 complete genome, isolate Mart-B36 HE815465.1 D HBV genotype D, serotype ayw3, complete genome AB554024.1 D HBV genotype D DNA, complete genome, isolate: GRS08538 AB554023.1 D HBV genotype D DNA, complete genome, isolate: GRS08457 AB554016.1 D HBV genotype D DNA, complete genome, isolate: TRF08226 AB267090.1 D Hepatitis B virus ayw/Japan/Ehime 22-HS/2005 DNA, complete genome HE974384.1 E HBV genotype E complete genome, isolate Mart-B84 HE974380.1 E HBV genotype E complete genome, isolate Mart-B63 AP007262.1 E HBV genotype E DNA, complete genome, isolate: HB-JI411F HE974369.1 F HBV genotype F2 complete genome, isolate Mart-B26 HE974368.1 F HBV genotype F4 complete genome, isolate Mart-B24 HE974366.1 F HBV genotype F2 complete genome, isolate Mart-B18 AB625343.1 G HBV genotype G DNA, complete genome, isolate: MEX921M AB625342.1 G HBV genotype G DNA, complete genome, isolate: MEX918M AP007264.1 G HBV genotype G DNA, complete genome, isolate: HB-JI444GF AB846650.1 H HBV genotype H DNA, complete genome, isolate: B-MHJ9014 AB516395.1 H HBV genotype H DNA, complete genome, isolate: MEX914M AB516394.1 H HBV genotype H DNA, complete genome, isolate: MEX912M AB516393.1 H HBV genotype H DNA, complete genome, isolate: 904MEXM AP007261.1 H HBV genotype H DNA, complete genome, isolate: HB-JI260F AB298362.1 H HBV genotype H DNA, complete genome, isolate: HBV ST0404 AB246338.1 Ae Hepatitis B virus DNA, complete genome, clone: Ae_JPN AB246341.1 Bj Hepatitis B virus DNA, complete genome, clone: Bj_JPN35 AB246345.1 C Hepatitis B virus DNA, complete genome, clone: C_JPNAT AB246347.1 D Hepatitis B virus DNA, complete genome, clone: D_IND60

[0284] Methods for Treating HBV Disease

[0285] Methods of this invention include the treatment and prevention of various diseases in mammalian subjects. A subject can be a human or mammal.

[0286] In the methods of this invention, a subject in need of treatment or prevention can be administered an effective amount of an oligomeric compound of this invention.

[0287] An effective amount of an oligomeric compound of this invention can be a dose ranging from 0.001 mg/kg to 50.0 mg/kg.

[0288] In the methods of this invention, target mRNA expression can be reduced in a subject for at least 5 days. In certain embodiments, target mRNA expression can be reduced in a subject for at least 10 days, or 15 days.

[0289] In the methods of this disclosure, the administration of an oligomeric compound may not result in an inflammatory response.

[0290] In further embodiments, this invention includes methods for inhibiting expression of a target gene in a cell, by treating the cell with an oligomeric compound of this invention.

[0291] In additional embodiments, this invention includes methods for inhibiting expression of a target gene in a mammal, by administering to the mammal a composition containing an oligomeric compound of this invention.

[0292] Pharmaceutical Compositions

[0293] In some aspects, this invention provides pharmaceutical compositions containing an oligomeric compound and a pharmaceutically acceptable carrier.

[0294] A pharmaceutical composition can be capable of local or systemic administration. In some aspects, a pharmaceutical composition can be capable of any modality of administration. In certain aspects, the administration can be intravenous, subcutaneous, pulmonary, intramuscular, intraperitoneal, dermal, oral, or nasal administration.

[0295] Embodiments of this invention include pharmaceutical compositions containing an oligomeric compound in a lipid formulation.

[0296] In some embodiments, a pharmaceutical composition may comprise one or more lipids selected from cationic lipids, anionic lipids, sterols, pegylated lipids, and any combination of the foregoing.

[0297] In certain embodiments, a pharmaceutical composition can be substantially free of liposomes.

[0298] In further embodiments, a pharmaceutical composition can include liposomes or nanoparticles.

[0299] Some examples of lipids and lipid compositions for delivery of an active molecule of this invention are given in WO/2015/074085, which is hereby incorporated by reference in its entirety.

[0300] In additional embodiments, a pharmaceutical composition can contain an oligomeric compound within a viral or bacterial vector.

[0301] A pharmaceutical composition of this disclosure may include carriers, diluents or excipients as are known in the art. Examples of pharmaceutical compositions are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro ed. 1985).

[0302] Examples of excipients for a pharmaceutical composition include antioxidants, suspending agents, dispersing agents, preservatives, buffering agents, tonicity agents, and surfactants.

EXAMPLES

Example 1

Luciferase Reporter Assay

[0303] Luciferase-based reporter plasmid was constructed based on psiCHECK.TM.2 vector (Promega, Madison, Wis.). Reporter p(1-20) was generated with oligonucleotides containing the sequence from position 1 through 2500 relative to Eco RI digestion site cloned into the multiple cloning region downstream of the stop codon of the SV40 promoted Renilla luciferase gene in psiCHECK.TM.2, which made the expression of Renilla luciferase gene under the regulation of the artificial 3'UTR sequence. Renilla luciferase activity was then used as an indicator of the effect of the artificial 3'UTR on transcript stability and translation efficiency. The psiCHECK.TM.-2 Vector also contained a constitutively expressed Firefly luciferase gene, which served as an internal control to normalize transfection efficiency.

[0304] A total of 5,000 HepB3 cells (American Type Culture Collection) were plated onto a well of 96-well plate one day before the transfectrion. The cells were incubated at 37.degree. C. in 100 .mu.l of DMEM (Life Technologies, Carlsbad, Calif.) supplemented with 0.1 mM nonessential amino acids and 10% FBS (Life Technologies, Carlsbad, Calif.). The culture medium was changed to 90 .mu.l of fresh medium just before the transfection. The reporter plasmid and UNA Oligomer were co-transfected with transfection reagent, Lipofectamine.TM. 3000 (Life Technologies, Carlsbad, Calif.) was used to transfect reporter plasmid (100 ng) and a various amount of UNA Oligomer together with P3000 into the cells according to manufacturer's instruction.

[0305] Dual-Luciferase Reporter Assay System (DLR assay system, Promega, Madison, Wis.) was used to perform dual-reporter assays on psiCHECK2 based reporter systems. Twenty-four hours after transfection, the cells were washed gently with phosphate buffered saline once. A 50 .mu.l well of Passive Lysis Buffer (Promega, Madison, Wis.) was added to the cells and incubated with gentle rocking for 20 min at room temperature. Luciferase activities were measured using Cytation 3 imaging reader (BioTek, Winooski, Vt.) and the effect of the UNA Oligomer on reporter expression was calculated based on ratio of Renilla/Firefly to normalize cell number and transfection efficiency.

Example 2

[0306] The HBV inhibitory effect of UNA oligomers was observed with a psiCHECK2 assay. At 1 nM concentration for 6 days, the percent inhibition of target expression for each of the UNA oligomeric compounds in Table 19 designated as having Reference Position 1578 was determined to be from 77% to 97%. Thus, all of the UNA oligomeric compounds in Table 19 having Reference Position 1578 were operable for silencing target expression.

Example 3

[0307] The HBV inhibitory effect of UNA oligomers was observed with a psiCHECK2 assay. At 1 nM concentration for 6 days, the percent inhibition of target expression for each of the UNA oligomeric compounds in Table 19 designated as having Reference Position 1777 was determined to be from 77% to 92%. Thus, all of the UNA oligomeric compounds in Table 19 having Reference Position 1777 were operable for silencing target expression.

Example 4

[0308] The HBV inhibitory effect of UNA oligomers was observed with a psiCHECK2 assay. At 1 nM concentration for 6 days, the percent inhibition of target expression for each of the UNA oligomeric compounds in Table 19 designated as having Reference Position 380 was determined to be from 87% to 94%. Thus, all of the UNA oligomeric compounds in Table 19 having Reference Position 380 were operable for silencing target expression.

Example 5

[0309] The HBV inhibitory effect of UNA oligomers was observed with a psiCHECK2 assay. At 1 nM concentration for 6 days, the percent inhibition of target expression for the UNA oligomeric compound in Table 19 designated as having Reference Position 1576 was determined to be 93%. Thus, UNA oligomeric compounds having Reference Position 1576 were operable for modulating target expression.

Example 6

[0310] The HBV inhibitory effect of UNA oligomers was observed with a psiCHECK2 assay. At 1 nM concentration for 6 days, the percent inhibition of target expression for the UNA oligomeric compound in Table 19 designated as having Reference Position 1575 was determined to be 90%. Thus, UNA oligomeric compounds having Reference Position 1575 were operable for modulating target expression.

Example 7

[0311] The HBV inhibitory effect of UNA oligomers was observed with a psiCHECK2 assay. At 1 nM concentration for 6 days, the percent inhibition of target expression for the UNA oligomeric compound in Table 19 designated as having Reference Position 1580 was determined to be 95%. Thus, UNA oligomeric compounds having Reference Position 1580 were operable for modulating target expression.

Example 8

[0312] The HBV inhibitory effect of UNA oligomers was observed with a psiCHECK2 assay. UNA oligomers of this invention in Table 17 were found to exhibit 1050 for inhibiting target expression as shown in Table 25.

TABLE-US-00026 TABLE 25 IC50 of UNA oligomers targeted to HBV Reference IC50 pM Position (6 days) 244 917 245 328 246 816 248 148 251 554 252 374 253 703 254 44 256 8 376 16 378 114 380 6.7 409 328 411 58 412 298 413 123 414 363 1575 65 1576 137 1577 472 1578 63 1580 255 1581 22 1776 461 1777 26 1779 348 1780 151 1781 227 1782 177 1818 49

[0313] Thus, UNA oligomeric compounds of this invention were operable for modulating HBV target expression. The UNA oligomeric compounds of this invention exhibited picomolar activity in vitro for inhibiting target expression. In some embodiments, the UNA oligomeric compounds of this invention exhibited surprisingly high activity in vitro of about IC50<200 pM for inhibiting target expression.

Example 9

[0314] The HBV inhibitory effect in vivo for UNA oligomers was observed in a humanized PXB Mouse model of HBV infection. The UNA oligomers of this invention exhibited profound reduction of HBV serum infection parameters in vivo. In this study, the UNA oligomers were contained in lipid nanoparticle formulations, -1 and -2.

[0315] The UNA oligomers were formulated or co-formulated in lipid nanoparticles and injected intravenously into HBV-infected Phoenix Bio (PXB) mice. The mice were Genotype: cDNA-uPA.sup.wild/+/SCID [cDNA-uPA.sup.wild/+: B6;129SvEv-Plau, SCID: C.B-17/Icr-scid/scid Jcl] containing human hepatocytes with an estimated replacement index of 70% or more.

[0316] The study used an ascending dose in which mice were treated with 3 mg/kg on day 0, then 5 mg/kg on day 4, then 10 mg/kg on day 8.

[0317] As shown in FIG. 2, treatment with both UNA oligomer 1576 and UNA oligomer triad (1576, 380, 177) caused a rapid and sustained reduction in viral endpoint serum HBsAg compared to PBS control group. (Mean.+-.SEM).

[0318] As shown in Table 26, treatment with both UNA oligomer 1576 and UNA oligomer triad (1576, 380, 177) caused a sustained reduction in viral endpoint serum HBeAg compared to PBS control group. (Mean.+-.SEM).

TABLE-US-00027 TABLE 26 Serum HBeAg viral endpoint HBeAg (% control) UNA oligomer (normalized to hAlb) formulation Day 12 PBS control 100 1576-1 48.2 1576-2 59.8 (1576, 380, 177)-1 10.5 (1576, 380, 177)-2 15.0

[0319] As shown in Table 27, treatment with both UNA oligomer 1576 and UNA oligomer triad (1576, 380, 177) caused a sustained reduction in viral endpoint serum HBV DNA compared to PBS control group. (Mean.+-.SEM).

TABLE-US-00028 TABLE 27 Serum HBV DNA viral endpoint HBV DNA (% control) UNA oligomer (normalized to hAlb) formulation Day 12 PBS control 100 1576-1 31.2 1576-2 52.4 (1576, 380, 1777)-1 4.1 (1576, 380, 1777)-2 7.7

[0320] The compositions in FIG. 2 and Tables 26 and 27 were UNA oligomer triad composition (1777 (SEQ ID NO:1005 and 1006), 380 (SEQ ID NO:973 and 974), 1576 (SEQ ID NO:989 and 990)).

[0321] Thus, the UNA oligomers of this invention demonstrated significant and unexpectedly advantageous HBV inhibition efficacy in vivo. For all viral endpoints, HBsAg, HBeAg, and HBV DNA, the treatment with UNA oligomer triad composition (1576, 380, 177) was significantly superior to UNA oligomer 1576.

Example 10

[0322] The HBV inhibitory effect in vivo for UNA oligomers was observed in a PXB Mouse model of HBV infection. The UNA oligomers of this invention exhibited profound reduction of HBV serum infection parameters in vivo. In this study, the UNA oligomers were contained in lipid nanoparticle formulation.

[0323] The UNA oligomers were co-formulated in lipid nanoparticles and injected intravenously into HBV-infected Phoenix Bio (PXB) mice. The mice were Genotype: cDNA-uPA.sup.wild/+/SCID [cDNA-uPA.sup.wild/+: B6;129SvEv-Plau, SCID: C.B-17/Icr-scid/scid Jcl] containing human hepatocytes with an estimated replacement index of 70% or more.

[0324] The study used an ascending dose in which mice were administered every 4 days, up to day 40, and viral endpoints were monitored every 4 days through day 44.

[0325] As shown in FIG. 3, treatment with UNA oligomer triad (1576, 380, 1777) caused a rapid and sustained reduction in viral endpoint serum HBsAg compared to PBS control group. (Mean.+-.SEM). The dose-dependent response in vivo shows a pharmacological effect of the UNA oligomer composition. The composition in FIG. 3 was UNA oligomer triad composition (1777 (SEQ ID NO:1005 and 1006), 380 (SEQ ID NO:973 and 974), 1576 (SEQ ID NO:989 and 990)).

[0326] As shown in FIG. 4, treatment with UNA oligomer triad (1576, 380, 1777) caused a rapid and sustained reduction in viral endpoint serum HBeAg compared to PBS control group. (Mean.+-.SEM). The dose-dependent response in vivo shows a pharmacological effect of the UNA oligomer composition. The composition in FIG. 4 was UNA oligomer triad composition (1777 (SEQ ID NO:1005 and 1006), 380 (SEQ ID NO:973 and 974), 1576 (SEQ ID NO:989 and 990)).

[0327] As shown in FIG. 5, treatment with UNA oligomer triad (1576, 380, 1777) caused a rapid and sustained reduction in viral endpoint serum HBV DNA compared to PBS control group. (Mean.+-.SEM). The dose-dependent response in vivo shows a pharmacological effect of the UNA oligomer composition. The composition in FIG. 5 was UNA oligomer triad composition (1777 (SEQ ID NO:1005 and 1006), 380 (SEQ ID NO:973 and 974), 1576 (SEQ ID NO:989 and 990)).

[0328] Thus, the UNA oligomers of this invention demonstrated significant and unexpectedly advantageous HBV inhibition efficacy in vivo.

Example 11

[0329] The HBV inhibitory effect in vivo for UNA oligomers was observed in a PXB Mouse model of HBV infection. The UNA oligomers of this invention exhibited profound reduction of HBV serum infection parameters in vivo. In this study, the UNA oligomers were contained in lipid nanoparticle formulation.

[0330] The UNA oligomers were formulated or co-formulated in lipid nanoparticles and injected intravenously into HBV-infected Phoenix Bio (PXB) mice. The mice were Genotype: cDNA-uPA.sup.wild/+/SCID [cDNA-uPA.sup.wild/+: B6;129SvEv-Plau, SCID: C.B-17/Icr-scid/scid Jcl] containing human hepatocytes with an estimated replacement index of 70% or more.

[0331] Serum viral endpoints were monitored up to 15 days after the single injection.

[0332] As shown in FIG. 6, treatment with each of UNA oligomers 1777 (SEQ ID NO:1179 and 1180), 380 (SEQ ID NO:1173 and 1174) and 1578 (SEQ ID NO:1175 and 1176) caused a rapid and sustained reduction in viral endpoint serum HBsAg compared to PBS control group. (Mean.+-.SEM).

[0333] As shown in FIG. 7, treatment with each of UNA oligomers 1777 (SEQ ID NO:1179 and 1180), 380 (SEQ ID NO:1173 and 1174) and 1578 (SEQ ID NO:1175 and 1176) caused a rapid and sustained reduction in viral endpoint serum HBeAg compared to PBS control group. (Mean.+-.SEM).

[0334] As shown in FIG. 8, treatment with each of UNA oligomers 1777 (SEQ ID NO:1179 and 1180), 380 (SEQ ID NO:1173 and 1174) and 1578 (SEQ ID NO:1175 and 1176) caused a rapid and sustained reduction in viral endpoint serum HBV DNA compared to PBS control group. (Mean.+-.SEM).

[0335] As shown in FIG. 9, treatment with UNA oligomer triad composition (1777 (SEQ ID NO:1179 and 1180), 380 (SEQ ID NO:1173 and 1174), 1578 (SEQ ID NO:1175 and 1176)) caused a rapid and sustained reduction in viral endpoint serum HBsAg compared to PBS control group. (Mean.+-.SEM). The dose-dependent response in vivo shows a pharmacological effect of the UNA oligomer composition.

[0336] As shown in FIG. 10, treatment with UNA oligomer triad composition (1777 (SEQ ID NO:1179 and 1180), 380 (SEQ ID NO:1173 and 1174), 1578 (SEQ ID NO:1175 and 1176)) caused a rapid and sustained reduction in viral endpoint serum HBeAg compared to PBS control group. (Mean.+-.SEM). The dose-dependent response in vivo shows a pharmacological effect of the UNA oligomer composition.

[0337] As shown in FIG. 11, treatment with UNA oligomer triad composition (1777 (SEQ ID NO:1179 and 1180), 380 (SEQ ID NO:1173 and 1174), 1578 (SEQ ID NO:1175 and 1176)) caused a rapid and sustained reduction in viral endpoint serum HBV DNA compared to PBS control group. (Mean.+-.SEM). The dose-dependent response in vivo shows a pharmacological effect of the UNA oligomer composition.

[0338] Thus, the UNA oligomers of this invention demonstrated significant and unexpectedly advantageous HBV inhibition efficacy in vivo.

Example 12

[0339] The HBV inhibitory effect in vivo for UNA oligomers was observed in an AAV-HBV mouse model of HBV infection. The UNA oligomers of this invention exhibited profound reduction of HBV serum infection parameters in vivo. In general, the AAV-HBV mouse model is a robust model for investigating HBV infection, and can provide direct clinical pertinence for drug efficacy and potency. In this study, the UNA oligomers were contained in lipid nanoparticle formulation.

[0340] The UNA oligomers were formulated or co-formulated in lipid nanoparticles and injected intravenously into C57Bl/6 mice with active HBV replication after AAV-mediated delivery of a recombinant HBV genome to the liver.

[0341] The study was an ascending dose design in which mice were treated with 3 mg/kg on day 0, then 5 mg/kg on day 4, then 10 mg/kg on day 8.

[0342] Serum viral endpoints were monitored 15 days before, and at least 22 days after treatment.

[0343] As shown in FIG. 12, treatment with each of UNA oligomers 380 (SEQ ID NO:973 and 974), 1777 (SEQ ID NO:1005 and 1006), and 1576 (SEQ ID NO:1003 and 1004) caused a rapid and sustained reduction in viral endpoint serum HBsAg compared to PBS control group. (Mean.+-.SEM).

[0344] As shown in FIG. 13, treatment with each of UNA oligomers 380 (SEQ ID NO:973 and 974), 1777 (SEQ ID NO:1005 and 1006), and 1576 (SEQ ID NO:1003 and 1004), as well as the UNA oligomer triad composition of the same compounds (1576, 380, 1777) caused a rapid and sustained reduction in viral endpoint serum HBeAg compared to PBS control group. (Mean.+-.SEM). This head-to-head comparison shows that the triad composition provided surprisingly increased potency throughout the duration of the effect, relative to the individual oligomers.

[0345] As shown in FIG. 14, treatment with each of UNA oligomers 380 (SEQ ID NO:973 and 974), 1777 (SEQ ID NO:1005 and 1006), and 1576 (SEQ ID NO:1003 and 1004) caused a rapid and sustained reduction in viral endpoint serum HBV DNA compared to PBS control group. (Mean.+-.SEM).

[0346] Thus, the UNA oligomers of this invention demonstrated significant and unexpectedly advantageous HBV inhibition efficacy in vivo.

Example 13

[0347] The HBV inhibitory effect in vivo for UNA oligomers was observed in an AAV-HBV mouse model of HBV infection. The UNA oligomers of this invention exhibited profound reduction of HBV serum infection parameters in vivo. In this study, the UNA oligomers were contained in lipid nanoparticle formulation.

[0348] The UNA oligomers were co-formulated in lipid nanoparticles and injected intravenously into C57Bl/6 mice with active HBV replication after AAV-mediated delivery of a recombinant HBV genome to the liver.

[0349] The study was an ascending dose design in which mice were treated with 3 mg/kg on day 0, then 5 mg/kg on day 4, then 10 mg/kg on day 8.

[0350] Serum viral endpoints were monitored up to day 12 after treatment.

[0351] As shown in FIG. 15, treatment with the UNA oligomer triad composition (1777 (SEQ ID NO:1179 and 1180), 380 (SEQ ID NO:1173 and 1174), 1578 (SEQ ID NO:1175 and 1176)) caused a rapid and sustained reduction in viral endpoint serum HBsAg compared to PBS control group. (Mean.+-.SEM). The dose-dependent response in vivo shows a pharmacological effect of the UNA oligomer composition.

[0352] Thus, the UNA oligomers of this invention demonstrated significant and unexpectedly advantageous HBV inhibition efficacy in vivo.

Example 14

[0353] The HBV inhibitory effect in vivo for UNA oligomers was observed in an AAV-HBV mouse model of HBV infection. The UNA oligomers of this invention exhibited profound reduction of HBV serum infection parameters in vivo. In general, the AAV-HBV mouse model is a robust model for investigating HBV infection, and can provide direct clinical pertinence for drug efficacy and potency. In this study, the UNA oligomers were contained in lipid nanoparticle formulation.

[0354] The UNA oligomers were formulated or co-formulated in lipid nanoparticles and injected intravenously into C57Bl/6 mice with active HBV replication after AAV-mediated delivery of a recombinant HBV genome to the liver.

[0355] The study was an ascending dose design in which mice were treated with 3 mg/kg on day 0, then 5 mg/kg on day 4, then 10 mg/kg on day 8.

[0356] Serum viral endpoints were monitored 15 days before, and at least 22 days after treatment.

[0357] As shown in FIG. 16, treatment with each of UNA oligomers 1578 (SEQ ID NO:993 and 994) and 1575 (SEQ ID NO:988 and 989) caused a rapid and sustained reduction in viral endpoint serum HBsAg compared to PBS control group. (Mean.+-.SEM).

[0358] As shown in FIG. 17, treatment with each of UNA oligomers 1578 (SEQ ID NO:993 and 994) and 1575 (SEQ ID NO:988 and 989) caused a rapid and sustained reduction in viral endpoint serum HBeAg compared to PBS control group. (Mean.+-.SEM).

[0359] As shown in FIG. 18, treatment with each of UNA oligomers 1578 (SEQ ID NO:993 and 994) and 1575 (SEQ ID NO:988 and 989) caused a rapid and sustained reduction in viral endpoint serum HBV DNA compared to PBS control group. (Mean.+-.SEM).

[0360] Thus, the UNA oligomers of this invention demonstrated significant and unexpectedly advantageous HBV inhibition efficacy in vivo.

Example 15

[0361] The HBV inhibitory effect of UNA oligomers was observed with a psiCHECK2 assay. The percent inhibition of target expression for UNA oligomeric compounds containing one or more 2'-deoxy-2'-fluoro ribonucleotides was measured.

[0362] As shown in Table 28, UNA oligomeric compounds exhibited at least 87% inhibition of target expression at 10 nM.

TABLE-US-00029 TABLE 28 Activity of UNA oligomer Relative RLuc/FLuc UNA oligomer at 0.1 nM, 1 nM, 10 nM 1578 (SEQ ID NO: 1127 and 1128) 0.65, 0.18, 0.08 1777 (SEQ ID NO: 1135 and 1136) 0.56, 0.14, 0.13 380 (SEQ ID NO: 1143 and 1144) 0.40, 0.14, 0.13

[0363] Thus, the UNA oligomers of this invention demonstrated advantageous HBV inhibition efficacy in vitro.

Example 16

[0364] The HBV inhibitory effect in vivo for UNA oligomers was observed in a PXB Mouse model of HBV infection. The UNA oligomers of this invention exhibited profound reduction of HBV serum infection parameters in vivo. In this study, the UNA oligomers were contained in lipid nanoparticle formulation.

[0365] The UNA oligomers were formulated or co-formulated in lipid nanoparticles and injected intravenously into HBV-infected Phoenix Bio (PXB) mice. The mice were Genotype: cDNA-uPA.sup.wild/+/SCID [cDNA-uPA.sup.wild/+: B6;129SvEv-Plau, SCID: C.B-17/Icr-scid/scid Jcl] containing human hepatocytes with an estimated replacement index of 70% or more.

[0366] As shown in Table 29, treatment with both UNA oligomers caused a rapid and sustained reduction in viral endpoint serum HBsAg compared to a PBS control group.

TABLE-US-00030 TABLE 29 HBsAg (% control) (normalized to hAlb) % % % % Inhibition Inhibition Inhibition Inhibition UNA oligomer Day 5 Day 10 Day 15 Day 20 Ref. Pos. 3.3 nM 3.3 nM 3.3 nM 3.3 nM 1580 (SEQ ID 72.0 71.0 59.0 49.0 NO: 997 and 998) 1578 (SEQ ID 70.0 59.0 39.0 25.3 NO: 993 and 994) 1575 (SEQ ID 75.0 58.0 39.0 22.2 NO: 987 and 988) 1818 (SEQ ID 55.0 56.0 56.0 17.7 NO: 1015 and 1016) 380 (SEQ ID 62.0 55.0 33.0 30.5 NO: 973 and 974) 1576 (SEQ ID 42.0 48.0 44.0 38.2 NO: 989 and 990) 1777 (SEQ ID 65.0 43.0 21.0 12.7 NO: 1005 and 1006) 1782 (SEQ ID 65.0 43.0 25.0 20.4 NO: 1013 and 1014) 1581 (SEQ ID 50.0 42.0 28.0 11.7 NO: 999 and 1000)

[0367] Thus, the UNA oligomers of this invention demonstrated significant and unexpectedly advantageous HBV inhibition efficacy in vivo.

Example 17

[0368] The HBV inhibitory effect in vivo for UNA oligomers was observed in a PXB Mouse model of HBV infection. The UNA oligomers of this invention exhibited profound reduction of HBV serum infection parameters in vivo. In this study, the UNA oligomers were contained in lipid nanoparticle formulation.

[0369] The UNA oligomers were formulated or co-formulated in lipid nanoparticles and injected intravenously into HBV-infected Phoenix Bio (PXB) mice. The mice were Genotype: cDNA-uPA.sup.wild/+/SCID [cDNA-uPA.sup.wild/+: B6;129SvEv-Plau, SCID: C.B-17/Icr-scid/scid Jcl] containing human hepatocytes with an estimated replacement index of 70% or more.

[0370] As shown in Table 30, treatment with a triad UNA oligomer composition caused a rapid and sustained reduction in viral endpoint serum HBsAg compared to a PBS control group.

TABLE-US-00031 TABLE 30 Serum HBsAg (% control) (normalized to hAlb) % % % % UNA oligomer Inhibition Inhibition Inhibition Inhibition composition Day 5 Day 10 Day 15 Day 20 Ref. Pos. 3.3 nM 3.3 nM 3.3 nM 3.3 nM 380/1777/1575 82.0 67.0 39.9 28.0 380/1777/1578 82.0 70.0 47.3 33.2 380/1777/1576 79.0 64.0 44.8 29.1

[0371] The compositions in Table 30 were:

UNA oligomer triad composition (1777 (SEQ ID NO:1005 and 1006), 380 (SEQ ID NO:973 and 974), 1575 (SEQ ID NO:987 and 988)); UNA oligomer triad composition (1777 (SEQ ID NO:1005 and 1006), 380 (SEQ ID NO:973 and 974), 1578 (SEQ ID NO:993 and 994)); and UNA oligomer triad composition (1777 (SEQ ID NO:1005 and 1006), 380 (SEQ ID NO:973 and 974), 1576 (SEQ ID NO:989 and 990)).

[0372] Thus, the triad UNA oligomer compositions of this invention demonstrated significant and unexpectedly advantageous HBV inhibition efficacy in vivo.

Example 18

[0373] The HBV inhibitory effect in vivo for UNA oligomers was observed in a PXB Mouse model of HBV infection. The UNA oligomers of this invention exhibited profound reduction of HBV serum infection parameters in vivo. In this study, the UNA oligomers were contained in lipid nanoparticle formulation.

[0374] The UNA oligomers were formulated or co-formulated in lipid nanoparticles and injected intravenously into HBV-infected Phoenix Bio (PXB) mice. The mice were Genotype: cDNA-uPA.sup.wild/+/SCID [cDNA-uPA.sup.wild/+: B6;129SvEv-Plau, SCID: C.B-17/Icr-scid/scid Jcl] containing human hepatocytes with an estimated replacement index of 70% or more.

[0375] As shown in Table 31, treatment with a triad UNA oligomer composition caused a rapid and sustained reduction in viral endpoint serum HBsAg compared to a PBS control group, for Genotypes Ae, Bj, C, and D.

TABLE-US-00032 TABLE 31 Serum HBsAg (% control) (normalized to hAlb) % % % % UNA oligomer Inhibition Inhibition Inhibition Inhibition composition Geno- Day 5 Day 10 Day 5 Day 10 (Ref. Pos.) type 3 nM 3 nM 15 nM 15 nM 380/1777/1578 Ae 79.2 71.0 87.5 79.0 380/1777/1578 Bj 75.4 62.2 85.0 79.0 380/1777/1578 C -- 68.8 -- 82.8 380/1777/1578 D 80.7 68.9 88.5 81.4

[0376] The composition in Table 31 was UNA oligomer triad composition (1777 (SEQ ID NO:1005 and 1006), 380 (SEQ ID NO:973 and 974), 1578 (SEQ ID NO:993 and 994)).

[0377] Thus, the triad UNA oligomer compositions of this invention demonstrated significant and unexpectedly advantageous HBV inhibition efficacy in vivo over a range of genotypes.

Example 19

[0378] The HBV inhibitory effect in vivo for UNA oligomers was observed in a PXB Mouse model of HBV infection. The UNA oligomers of this invention exhibited profound reduction of HBV serum infection parameters in vivo with phosphorothioate linkages present. In this study, the UNA oligomers were contained in lipid nanoparticle formulation.

[0379] The UNA oligomers were formulated or co-formulated in lipid nanoparticles and injected intravenously into HBV-infected Phoenix Bio (PXB) mice. The mice were Genotype: cDNA-uPA.sup.wild/+/SCID [cDNA-uPA.sup.wild/+: B6;129SvEv-Plau, SCID: C.B-17/Icr-scid/scid Jcl] containing human hepatocytes with an estimated replacement index of 70% or more.

[0380] As shown in Table 32, treatment with UNA oligomers caused a rapid and sustained reduction in viral endpoint serum HBsAg compared to a PBS control group.

TABLE-US-00033 TABLE 32 HBsAg (% control) (normalized to hAlb) % % % % Inhibition Inhibition Inhibition Inhibition UNA oligomer Day 5 Day 10 Day 15 Day 20 Ref. Pos. 3.3 nM 3.3 nM 3.3 nM 3.3 nM 1575 (SEQ ID 76.2 60.4 25.0 3.0 NO: 987 and 988) 1575PS (SEQ ID 79.0 77.5 58.5 35.7 NO: 1117 and 1118) 1578 (SEQ ID 77.0 65.6 34.4 5.7 NO: 993 and 994) 1578PS (SEQ ID 78.1 72.7 53.5 18.3 NO: 1069 and 1070) 380 (SEQ ID 72.4 69.5 48.1 23.9 NO: 973 and 974) 380PS (SEQ ID 68.1 69.9 52.4 35.2 NO: 1107 and 1108)

[0381] Thus, the UNA oligomers of this invention with phosphorothioate linkages (PS) demonstrated significant and unexpectedly advantageous HBV inhibition efficacy in vivo with longer duration (Day 15 to Day 20). The phosphorothioate linkages were as follows: one phosphorothioate linkage between two monomers at the 5' end of the first strand, one phosphorothioate linkage between two monomers at the 3' end of the first strand, one phosphorothioate linkage between monomers at the second and third positions from the 3' end of the first strand, and one phosphorothioate linkage between two monomers at the 3' end of the second strand.

Example 20

HBV Reference Genome HB974376 (3221 bp)

TABLE-US-00034 [0382] SEQ ID NO: 1181 1 ttccactgcc ttccaccaag ctctgcagga tcccagagtc aggggtctgt attttcctgc 61 tggtggctcc agttcaggaa cagtaaaccc tgctccgaat attgcctctc acatctcgtc 121 aatctccgcg aggactgggg accctgtgac gaacatggag aacatcacat caggattcct 181 aggacccctg ctcgtgttac aggcggggtt tttcttgttg acaagaatcc tcacaatacc 241 gcagagtcta gactcgtggt ggacttctct caattttcta gggggatcac ccgtgtgtct 301 tggccaaaat tcgcagtccc caacctccaa tcactcacca acctcctgtc ctccaatttg 361 tcctggttat cgctggatgt gtctgcggcg ttttatcata ttcctcttca tcctgctgct 421 atgcctcatc ttcttattgg ttcttctgga ttatcaaggt atgttgcccg tttgtcctct 481 aattccagga tcaacaacaa ccagtacggg accatgcaaa acctgcacga ctcctgctca 541 aggcaactct atgtttccct catgttgctg tacaaaacct acggatggaa attgcacctg 601 tattcccatc ccatcgtcct gggctttcgc aaaataccta tgggagtggg cctcagtccg 661 tttctcttgg ctcagtttac tagtgccatt tgttcagtgg ttcgtagggc tttcccccac 721 tgtttggctt tcagctatat ggatgatgtg gtattggggg ccaagtctgt acagcatcgt 781 gagtcccttt ataccgctgt taccaatttt cttttgtctc tgggtataca tttaaaccct 841 aacaaaacaa aaagatgggg ttattcccta aacttcatgg gttacataat tggaagttgg 901 ggaactttgc cacaggatca tattgtacaa aagatcaaac actgttttag aaaacttcct 961 gttaacaggc ctattgattg gaaagtatgt caaagaattg tgggtctttt gggctttgct 1021 gctccattta cacaatgtgg atatcctgcc ttaatgcctt tgtatgcatg tatacaagct 1081 aaacaggctt tcactttctc gccaacttac aaggcctttc taagtaaaca gtacatgaac 1141 ctttaccccg ttgctcggca acggcctggt ctgtgccaag tgtttgctga cgcaaccccc 1201 actggctggg gcttggccat aggccatcag cgcatgcgtg gaacctttgt ggctcctctg 1261 ccgatccata ctgcggaact cctagccgct tgttttgctc gcagccggtc tggagcaaag 1321 ctcatcggaa ctgacaattc tgtcgtcctc tcgcggaaat atacatcgtt tccatggctg 1381 ctaggctgta ctgccaactg gatccttcgc gggacgtcct ttgtttacgt cccgtcggcg 1441 ctgaatcccg cggacgaccc ctctcggggc cgcttgggac tctctcgtcc ccttctccgt 1501 ctgccgttcc agccgaccac ggggcgcacc tctctttacg cggtctcccc gtctgtgcct 1561 tctcatctgc cggtccgtgt gcacttcgct tcacctctgc acgttgcatg gagaccaccg 1621 tgaacgccca tcagatcctg cccaaggtct tacataagag gactcttgga ctcccagcaa 1681 tgtcaacgac cgaccttgag gcctacttca aagactgtgt gtttaaagac tgggaggagc 1741 tgggggagga gattaggtta aaggtctttg tattaggagg ctgtaggcat aaattggtct 1801 gcgcaccagc accatgcaac tttttcacct ctgcctaatc atctcttgta catgtcccac 1861 tgttcaagcc tccaagctgt gccttgggtg gctttggggc atggacattg acccttataa 1921 agaatttgga gctactgtgg agttactctc gtttttgcct tctgacttct ttccttccgt 1981 cagagatctc ctagacaccg cctcagctct gtatcgagaa gccttagaat ctcctgagca 2041 ttgctcacct caccatactg cactcaggca agccattctc tgctgggggg aattgatgac 2101 tctagctacc tgggtgggta ataatttgga agatccagca tccagggatc tagtagtcaa 2161 ttatgttaat actaacatgg gtttaaagat caggcaacta ttgtggtttc atatatcttg 2221 ccttactttt ggaagagaga ctgtacttga atatttggtc tctttcggag tgtggattcg 2281 cactcctcca gcctatagac caccaaatgc ccctatctta tcaacacttc cggaaactac 2341 tgttgttaga cgacgggacc gaggcaggtc ccctagaaga agaactccct cgcctcgcag 2401 acgcagatct caatcgccgc gtcgcagaag atctcaatct cgggaatctc aatgttagta 2461 ttccttggac tcataaggtg ggaaacttta cggggcttta ttcctctaca gtacctatct 2521 ttaatcctga atggcaaact ccttcctttc ctaagattca tttacaagag gacattatta 2581 ataggtgtca acaatttgtg ggccctctca ctgtaaatga aaagagaaga ttgaaattaa 2641 ttatgcctgc tagattctat cctactcaca ctaaatattt gcccttagac aaaggaatta 2701 aaccttatta tccagatcag gtagttaatc attacttcca aaccagacat tatttacata 2761 ctctttggaa ggctggtatt ctatataaga gggaaaccac acgtagcgca tcattttgtg 2821 ggtcaccata ttcttgggaa caagagctac agcatgggag gttggtcatc aaaacctcgc 2881 aaaggcatgg ggacgaatct ttctgttccc aaccctctgg gattctttcc cgatcatcag 2941 ttggaccctg cattcggagc caactcaaac aatccagatt gggacttcaa ccccatcaag 3001 gaccactggc cagcagccaa ccaggtagga gcgggagcat tcgggccagg gctcacccct 3061 ccacacggcg gtattctggg gtggagccct caggctcagg gcatattgac cacagtgtca 3121 acaattcctc ctcctgcctc caccaatcgg cagtcaggaa ggcagcctac tcccatctct 3181 ccacctctaa gagacagtca tcctcaggcc atgcagtgga a

[0383] All publications, patents and literature specifically mentioned herein are incorporated by reference for all purposes.

[0384] It is understood that this invention is not limited to the particular methodology, protocols, materials, and reagents described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which will be encompassed by the appended claims.

[0385] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. As well, the terms "a" (or "an"), "one or more" and "at least one" can be used interchangeably herein. It is also to be noted that the terms "comprises," "comprising", "containing," "including", and "having" can be used interchangeably.

[0386] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

[0387] All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose.

Sequence CWU 1

1

1181122RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1nnnnnnnnnn nnnnnnnnnn nn 22221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 2nnnnnnnnnn nnnnnnnnnn n 21322RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 3nnnnnnnnnn nnnnnnnnnn nn 22421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 4nnnnnnnnnn nnnnnnnnnn n 21522RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 5nnnnnnnnnn nnnnnnnnnn nn 22621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 6nnnnnnnnnn nnnnnnnnnn n 21722RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 7nnnnnnnnnn nnnnnnnnnn nn 22821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 8nnnnnnnnnn nnnnnnnnnn n 21922RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 9nnnnnnnnnn nnnnnnnnnn nn 221021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 10nnnnnnnnnn nnnnnnnnnn n 211122RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 11nnnnnnnnnn nnnnnnnnnn nn 221221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 12nnnnnnnnnn nnnnnnnnnn n 211322RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 13nnnnnnnnnn nnnnnnnnnn nn 221421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 14nnnnnnnnnn nnnnnnnnnn n 211522RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 15nnnnnnnnnn nnnnnnnnnn nn 221621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 16nnnnnnnnnn nnnnnnnnnn n 211722RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 17nnnnnnnnnn nnnnnnnnnn nn 221821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 18nnnnnnnnnn nnnnnnnnnn n 211922RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 19nnnnnnnnnn nnnnnnnnnn nn 222021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 20nnnnnnnnnn nnnnnnnnnn n 212122RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 21nnnnnnnnnn nnnnnnnnnn nn 222221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 22nnnnnnnnnn nnnnnnnnnn n 212322RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 23nnnnnnnnnn nnnnnnnnnn nn 222421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 24nnnnnnnnnn nnnnnnnnnn n 212522RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 25nnnnnnnnnn nnnnnnnnnn nn 222621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 26nnnnnnnnnn nnnnnnnnnn n 212722RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 27nnnnnnnnnn nnnnnnnnnn nn 222821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 28nnnnnnnnnn nnnnnnnnnn n 212922RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 29nnnnnnnnnn nnnnnnnnnn nn 223021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 30nnnnnnnnnn nnnnnnnnnn n 213122RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 31nnnnnnnnnn nnnnnnnnnn nn 223221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 32nnnnnnnnnn nnnnnnnnnn n 213322RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 33nnnnnnnnnn nnnnnnnnnn nn 223421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 34nnnnnnnnnn nnnnnnnnnn n 213522RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 35nnnnnnnnnn nnnnnnnnnn nn 223621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 36nnnnnnnnnn nnnnnnnnnn n 213722RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 37nnnnnnnnnn nnnnnnnnnn nn 223821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 38nnnnnnnnnn nnnnnnnnnn n 213922RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 39nnnnnnnnnn nnnnnnnnnn nn 224021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 40nnnnnnnnnn nnnnnnnnnn n 214122RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 41nnnnnnnnnn nnnnnnnnnn nn 224221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 42nnnnnnnnnn nnnnnnnnnn n 214322RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 43nnnnnnnnnn nnnnnnnnnn nn 224421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 44nnnnnnnnnn nnnnnnnnnn n 214522RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 45nnnnnnnnnn nnnnnnnnnn nn 224621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 46nnnnnnnnnn nnnnnnnnnn n 214722RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 47nnnnnnnnnn nnnnnnnnnn nn 224821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 48nnnnnnnnnn nnnnnnnnnn n 214922RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 49nnnnnnnnnn nnnnnnnnnn nn 225021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 50nnnnnnnnnn nnnnnnnnnn n 215122RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 51nnnnnnnnnn nnnnnnnnnn nn 225221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 52nnnnnnnnnn nnnnnnnnnn n 215322RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 53nnnnnnnnnn nnnnnnnnnn nn 225421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 54nnnnnnnnnn nnnnnnnnnn n 215522RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 55nnnnnnnnnn nnnnnnnnnn nn 225621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 56nnnnnnnnnn nnnnnnnnnn n 215722RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 57nnnnnnnnnn nnnnnnnnnn nn 225821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 58nnnnnnnnnn nnnnnnnnnn n 215921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 59nnnnnnnnnn nnnnnnnnnn n 216021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 60nnnnnnnnnn nnnnnnnnnn n 216121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 61nnnnnnnnnn nnnnnnnnnn n 216221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 62nnnnnnnnnn nnnnnnnnnn n 216321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 63nnnnnnnnnn nnnnnnnnnn n 216421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 64nnnnnnnnnn nnnnnnnnnn n 216521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 65nnnnnnnnnn nnnnnnnnnn n 216621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 66nnnnnnnnnn nnnnnnnnnn n 216721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 67nnnnnnnnnn nnnnnnnnnn n 216821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 68nnnnnnnnnn nnnnnnnnnn n 216921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 69nnnnnnnnnn nnnnnnnnnn n 217021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 70nnnnnnnnnn nnnnnnnnnn n 217121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 71nnnnnnnnnn nnnnnnnnnn n 217221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 72nnnnnnnnnn nnnnnnnnnn n 217321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 73nnnnnnnnnn nnnnnnnnnn n 217421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 74nnnnnnnnnn nnnnnnnnnn n 217521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 75nnnnnnnnnn nnnnnnnnnn n 217621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 76nnnnnnnnnn nnnnnnnnnn n 217721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 77nnnnnnnnnn nnnnnnnnnn n 217821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 78nnnnnnnnnn nnnnnnnnnn n 217921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 79nnnnnnnnnn nnnnnnnnnn n 218021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 80nnnnnnnnnn nnnnnnnnnn n 218121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 81nnnnnnnnnn nnnnnnnnnn n 218221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 82nnnnnnnnnn nnnnnnnnnn n 218321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 83nnnnnnnnnn nnnnnnnnnn n 218421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 84nnnnnnnnnn nnnnnnnnnn n 218521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 85nnnnnnnnnn nnnnnnnnnn n 218621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 86nnnnnnnnnn nnnnnnnnnn n 218721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 87nnnnnnnnnn nnnnnnnnnn n 218821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 88nnnnnnnnnn nnnnnnnnnn n 218921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 89nnnnnnnnnn nnnnnnnnnn n 219021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 90nnnnnnnnnn nnnnnnnnnn n 219121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 91nnnnnnnnnn nnnnnnnnnn n 219221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 92nnnnnnnnnn nnnnnnnnnn n 219321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 93nnnnnnnnnn nnnnnnnnnn n 219421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 94nnnnnnnnnn nnnnnnnnnn n 219521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 95nnnnnnnnnn nnnnnnnnnn n 219621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 96nnnnnnnnnn nnnnnnnnnn n 219721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 97nnnnnnnnnn nnnnnnnnnn n 219821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 98nnnnnnnnnn nnnnnnnnnn n 219921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 99nnnnnnnnnn nnnnnnnnnn n 2110021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 100nnnnnnnnnn nnnnnnnnnn n 2110121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 101nnnnnnnnnn nnnnnnnnnn n 2110221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 102nnnnnnnnnn nnnnnnnnnn n 2110321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 103nnnnnnnnnn nnnnnnnnnn n 2110421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 104nnnnnnnnnn nnnnnnnnnn n 2110521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 105nnnnnnnnnn nnnnnnnnnn n 2110621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 106nnnnnnnnnn nnnnnnnnnn n 2110721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 107nnnnnnnnnn nnnnnnnnnn n

2110821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 108nnnnnnnnnn nnnnnnnnnn n 2110921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 109nnnnnnnnnn nnnnnnnnnn n 2111021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 110nnnnnnnnnn nnnnnnnnnn n 2111121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 111nnnnnnnnnn nnnnnnnnnn n 2111221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 112nnnnnnnnnn nnnnnnnnnn n 2111321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 113nnnnnnnnnn nnnnnnnnnn n 2111421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 114nnnnnnnnnn nnnnnnnnnn n 2111521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 115nnnnnnnnnn nnnnnnnnnn n 2111621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 116nnnnnnnnnn nnnnnnnnnn n 2111721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 117nnnnnnnnnn nnnnnnnnnn n 2111821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 118nnnnnnnnnn nnnnnnnnnn n 2111921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 119nnnnnnnnnn nnnnnnnnnn n 2112021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 120nnnnnnnnnn nnnnnnnnnn n 2112121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 121nnnnnnnnnn nnnnnnnnnn n 2112221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 122nnnnnnnnnn nnnnnnnnnn n 2112321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 123nnnnnnnnnn nnnnnnnnnn n 2112421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 124nnnnnnnnnn nnnnnnnnnn n 2112521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 125nnnnnnnnnn nnnnnnnnnn n 2112621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 126nnnnnnnnnn nnnnnnnnnn n 2112721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 127nnnnnnnnnn nnnnnnnnnn n 2112821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 128nnnnnnnnnn nnnnnnnnnn n 2112921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 129nnnnnnnnnn nnnnnnnnnn n 2113021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 130nnnnnnnnnn nnnnnnnnnn n 2113121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 131nnnnnnnnnn nnnnnnnnnn n 2113221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 132nnnnnnnnnn nnnnnnnnnn n 2113321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 133nnnnnnnnnn nnnnnnnnnn n 2113421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 134nnnnnnnnnn nnnnnnnnnn n 2113521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 135nnnnnnnnnn nnnnnnnnnn n 2113621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 136nnnnnnnnnn nnnnnnnnnn n 2113721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 137nnnnnnnnnn nnnnnnnnnn n 2113821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 138nnnnnnnnnn nnnnnnnnnn n 2113921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 139nnnnnnnnnn nnnnnnnnnn n 2114021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 140nnnnnnnnnn nnnnnnnnnn n 2114121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 141nnnnnnnnnn nnnnnnnnnn n 2114221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 142nnnnnnnnnn nnnnnnnnnn n 2114321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 143nnnnnnnnnn nnnnnnnnnn n 2114421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 144nnnnnnnnnn nnnnnnnnnn n 2114521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 145nnnnnnnnnn nnnnnnnnnn n 2114621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 146nnnnnnnnnn nnnnnnnnnn n 2114721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 147nnnnnnnnnn nnnnnnnnnn n 2114821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 148nnnnnnnnnn nnnnnnnnnn n 2114921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 149nnnnnnnnnn nnnnnnnnnn n 2115021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 150nnnnnnnnnn nnnnnnnnnn n 2115121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 151nnnnnnnnnn nnnnnnnnnn n 2115221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 152nnnnnnnnnn nnnnnnnnnn n 2115321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 153nnnnnnnnnn nnnnnnnnnn n 2115421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 154nnnnnnnnnn nnnnnnnnnn n 2115521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 155nnnnnnnnnn nnnnnnnnnn n 2115621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 156nnnnnnnnnn nnnnnnnnnn n 2115721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 157nnnnnnnnnn nnnnnnnnnn n 2115821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 158nnnnnnnnnn nnnnnnnnnn n 2115921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 159nnnnnnnnnn nnnnnnnnnn n 2116021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 160nnnnnnnnnn nnnnnnnnnn n 2116121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 161nnnnnnnnnn nnnnnnnnnn n 2116221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 162nnnnnnnnnn nnnnnnnnnn n 2116321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 163nnnnnnnnnn nnnnnnnnnn n 2116421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 164nnnnnnnnnn nnnnnnnnnn n 2116521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 165nnnnnnnnnn nnnnnnnnnn n 2116621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 166nnnnnnnnnn nnnnnnnnnn n 2116721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 167nnnnnnnnnn nnnnnnnnnn n 2116821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 168nnnnnnnnnn nnnnnnnnnn n 2116921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 169nnnnnnnnnn nnnnnnnnnn n 2117021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 170nnnnnnnnnn nnnnnnnnnn n 2117121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 171nnnnnnnnnn nnnnnnnnnn n 2117221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 172nnnnnnnnnn nnnnnnnnnn n 2117321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 173nnnnnnnnnn nnnnnnnnnn n 2117421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 174nnnnnnnnnn nnnnnnnnnn n 2117521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 175nnnnnnnnnn nnnnnnnnnn n 2117621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 176nnnnnnnnnn nnnnnnnnnn n 2117721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 177nnnnnnnnnn nnnnnnnnnn n 2117821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 178nnnnnnnnnn nnnnnnnnnn n 2117921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 179nnnnnnnnnn nnnnnnnnnn n 2118021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 180nnnnnnnnnn nnnnnnnnnn n 2118121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 181nnnnnnnnnn nnnnnnnnnn n 2118221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 182nnnnnnnnnn nnnnnnnnnn n 2118321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 183nnnnnnnnnn nnnnnnnnnn n 2118421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 184nnnnnnnnnn nnnnnnnnnn n 2118521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 185nnnnnnnnnn nnnnnnnnnn n 2118621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 186nnnnnnnnnn nnnnnnnnnn n 2118721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 187nnnnnnnnnn nnnnnnnnnn n 2118821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 188nnnnnnnnnn nnnnnnnnnn n 2118921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 189nnnnnnnnnn nnnnnnnnnn n 2119021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 190nnnnnnnnnn nnnnnnnnnn n 2119121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 191nnnnnnnnnn nnnnnnnnnn n 2119221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 192nnnnnnnnnn nnnnnnnnnn n 2119321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 193nnnnnnnnnn nnnnnnnnnn n 2119421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 194nnnnnnnnnn nnnnnnnnnn n 2119521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 195nnnnnnnnnn nnnnnnnnnn n 2119621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 196nnnnnnnnnn nnnnnnnnnn n 2119721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 197nnnnnnnnnn nnnnnnnnnn n 2119821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 198nnnnnnnnnn nnnnnnnnnn n 2119921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 199nnnnnnnnnn nnnnnnnnnn n 2120021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 200nnnnnnnnnn nnnnnnnnnn n 2120121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 201nnnnnnnnnn nnnnnnnnnn n 2120221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 202nnnnnnnnnn nnnnnnnnnn n 2120321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 203nnnnnnnnnn nnnnnnnnnn n 2120421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 204nnnnnnnnnn nnnnnnnnnn n 2120521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 205nnnnnnnnnn nnnnnnnnnn n 2120621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 206nnnnnnnnnn nnnnnnnnnn n 2120721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 207nnnnnnnnnn nnnnnnnnnn n 2120821RNAArtificial SequenceDescription of Artificial Sequence Synthetic

oligonucleotide 208nnnnnnnnnn nnnnnnnnnn n 2120921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 209nnnnnnnnnn nnnnnnnnnn n 2121021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 210nnnnnnnnnn nnnnnnnnnn n 2121121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 211nnnnnnnnnn nnnnnnnnnn n 2121221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 212nnnnnnnnnn nnnnnnnnnn n 2121321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 213nnnnnnnnnn nnnnnnnnnn n 2121421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 214nnnnnnnnnn nnnnnnnnnn n 2121521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 215nnnnnnnnnn nnnnnnnnnn n 2121621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 216nnnnnnnnnn nnnnnnnnnn n 2121721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 217nnnnnnnnnn nnnnnnnnnn n 2121821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 218nnnnnnnnnn nnnnnnnnnn n 2121921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 219nnnnnnnnnn nnnnnnnnnn n 2122021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 220nnnnnnnnnn nnnnnnnnnn n 2122121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 221nnnnnnnnnn nnnnnnnnnn n 2122221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 222nnnnnnnnnn nnnnnnnnnn n 2122321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 223nnnnnnnnnn nnnnnnnnnn n 2122421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 224nnnnnnnnnn nnnnnnnnnn n 2122521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 225nnnnnnnnnn nnnnnnnnnn n 2122621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 226nnnnnnnnnn nnnnnnnnnn n 2122721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 227nnnnnnnnnn nnnnnnnnnn n 2122821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 228nnnnnnnnnn nnnnnnnnnn n 2122921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 229nnnnnnnnnn nnnnnnnnnn n 2123021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 230nnnnnnnnnn nnnnnnnnnn n 2123121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 231nnnnnnnnnn nnnnnnnnnn n 2123221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 232nnnnnnnnnn nnnnnnnnnn n 2123321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 233nnnnnnnnnn nnnnnnnnnn n 2123421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 234nnnnnnnnnn nnnnnnnnnn n 2123521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 235nnnnnnnnnn nnnnnnnnnn n 2123621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 236nnnnnnnnnn nnnnnnnnnn n 2123719RNAHepatitis B virus 237cgcaccucuc uuuacgcgg 1923819RNAHepatitis B virus 238gacucguggu ggacuucuc 1923919RNAHepatitis B virus 239ucguggugga cuucucuca 1924019RNAHepatitis B virus 240uggauguguc ugcggcguu 1924119RNAHepatitis B virus 241ccgugugcac uucgcuuca 1924219RNAHepatitis B virus 242gugugcacuu cgcuucacc 1924319RNAHepatitis B virus 243ugugcacuuc gcuucaccu 1924419RNAHepatitis B virus 244gugcacuucg cuucaccuc 1924519RNAHepatitis B virus 245gcacuucgcu ucaccucug 1924619RNAHepatitis B virus 246uucaagccuc caagcugug 1924719RNAHepatitis B virus 247ucaagccucc aagcugugc 1924819RNAHepatitis B virus 248caagccucca agcugugcc 1924919RNAHepatitis B virus 249aagccuccaa gcugugccu 1925019RNAHepatitis B virus 250ucuagacucg ugguggacu 1925119RNAHepatitis B virus 251cuagacucgu gguggacuu 1925219RNAHepatitis B virus 252uagacucgug guggacuuc 1925319RNAHepatitis B virus 253agacucgugg uggacuucu 1925419RNAHepatitis B virus 254gaugugucug cggcguuuu 1925519RNAHepatitis B virus 255ugugucugcg gcguuuuau 1925619RNAHepatitis B virus 256ugucugcggc guuuuauca 1925719RNAHepatitis B virus 257ggaggcugua ggcauaaau 1925819RNAHepatitis B virus 258gaggcuguag gcauaaauu 1925919RNAHepatitis B virus 259ggcuguaggc auaaauugg 1926019RNAHepatitis B virus 260gcuguaggca uaaauuggu 1926119RNAHepatitis B virus 261aacuuuuuca ccucugccu 1926219RNAHepatitis B virus 262gagucuagac ucguggugg 1926319RNAHepatitis B virus 263agucuagacu cguggugga 1926419RNAHepatitis B virus 264gucuagacuc gugguggac 1926519RNAHepatitis B virus 265cauccugcug cuaugccuc 1926619RNAHepatitis B virus 266uccugcugcu augccucau 1926719RNAHepatitis B virus 267ccugcugcua ugccucauc 1926819RNAHepatitis B virus 268cugcugcuau gccucaucu 1926919RNAHepatitis B virus 269ugcugcuaug ccucaucuu 1927019RNAHepatitis B virus 270cuguaggcau aaauugguc 1927119RNAHepatitis B virus 271uguaggcaua aauuggucu 1927219RNAHepatitis B virus 272acucguggug gacuucucu 1927319RNAHepatitis B virus 273cucguggugg acuucucuc 1927419RNAHepatitis B virus 274cgugugcacu ucgcuucac 1927519RNAHepatitis B virus 275ugcacuucgc uucaccucu 1927619RNAHepatitis B virus 276cacuucgcuu caccucugc 1927719RNAHepatitis B virus 277acuucgcuuc accucugca 1927819RNAHepatitis B virus 278agccuccaag cugugccuu 1927919RNAHepatitis B virus 279gccuccaagc ugugccuug 1928019RNAHepatitis B virus 280gaacucccuc gccucgcag 1928119RNAHepatitis B virus 281aacucccucg ccucgcaga 1928219RNAHepatitis B virus 282acucccucgc cucgcagac 1928319RNAHepatitis B virus 283cucccucgcc ucgcagacg 1928419RNAHepatitis B virus 284ccugcuggug gcuccaguu 1928519RNAHepatitis B virus 285cugcuggugg cuccaguuc 1928619RNAHepatitis B virus 286ggaugugucu gcggcguuu 1928719RNAHepatitis B virus 287augugucugc ggcguuuua 1928819RNAHepatitis B virus 288gugucugcgg cguuuuauc 1928919RNAHepatitis B virus 289gucugcggcg uuuuaucau 1929019RNAHepatitis B virus 290ccuaugggag ugggccuca 1929119RNAHepatitis B virus 291cuaugggagu gggccucag 1929219RNAHepatitis B virus 292cuucgcuuca ccucugcac 1929319RNAHepatitis B virus 293uucgcuucac cucugcacg 1929419RNAHepatitis B virus 294ucgcuucacc ucugcacgu 1929519RNAHepatitis B virus 295aggcuguagg cauaaauug 1929619RNAHepatitis B virus 296acuuuuucac cucugccua 1929719RNAHepatitis B virus 297auccugcugc uaugccuca 1929819RNAHepatitis B virus 298gcugcuaugc cucaucuuc 1929919RNAHepatitis B virus 299cugcuaugcc ucaucuucu 1930019RNAHepatitis B virus 300ugcuaugccu caucuucuu 1930119RNAHepatitis B virus 301guaggcauaa auuggucug 1930219RNAHepatitis B virus 302ccuccaagcu gugccuugg 1930319RNAHepatitis B virus 303cgugguggac uucucucaa 1930419RNAHepatitis B virus 304gugguggacu ucucucaau 1930519RNAHepatitis B virus 305ugguggacuu cucucaauu 1930619RNAHepatitis B virus 306gguggacuuc ucucaauuu 1930719RNAHepatitis B virus 307guggacuucu cucaauuuu 1930819RNAHepatitis B virus 308uggacuucuc ucaauuuuc 1930919RNAHepatitis B virus 309gacuucucuc aauuuucua 1931019RNAHepatitis B virus 310acuucucuca auuuucuag 1931119RNAHepatitis B virus 311cuucucucaa uuuucuagg 1931219RNAHepatitis B virus 312uucucucaau uuucuaggg 1931319RNAHepatitis B virus 313ucucucaauu uucuagggg 1931419RNAHepatitis B virus 314auccauacug cggaacucc 1931519RNAHepatitis B virus 315uccauacugc ggaacuccu 1931619RNAHepatitis B virus 316gaagaagaac ucccucgcc 1931719RNAHepatitis B virus 317aagaagaacu cccucgccu 1931819RNAHepatitis B virus 318agaagaacuc ccucgccuc 1931919RNAHepatitis B virus 319gaagaacucc cucgccucg 1932019RNAHepatitis B virus 320aagaacuccc ucgccucgc 1932119RNAHepatitis B virus 321agaacucccu cgccucgca 1932219RNAHepatitis B virus 322agagucuaga cucguggug 1932319RNAHepatitis B virus 323ggacuucucu caauuuucu 1932419RNAHepatitis B virus 324gauccauacu gcggaacuc 1932519RNAHepatitis B virus 325ugcaacuuuu ucaccucug 1932619RNAHepatitis B virus 326gcaacuuuuu caccucugc 1932719RNAHepatitis B virus 327caacuuuuuc accucugcc 1932819RNAHepatitis B virus 328uggccaaaau ucgcagucc 1932919RNAHepatitis B virus 329ggccaaaauu cgcaguccc 1933019RNAHepatitis B virus 330ccgauccaua cugcggaac 1933119RNAHepatitis B virus 331cgauccauac ugcggaacu 1933219RNAHepatitis B virus 332cuuuuucacc ucugccuaa 1933319RNAHepatitis B virus 333uuuuucaccu cugccuaau 1933419RNAHepatitis B virus 334uuuucaccuc ugccuaauc 1933519RNAHepatitis B virus 335uuucaccucu gccuaauca 1933619RNAHepatitis B virus 336aagcugugcc uuggguggc 1933719RNAHepatitis B virus 337agcugugccu uggguggcu 1933819RNAHepatitis B virus 338gcugugccuu ggguggcuu 1933919RNAHepatitis B virus 339cugugccuug gguggcuuu 1934019RNAHepatitis B virus 340ggagugugga uucgcacuc 1934119RNAHepatitis B virus 341gaguguggau ucgcacucc 1934219RNAHepatitis B virus 342cagagucuag acucguggu 1934319RNAHepatitis B virus 343auaagaggac ucuuggacu 1934419RNAHepatitis B virus 344uaggaggcug uaggcauaa 1934519RNAHepatitis B virus 345aggaggcugu aggcauaaa 1934619RNAHepatitis B virus 346caugcaacuu uuucaccuc 1934719RNAHepatitis B virus 347augcaacuuu uucaccucu 1934819RNAHepatitis B virus 348uucaccucug ccuaaucau 1934919RNAHepatitis B virus 349ucaccucugc cuaaucauc 1935019RNAHepatitis B virus 350caccucugcc uaaucaucu 1935119RNAHepatitis B virus 351cuccaagcug ugccuuggg 1935219RNAHepatitis B virus 352uccaagcugu gccuugggu 1935319RNAHepatitis B virus 353ccaagcugug ccuugggug 1935419RNAHepatitis B virus 354caagcugugc cuugggugg 1935519RNAHepatitis B virus 355cuagaagaag aacucccuc 1935619RNAHepatitis B virus 356uagaagaaga acucccucg

1935719RNAHepatitis B virus 357agaagaagaa cucccucgc 1935819RNAHepatitis B virus 358guucaagccu ccaagcugu 1935919RNAHepatitis B virus 359agaccaccaa augccccua 1936019RNAHepatitis B virus 360gaccaccaaa ugccccuau 1936119RNAHepatitis B virus 361accaccaaau gccccuauc 1936219RNAHepatitis B virus 362uguauuccca ucccaucau 1936319RNAHepatitis B virus 363guauucccau cccaucauc 1936419RNAHepatitis B virus 364cguagggcuu ucccccacu 1936519RNAHepatitis B virus 365guagggcuuu cccccacug 1936619RNAHepatitis B virus 366uagggcuuuc ccccacugu 1936719RNAHepatitis B virus 367ugccgaucca uacugcgga 1936819RNAHepatitis B virus 368gccgauccau acugcggaa 1936919RNAHepatitis B virus 369cacggggcgc accucucuu 1937019RNAHepatitis B virus 370acggggcgca ccucucuuu 1937119RNAHepatitis B virus 371cggggcgcac cucucuuua 1937219RNAHepatitis B virus 372ggggcgcacc ucucuuuac 1937319RNAHepatitis B virus 373gggcgcaccu cucuuuacg 1937419RNAHepatitis B virus 374ggcgcaccuc ucuuuacgc 1937519RNAHepatitis B virus 375gcgcaccucu cuuuacgcg 1937619RNAHepatitis B virus 376acuguucaag ccuccaagc 1937719RNAHepatitis B virus 377cuguucaagc cuccaagcu 1937819RNAHepatitis B virus 378uguucaagcc uccaagcug 1937919RNAHepatitis B virus 379guauguugcc cguuugucc 1938019RNAHepatitis B virus 380uauguugccc guuuguccu 1938119RNAHepatitis B virus 381uguugcccgu uuguccucu 1938219RNAHepatitis B virus 382ugaaccuuua ccccguugc 1938319RNAHepatitis B virus 383ccauacugcg gaacuccua 1938419RNAHepatitis B virus 384cauacugcgg aacuccuag 1938519RNAHepatitis B virus 385auacugcgga acuccuagc 1938619RNAHepatitis B virus 386ccacggggcg caccucucu 1938719RNAHepatitis B virus 387cccuagaaga agaacuccc 1938819RNAHepatitis B virus 388ccuagaagaa gaacucccu 1938919RNAHepatitis B virus 389ucccucgccu cgcagacga 1939019RNAHepatitis B virus 390uuccucuuca uccugcugc 1939119RNAHepatitis B virus 391uccucuucau ccugcugcu 1939219RNAHepatitis B virus 392ccucuucauc cugcugcua 1939319RNAHepatitis B virus 393cucuucaucc ugcugcuau 1939419RNAHepatitis B virus 394ucuucauccu gcugcuaug 1939519RNAHepatitis B virus 395cuucauccug cugcuaugc 1939619RNAHepatitis B virus 396uucauccugc ugcuaugcc 1939719RNAHepatitis B virus 397ucauccugcu gcuaugccu 1939819RNAHepatitis B virus 398gguauguugc ccguuuguc 1939919RNAHepatitis B virus 399auguugcccg uuuguccuc 1940019RNAHepatitis B virus 400uacgucccgu cggcgcuga 1940119RNAHepatitis B virus 401acgucccguc ggcgcugaa 1940219RNAHepatitis B virus 402cgucccgucg gcgcugaau 1940319RNAHepatitis B virus 403gucccgucgg cgcugaauc 1940419RNAHepatitis B virus 404ucccgucggc gcugaaucc 1940519RNAHepatitis B virus 405aguguggauu cgcacuccu 1940619RNAHepatitis B virus 406ccccuagaag aagaacucc 1940719RNAHepatitis B virus 407caagguaugu ugcccguuu 1940819RNAHepatitis B virus 408aagguauguu gcccguuug 1940919RNAHepatitis B virus 409agguauguug cccguuugu 1941019RNAHepatitis B virus 410ccgaccacgg ggcgcaccu 1941119RNAHepatitis B virus 411cgaccacggg gcgcaccuc 1941219RNAHepatitis B virus 412gaccacgggg cgcaccucu 1941319RNAHepatitis B virus 413accacggggc gcaccucuc 1941419RNAHepatitis B virus 414cuccccgucu gugccuucu 1941519RNAHepatitis B virus 415uccccgucug ugccuucuc 1941619RNAHepatitis B virus 416ccgcgucgca gaagaucuc 1941719RNAHepatitis B virus 417cgcgucgcag aagaucuca 1941819RNAHepatitis B virus 418gcgucgcaga agaucucaa 1941919RNAHepatitis B virus 419cgucgcagaa gaucucaau 1942019RNAHepatitis B virus 420gucgcagaag aucucaauc 1942119RNAHepatitis B virus 421ucgcagaaga ucucaaucu 1942219RNAHepatitis B virus 422aggaccccug cucguguua 1942319RNAHepatitis B virus 423ggaccccugc ucguguuac 1942419RNAHepatitis B virus 424gaccccugcu cguguuaca 1942519RNAHepatitis B virus 425accccugcuc guguuacag 1942619RNAHepatitis B virus 426ccccugcucg uguuacagg 1942719RNAHepatitis B virus 427uaucgcugga ugugucugc 1942819RNAHepatitis B virus 428aucgcuggau gugucugcg 1942919RNAHepatitis B virus 429ucgcuggaug ugucugcgg 1943019RNAHepatitis B virus 430cgcuggaugu gucugcggc 1943119RNAHepatitis B virus 431gcuggaugug ucugcggcg 1943219RNAHepatitis B virus 432cuggaugugu cugcggcgu 1943319RNAHepatitis B virus 433guugcccguu uguccucua 1943419RNAHepatitis B virus 434ccauuuguuc agugguucg 1943519RNAHepatitis B virus 435uuaccaauuu ucuuuuguc 1943619RNAHepatitis B virus 436ccaacuuaca aggccuuuc 1943719RNAHepatitis B virus 437caacuuacaa ggccuuucu 1943819RNAHepatitis B virus 438uuugcugacg caaccccca 1943919RNAHepatitis B virus 439uugcugacgc aacccccac 1944019RNAHepatitis B virus 440ugcugacgca acccccacu 1944119RNAHepatitis B virus 441gcugacgcaa cccccacug 1944219RNAHepatitis B virus 442cugacgcaac ccccacugg 1944319RNAHepatitis B virus 443cugugccuuc ucaucugcc 1944419RNAHepatitis B virus 444ugugccuucu caucugccg 1944519RNAHepatitis B virus 445gugccuucuc aucugccgg 1944619RNAHepatitis B virus 446accagcacca ugcaacuuu 1944719RNAHepatitis B virus 447ccagcaccau gcaacuuuu 1944819RNAHepatitis B virus 448cagcaccaug caacuuuuu 1944919RNAHepatitis B virus 449agcaccaugc aacuuuuuc 1945019RNAHepatitis B virus 450gcaccaugca acuuuuuca 1945119RNAHepatitis B virus 451caccaugcaa cuuuuucac 1945219RNAHepatitis B virus 452accaugcaac uuuuucacc 1945319RNAHepatitis B virus 453ccaugcaacu uuuucaccu 1945419RNAHepatitis B virus 454cgcagaagau cucaaucuc 1945519RNAHepatitis B virus 455uccuaggacc ccugcucgu 1945619RNAHepatitis B virus 456ccuaggaccc cugcucgug 1945719RNAHepatitis B virus 457cuaggacccc ugcucgugu 1945819RNAHepatitis B virus 458uaggaccccu gcucguguu 1945919RNAHepatitis B virus 459cccugcucgu guuacaggc 1946019RNAHepatitis B virus 460ccugcucgug uuacaggcg 1946119RNAHepatitis B virus 461cugcucgugu uacaggcgg 1946219RNAHepatitis B virus 462gccauuuguu cagugguuc 1946319RNAHepatitis B virus 463ucgccaacuu acaaggccu 1946419RNAHepatitis B virus 464cgccaacuua caaggccuu 1946519RNAHepatitis B virus 465gccaacuuac aaggccuuu 1946619RNAHepatitis B virus 466gcgcaugcgu ggaaccuuu 1946719RNAHepatitis B virus 467cugccgaucc auacugcgg 1946819RNAHepatitis B virus 468gcauggagac caccgugaa 1946919RNAHepatitis B virus 469cauggagacc accgugaac 1947019RNAHepatitis B virus 470auggagacca ccgugaacg 1947119RNAHepatitis B virus 471uggagaccac cgugaacgc 1947219RNAHepatitis B virus 472ggagaccacc gugaacgcc 1947319RNAHepatitis B virus 473gagaccaccg ugaacgccc 1947419RNAHepatitis B virus 474caccagcacc augcaacuu 1947519RNAHepatitis B virus 475cccucgccuc gcagacgaa 1947619RNAHepatitis B virus 476ugggguggag cccucaggc 1947719RNAHepatitis B virus 477gccaaaauuc gcagucccc 1947819RNAHepatitis B virus 478ccaaaauucg cagucccca 1947919RNAHepatitis B virus 479caaaauucgc aguccccaa 1948019RNAHepatitis B virus 480uaccaauuuu cuuuugucu 1948119RNAHepatitis B virus 481ugccaagugu uugcugacg 1948219RNAHepatitis B virus 482gccaaguguu ugcugacgc 1948319RNAHepatitis B virus 483ccaaguguuu gcugacgca 1948419RNAHepatitis B virus 484ccucgccucg cagacgaag 1948519RNAHepatitis B virus 485ucucaaucgc cgcgucgca 1948619RNAHepatitis B virus 486cucaaucgcc gcgucgcag 1948719RNAHepatitis B virus 487ucaaucgccg cgucgcaga 1948819RNAHepatitis B virus 488ccuuggacuc auaaggugg 1948919RNAHepatitis B virus 489cuuggacuca uaagguggg 1949019RNAHepatitis B virus 490uccugcuggu ggcuccagu 1949119RNAHepatitis B virus 491uggcucaguu uacuagugc 1949219RNAHepatitis B virus 492uucguagggc uuuccccca 1949319RNAHepatitis B virus 493caaguguuug cugacgcaa 1949419RNAHepatitis B virus 494aaguguuugc ugacgcaac 1949519RNAHepatitis B virus 495aguguuugcu gacgcaacc 1949619RNAHepatitis B virus 496guguuugcug acgcaaccc 1949719RNAHepatitis B virus 497uguuugcuga cgcaacccc 1949819RNAHepatitis B virus 498guuugcugac gcaaccccc 1949919RNAHepatitis B virus 499augucaacga ccgaccuug 1950019RNAHepatitis B virus 500ugucaacgac cgaccuuga 1950119RNAHepatitis B virus 501gucaacgacc gaccuugag 1950219RNAHepatitis B virus 502ucaacgaccg accuugagg 1950319RNAHepatitis B virus 503caacgaccga ccuugaggc 1950419RNAHepatitis B virus 504caaucgccgc gucgcagaa 1950519RNAHepatitis B virus 505aaucgccgcg ucgcagaag 1950619RNAHepatitis B virus 506aucgccgcgu cgcagaaga 1950719RNAHepatitis B virus 507ucgccgcguc gcagaagau 1950819RNAHepatitis B virus 508cgccgcgucg cagaagauc 1950919RNAHepatitis B virus 509gccgcgucgc agaagaucu 1951019RNAHepatitis B virus 510uuccugcugg uggcuccag 1951119RNAHepatitis B virus 511guucguaggg cuuuccccc 1951219RNAHepatitis B virus 512ucguagggcu uucccccac 1951319RNAHepatitis B virus 513cuccucugcc gauccauac 1951419RNAHepatitis B virus 514uccucugccg auccauacu 1951519RNAHepatitis B virus 515ccucugccga uccauacug 1951619RNAHepatitis B virus 516cgcugaaucc cgcggacga 1951719RNAHepatitis B virus 517ccccgucugu gccuucuca 1951819RNAHepatitis B virus 518cccgucugug ccuucucau 1951919RNAHepatitis B virus 519ccgucugugc cuucucauc 1952019RNAHepatitis B virus 520cgucugugcc uucucaucu 1952119RNAHepatitis B virus 521cauaagagga cucuuggac 1952219RNAHepatitis B virus 522gacccuuaua aagaauuug 1952319RNAHepatitis B virus 523guguggauuc gcacuccuc 1952419RNAHepatitis B virus 524gaggcagguc

cccuagaag 1952519RNAHepatitis B virus 525aggcaggucc ccuagaaga 1952619RNAHepatitis B virus 526guccccaacc uccaaucac 1952719RNAHepatitis B virus 527uccccaaccu ccaaucacu 1952819RNAHepatitis B virus 528uaucaaggua uguugcccg 1952919RNAHepatitis B virus 529aucaagguau guugcccgu 1953019RNAHepatitis B virus 530cauuuguuca gugguucgu 1953119RNAHepatitis B virus 531uuuguucagu gguucguag 1953219RNAHepatitis B virus 532uuguucagug guucguagg 1953319RNAHepatitis B virus 533uguucagugg uucguaggg 1953419RNAHepatitis B virus 534guucaguggu ucguagggc 1953519RNAHepatitis B virus 535uucagugguu cguagggcu 1953619RNAHepatitis B virus 536ucagugguuc guagggcuu 1953719RNAHepatitis B virus 537cagugguucg uagggcuuu 1953819RNAHepatitis B virus 538agugguucgu agggcuuuc 1953919RNAHepatitis B virus 539gugguucgua gggcuuucc 1954019RNAHepatitis B virus 540ugguucguag ggcuuuccc 1954119RNAHepatitis B virus 541gguucguagg gcuuucccc 1954219RNAHepatitis B virus 542cagcgcaugc guggaaccu 1954319RNAHepatitis B virus 543agcgcaugcg uggaaccuu 1954419RNAHepatitis B virus 544cgcaugcgug gaaccuuug 1954519RNAHepatitis B virus 545cucugccgau ccauacugc 1954619RNAHepatitis B virus 546ucugccgauc cauacugcg 1954719RNAHepatitis B virus 547gcgcugaauc ccgcggacg 1954819RNAHepatitis B virus 548accucugccu aaucaucuc 1954919RNAHepatitis B virus 549ccgcguaaag agaggugcg 1955019RNAHepatitis B virus 550gagaagucca ccacgaguc 1955119RNAHepatitis B virus 551ugagagaagu ccaccacga 1955219RNAHepatitis B virus 552aacgccgcag acacaucca 1955319RNAHepatitis B virus 553ugaagcgaag ugcacacgg 1955419RNAHepatitis B virus 554ggugaagcga agugcacac 1955519RNAHepatitis B virus 555aggugaagcg aagugcaca 1955619RNAHepatitis B virus 556gaggugaagc gaagugcac 1955719RNAHepatitis B virus 557cagaggugaa gcgaagugc 1955819RNAHepatitis B virus 558cacagcuugg aggcuugaa 1955919RNAHepatitis B virus 559gcacagcuug gaggcuuga 1956019RNAHepatitis B virus 560ggcacagcuu ggaggcuug 1956119RNAHepatitis B virus 561aggcacagcu uggaggcuu 1956219RNAHepatitis B virus 562aguccaccac gagucuaga 1956319RNAHepatitis B virus 563aaguccacca cgagucuag 1956419RNAHepatitis B virus 564gaaguccacc acgagucua 1956519RNAHepatitis B virus 565agaaguccac cacgagucu 1956619RNAHepatitis B virus 566aaaacgccgc agacacauc 1956719RNAHepatitis B virus 567auaaaacgcc gcagacaca 1956819RNAHepatitis B virus 568ugauaaaacg ccgcagaca 1956919RNAHepatitis B virus 569auuuaugccu acagccucc 1957019RNAHepatitis B virus 570aauuuaugcc uacagccuc 1957119RNAHepatitis B virus 571ccaauuuaug ccuacagcc 1957219RNAHepatitis B virus 572accaauuuau gccuacagc 1957319RNAHepatitis B virus 573aggcagaggu gaaaaaguu 1957419RNAHepatitis B virus 574ccaccacgag ucuagacuc 1957519RNAHepatitis B virus 575uccaccacga gucuagacu 1957619RNAHepatitis B virus 576guccaccacg agucuagac 1957719RNAHepatitis B virus 577gaggcauagc agcaggaug 1957819RNAHepatitis B virus 578augaggcaua gcagcagga 1957919RNAHepatitis B virus 579gaugaggcau agcagcagg 1958019RNAHepatitis B virus 580agaugaggca uagcagcag 1958119RNAHepatitis B virus 581aagaugaggc auagcagca 1958219RNAHepatitis B virus 582gaccaauuua ugccuacag 1958319RNAHepatitis B virus 583agaccaauuu augccuaca 1958419RNAHepatitis B virus 584agagaagucc accacgagu 1958519RNAHepatitis B virus 585gagagaaguc caccacgag 1958619RNAHepatitis B virus 586gugaagcgaa gugcacacg 1958719RNAHepatitis B virus 587agaggugaag cgaagugca 1958819RNAHepatitis B virus 588gcagagguga agcgaagug 1958919RNAHepatitis B virus 589ugcagaggug aagcgaagu 1959019RNAHepatitis B virus 590aaggcacagc uuggaggcu 1959119RNAHepatitis B virus 591caaggcacag cuuggaggc 1959219RNAHepatitis B virus 592cugcgaggcg agggaguuc 1959319RNAHepatitis B virus 593ucugcgaggc gagggaguu 1959419RNAHepatitis B virus 594gucugcgagg cgagggagu 1959519RNAHepatitis B virus 595cgucugcgag gcgagggag 1959619RNAHepatitis B virus 596aacuggagcc accagcagg 1959719RNAHepatitis B virus 597gaacuggagc caccagcag 1959819RNAHepatitis B virus 598aaacgccgca gacacaucc 1959919RNAHepatitis B virus 599uaaaacgccg cagacacau 1960019RNAHepatitis B virus 600gauaaaacgc cgcagacac 1960119RNAHepatitis B virus 601augauaaaac gccgcagac 1960219RNAHepatitis B virus 602ugaggcccac ucccauagg 1960319RNAHepatitis B virus 603cugaggccca cucccauag 1960419RNAHepatitis B virus 604gugcagaggu gaagcgaag 1960519RNAHepatitis B virus 605cgugcagagg ugaagcgaa 1960619RNAHepatitis B virus 606acgugcagag gugaagcga 1960719RNAHepatitis B virus 607caauuuaugc cuacagccu 1960819RNAHepatitis B virus 608uaggcagagg ugaaaaagu 1960919RNAHepatitis B virus 609ugaggcauag cagcaggau 1961019RNAHepatitis B virus 610gaagaugagg cauagcagc 1961119RNAHepatitis B virus 611agaagaugag gcauagcag 1961219RNAHepatitis B virus 612aagaagauga ggcauagca 1961319RNAHepatitis B virus 613cagaccaauu uaugccuac 1961419RNAHepatitis B virus 614ccaaggcaca gcuuggagg 1961519RNAHepatitis B virus 615uugagagaag uccaccacg 1961619RNAHepatitis B virus 616auugagagaa guccaccac 1961719RNAHepatitis B virus 617aauugagaga aguccacca 1961819RNAHepatitis B virus 618aaauugagag aaguccacc 1961919RNAHepatitis B virus 619aaaauugaga gaaguccac 1962019RNAHepatitis B virus 620gaaaauugag agaagucca 1962119RNAHepatitis B virus 621uagaaaauug agagaaguc 1962219RNAHepatitis B virus 622cuagaaaauu gagagaagu 1962319RNAHepatitis B virus 623ccuagaaaau ugagagaag 1962419RNAHepatitis B virus 624cccuagaaaa uugagagaa 1962519RNAHepatitis B virus 625ccccuagaaa auugagaga 1962619RNAHepatitis B virus 626ggaguuccgc aguauggau 1962719RNAHepatitis B virus 627aggaguuccg caguaugga 1962819RNAHepatitis B virus 628ggcgagggag uucuucuuc 1962919RNAHepatitis B virus 629aggcgaggga guucuucuu 1963019RNAHepatitis B virus 630gaggcgaggg aguucuucu 1963119RNAHepatitis B virus 631cgaggcgagg gaguucuuc 1963219RNAHepatitis B virus 632gcgaggcgag ggaguucuu 1963319RNAHepatitis B virus 633ugcgaggcga gggaguucu 1963419RNAHepatitis B virus 634caccacgagu cuagacucu 1963519RNAHepatitis B virus 635agaaaauuga gagaagucc 1963619RNAHepatitis B virus 636gaguuccgca guauggauc 1963719RNAHepatitis B virus 637cagaggugaa aaaguugca 1963819RNAHepatitis B virus 638gcagagguga aaaaguugc 1963919RNAHepatitis B virus 639ggcagaggug aaaaaguug 1964019RNAHepatitis B virus 640ggacugcgaa uuuuggcca 1964119RNAHepatitis B virus 641gggacugcga auuuuggcc 1964219RNAHepatitis B virus 642guuccgcagu auggaucgg 1964319RNAHepatitis B virus 643aguuccgcag uauggaucg 1964419RNAHepatitis B virus 644uuaggcagag gugaaaaag 1964519RNAHepatitis B virus 645auuaggcaga ggugaaaaa 1964619RNAHepatitis B virus 646gauuaggcag aggugaaaa 1964719RNAHepatitis B virus 647ugauuaggca gaggugaaa 1964819RNAHepatitis B virus 648gccacccaag gcacagcuu 1964919RNAHepatitis B virus 649agccacccaa ggcacagcu 1965019RNAHepatitis B virus 650aagccaccca aggcacagc 1965119RNAHepatitis B virus 651aaagccaccc aaggcacag 1965219RNAHepatitis B virus 652gagugcgaau ccacacucc 1965319RNAHepatitis B virus 653ggagugcgaa uccacacuc 1965419RNAHepatitis B virus 654accacgaguc uagacucug 1965519RNAHepatitis B virus 655aguccaagag uccucuuau 1965619RNAHepatitis B virus 656uuaugccuac agccuccua 1965719RNAHepatitis B virus 657uuuaugccua cagccuccu 1965819RNAHepatitis B virus 658gaggugaaaa aguugcaug 1965919RNAHepatitis B virus 659agaggugaaa aaguugcau 1966019RNAHepatitis B virus 660augauuaggc agaggugaa 1966119RNAHepatitis B virus 661gaugauuagg cagagguga 1966219RNAHepatitis B virus 662agaugauuag gcagaggug 1966319RNAHepatitis B virus 663cccaaggcac agcuuggag 1966419RNAHepatitis B virus 664acccaaggca cagcuugga 1966519RNAHepatitis B virus 665cacccaaggc acagcuugg 1966619RNAHepatitis B virus 666ccacccaagg cacagcuug 1966719RNAHepatitis B virus 667gagggaguuc uucuucuag 1966819RNAHepatitis B virus 668cgagggaguu cuucuucua 1966919RNAHepatitis B virus 669gcgagggagu ucuucuucu 1967019RNAHepatitis B virus 670acagcuugga ggcuugaac 1967119RNAHepatitis B virus 671uaggggcauu ugguggucu 1967219RNAHepatitis B virus 672auaggggcau uuggugguc 1967319RNAHepatitis B virus 673gauaggggca uuugguggu 1967419RNAHepatitis B virus 674augaugggau gggaauaca 1967519RNAHepatitis B virus 675gaugauggga ugggaauac 1967619RNAHepatitis B virus 676agugggggaa agcccuacg 1967719RNAHepatitis B virus 677caguggggga aagcccuac 1967819RNAHepatitis B virus 678acaguggggg aaagcccua 1967919RNAHepatitis B virus 679uccgcaguau ggaucggca 1968019RNAHepatitis B virus 680uuccgcagua uggaucggc 1968119RNAHepatitis B virus 681aagagaggug cgccccgug 1968219RNAHepatitis B virus 682aaagagaggu gcgccccgu 1968319RNAHepatitis B virus 683uaaagagagg ugcgccccg 1968419RNAHepatitis B virus 684guaaagagag gugcgcccc 1968519RNAHepatitis B virus 685cguaaagaga ggugcgccc 1968619RNAHepatitis B virus 686gcguaaagag aggugcgcc 1968719RNAHepatitis B virus 687cgcguaaaga gaggugcgc 1968819RNAHepatitis B virus 688gcuuggaggc uugaacagu 1968919RNAHepatitis B virus 689agcuuggagg cuugaacag 1969019RNAHepatitis B virus 690cagcuuggag gcuugaaca 1969119RNAHepatitis B virus 691ggacaaacgg gcaacauac

1969219RNAHepatitis B virus 692aggacaaacg ggcaacaua 1969319RNAHepatitis B virus 693agaggacaaa cgggcaaca 1969419RNAHepatitis B virus 694gcaacggggu aaagguuca 1969519RNAHepatitis B virus 695uaggaguucc gcaguaugg 1969619RNAHepatitis B virus 696cuaggaguuc cgcaguaug 1969719RNAHepatitis B virus 697gcuaggaguu ccgcaguau 1969819RNAHepatitis B virus 698agagaggugc gccccgugg 1969919RNAHepatitis B virus 699gggaguucuu cuucuaggg 1970019RNAHepatitis B virus 700agggaguucu ucuucuagg 1970119RNAHepatitis B virus 701ucgucugcga ggcgaggga 1970219RNAHepatitis B virus 702gcagcaggau gaagaggaa 1970319RNAHepatitis B virus 703agcagcagga ugaagagga 1970419RNAHepatitis B virus 704uagcagcagg augaagagg 1970519RNAHepatitis B virus 705auagcagcag gaugaagag 1970619RNAHepatitis B virus 706cauagcagca ggaugaaga 1970719RNAHepatitis B virus 707gcauagcagc aggaugaag 1970819RNAHepatitis B virus 708ggcauagcag caggaugaa 1970919RNAHepatitis B virus 709aggcauagca gcaggauga 1971019RNAHepatitis B virus 710gacaaacggg caacauacc 1971119RNAHepatitis B virus 711gaggacaaac gggcaacau 1971219RNAHepatitis B virus 712ucagcgccga cgggacgua 1971319RNAHepatitis B virus 713uucagcgccg acgggacgu 1971419RNAHepatitis B virus 714auucagcgcc gacgggacg 1971519RNAHepatitis B virus 715gauucagcgc cgacgggac 1971619RNAHepatitis B virus 716ggauucagcg ccgacggga 1971719RNAHepatitis B virus 717aggagugcga auccacacu 1971819RNAHepatitis B virus 718ggaguucuuc uucuagggg 1971919RNAHepatitis B virus 719aaacgggcaa cauaccuug 1972019RNAHepatitis B virus 720caaacgggca acauaccuu 1972119RNAHepatitis B virus 721acaaacgggc aacauaccu 1972219RNAHepatitis B virus 722aggugcgccc cguggucgg 1972319RNAHepatitis B virus 723gaggugcgcc ccguggucg 1972419RNAHepatitis B virus 724agaggugcgc cccgugguc 1972519RNAHepatitis B virus 725gagaggugcg ccccguggu 1972619RNAHepatitis B virus 726agaaggcaca gacggggag 1972719RNAHepatitis B virus 727gagaaggcac agacgggga 1972819RNAHepatitis B virus 728gagaucuucu gcgacgcgg 1972919RNAHepatitis B virus 729ugagaucuuc ugcgacgcg 1973019RNAHepatitis B virus 730uugagaucuu cugcgacgc 1973119RNAHepatitis B virus 731auugagaucu ucugcgacg 1973219RNAHepatitis B virus 732gauugagauc uucugcgac 1973319RNAHepatitis B virus 733agauugagau cuucugcga 1973419RNAHepatitis B virus 734uaacacgagc agggguccu 1973519RNAHepatitis B virus 735guaacacgag caggggucc 1973619RNAHepatitis B virus 736uguaacacga gcagggguc 1973719RNAHepatitis B virus 737cuguaacacg agcaggggu 1973819RNAHepatitis B virus 738ccuguaacac gagcagggg 1973919RNAHepatitis B virus 739gcagacacau ccagcgaua 1974019RNAHepatitis B virus 740cgcagacaca uccagcgau 1974119RNAHepatitis B virus 741ccgcagacac auccagcga 1974219RNAHepatitis B virus 742gccgcagaca cauccagcg 1974319RNAHepatitis B virus 743cgccgcagac acauccagc 1974419RNAHepatitis B virus 744acgccgcaga cacauccag 1974519RNAHepatitis B virus 745uagaggacaa acgggcaac 1974619RNAHepatitis B virus 746cgaaccacug aacaaaugg 1974719RNAHepatitis B virus 747gacaaaagaa aauugguaa 1974819RNAHepatitis B virus 748gaaaggccuu guaaguugg 1974919RNAHepatitis B virus 749agaaaggccu uguaaguug 1975019RNAHepatitis B virus 750uggggguugc gucagcaaa 1975119RNAHepatitis B virus 751guggggguug cgucagcaa 1975219RNAHepatitis B virus 752aguggggguu gcgucagca 1975319RNAHepatitis B virus 753cagugggggu ugcgucagc 1975419RNAHepatitis B virus 754ccaguggggg uugcgucag 1975519RNAHepatitis B virus 755ggcagaugag aaggcacag 1975619RNAHepatitis B virus 756cggcagauga gaaggcaca 1975719RNAHepatitis B virus 757ccggcagaug agaaggcac 1975819RNAHepatitis B virus 758aaaguugcau ggugcuggu 1975919RNAHepatitis B virus 759aaaaguugca uggugcugg 1976019RNAHepatitis B virus 760aaaaaguugc auggugcug 1976119RNAHepatitis B virus 761gaaaaaguug cauggugcu 1976219RNAHepatitis B virus 762ugaaaaaguu gcauggugc 1976319RNAHepatitis B virus 763gugaaaaagu ugcauggug 1976419RNAHepatitis B virus 764ggugaaaaag uugcauggu 1976519RNAHepatitis B virus 765aggugaaaaa guugcaugg 1976619RNAHepatitis B virus 766gagauugaga ucuucugcg 1976719RNAHepatitis B virus 767acgagcaggg guccuagga 1976819RNAHepatitis B virus 768cacgagcagg gguccuagg 1976919RNAHepatitis B virus 769acacgagcag ggguccuag 1977019RNAHepatitis B virus 770aacacgagca gggguccua 1977119RNAHepatitis B virus 771gccuguaaca cgagcaggg 1977219RNAHepatitis B virus 772cgccuguaac acgagcagg 1977319RNAHepatitis B virus 773ccgccuguaa cacgagcag 1977419RNAHepatitis B virus 774gaaccacuga acaaauggc 1977519RNAHepatitis B virus 775aggccuugua aguuggcga 1977619RNAHepatitis B virus 776aaggccuugu aaguuggcg 1977719RNAHepatitis B virus 777aaaggccuug uaaguuggc 1977819RNAHepatitis B virus 778aaagguucca cgcaugcgc 1977919RNAHepatitis B virus 779ccgcaguaug gaucggcag 1978019RNAHepatitis B virus 780uucacggugg ucuccaugc 1978119RNAHepatitis B virus 781guucacggug gucuccaug 1978219RNAHepatitis B virus 782cguucacggu ggucuccau 1978319RNAHepatitis B virus 783gcguucacgg uggucucca 1978419RNAHepatitis B virus 784ggcguucacg guggucucc 1978519RNAHepatitis B virus 785gggcguucac gguggucuc 1978619RNAHepatitis B virus 786aaguugcaug gugcuggug 1978719RNAHepatitis B virus 787uucgucugcg aggcgaggg 1978819RNAHepatitis B virus 788gccugagggc uccacccca 1978919RNAHepatitis B virus 789ggggacugcg aauuuuggc 1979019RNAHepatitis B virus 790uggggacugc gaauuuugg 1979119RNAHepatitis B virus 791uuggggacug cgaauuuug 1979219RNAHepatitis B virus 792agacaaaaga aaauuggua 1979319RNAHepatitis B virus 793cgucagcaaa cacuuggca 1979419RNAHepatitis B virus 794gcgucagcaa acacuuggc 1979519RNAHepatitis B virus 795ugcgucagca aacacuugg 1979619RNAHepatitis B virus 796cuucgucugc gaggcgagg 1979719RNAHepatitis B virus 797ugcgacgcgg cgauugaga 1979819RNAHepatitis B virus 798cugcgacgcg gcgauugag 1979919RNAHepatitis B virus 799ucugcgacgc ggcgauuga 1980019RNAHepatitis B virus 800ccaccuuaug aguccaagg 1980119RNAHepatitis B virus 801cccaccuuau gaguccaag 1980219RNAHepatitis B virus 802acuggagcca ccagcagga 1980319RNAHepatitis B virus 803gcacuaguaa acugagcca 1980419RNAHepatitis B virus 804ugggggaaag cccuacgaa 1980519RNAHepatitis B virus 805uugcgucagc aaacacuug 1980619RNAHepatitis B virus 806guugcgucag caaacacuu 1980719RNAHepatitis B virus 807gguugcguca gcaaacacu 1980819RNAHepatitis B virus 808ggguugcguc agcaaacac 1980919RNAHepatitis B virus 809gggguugcgu cagcaaaca 1981019RNAHepatitis B virus 810ggggguugcg ucagcaaac 1981119RNAHepatitis B virus 811caaggucggu cguugacau 1981219RNAHepatitis B virus 812ucaaggucgg ucguugaca 1981319RNAHepatitis B virus 813cucaaggucg gucguugac 1981419RNAHepatitis B virus 814ccucaagguc ggucguuga 1981519RNAHepatitis B virus 815gccucaaggu cggucguug 1981619RNAHepatitis B virus 816uucugcgacg cggcgauug 1981719RNAHepatitis B virus 817cuucugcgac gcggcgauu 1981819RNAHepatitis B virus 818ucuucugcga cgcggcgau 1981919RNAHepatitis B virus 819aucuucugcg acgcggcga 1982019RNAHepatitis B virus 820gaucuucugc gacgcggcg 1982119RNAHepatitis B virus 821agaucuucug cgacgcggc 1982219RNAHepatitis B virus 822cuggagccac cagcaggaa 1982319RNAHepatitis B virus 823gggggaaagc ccuacgaac 1982419RNAHepatitis B virus 824gugggggaaa gcccuacga 1982519RNAHepatitis B virus 825guauggaucg gcagaggag 1982619RNAHepatitis B virus 826aguauggauc ggcagagga 1982719RNAHepatitis B virus 827caguauggau cggcagagg 1982819RNAHepatitis B virus 828ucguccgcgg gauucagcg 1982919RNAHepatitis B virus 829ugagaaggca cagacgggg 1983019RNAHepatitis B virus 830augagaaggc acagacggg 1983119RNAHepatitis B virus 831gaugagaagg cacagacgg 1983219RNAHepatitis B virus 832agaugagaag gcacagacg 1983319RNAHepatitis B virus 833guccaagagu ccucuuaug 1983419RNAHepatitis B virus 834caaauucuuu auaaggguc 1983519RNAHepatitis B virus 835gaggagugcg aauccacac 1983619RNAHepatitis B virus 836cuucuagggg accugccuc 1983719RNAHepatitis B virus 837ucuucuaggg gaccugccu 1983819RNAHepatitis B virus 838gugauuggag guuggggac 1983919RNAHepatitis B virus 839agugauugga gguugggga 1984019RNAHepatitis B virus 840cgggcaacau accuugaua 1984119RNAHepatitis B virus 841acgggcaaca uaccuugau 1984219RNAHepatitis B virus 842acgaaccacu gaacaaaug 1984319RNAHepatitis B virus 843cuacgaacca cugaacaaa 1984419RNAHepatitis B virus 844ccuacgaacc acugaacaa 1984519RNAHepatitis B virus 845cccuacgaac cacugaaca 1984619RNAHepatitis B virus 846gcccuacgaa ccacugaac 1984719RNAHepatitis B virus 847agcccuacga accacugaa 1984819RNAHepatitis B virus 848aagcccuacg aaccacuga 1984919RNAHepatitis B virus 849aaagcccuac gaaccacug 1985019RNAHepatitis B virus 850gaaagcccua cgaaccacu 1985119RNAHepatitis B virus 851ggaaagcccu acgaaccac 1985219RNAHepatitis B virus 852gggaaagccc uacgaacca 1985319RNAHepatitis B virus 853ggggaaagcc cuacgaacc 1985419RNAHepatitis B virus 854agguuccacg caugcgcug 1985519RNAHepatitis B virus 855aagguuccac gcaugcgcu 1985619RNAHepatitis B virus 856caaagguucc acgcaugcg 1985719RNAHepatitis B virus 857gcaguaugga ucggcagag 1985819RNAHepatitis B virus 858cgcaguaugg aucggcaga

1985919RNAHepatitis B virus 859cguccgcggg auucagcgc 1986019RNAHepatitis B virus 860gagaugauua ggcagaggu 1986119RNAHepatitis B virus 861cgcaccucuc uuuacgcgg 1986219RNAHepatitis B virus 862gacucguggu ggacuucuc 1986319RNAHepatitis B virus 863ucguggugga cuucucuca 1986419RNAHepatitis B virus 864uggauguguc ugcggcguu 1986519RNAHepatitis B virus 865ccgugugcac uucgcuuca 1986619RNAHepatitis B virus 866gugugcacuu cgcuucacc 1986719RNAHepatitis B virus 867ugugcacuuc gcuucaccu 1986819RNAHepatitis B virus 868gugcacuucg cuucaccuc 1986919RNAHepatitis B virus 869gcacuucgcu ucaccucug 1987019RNAHepatitis B virus 870ucuagacucg ugguggacu 1987119RNAHepatitis B virus 871cuagacucgu gguggacuu 1987219RNAHepatitis B virus 872uagacucgug guggacuuc 1987319RNAHepatitis B virus 873agacucgugg uggacuucu 1987419RNAHepatitis B virus 874ggaggcugua ggcauaaau 1987519RNAHepatitis B virus 875gaggcuguag gcauaaauu 1987619RNAHepatitis B virus 876ggcuguaggc auaaauugg 1987719RNAHepatitis B virus 877gcuguaggca uaaauuggu 1987819RNAHepatitis B virus 878cuguaggcau aaauugguc 1987919RNAHepatitis B virus 879uguaggcaua aauuggucu 1988019RNAHepatitis B virus 880gugguggacu ucucucaau 1988119RNAHepatitis B virus 881uucaagccuc caagcugug 1988219RNAHepatitis B virus 882ucaagccucc aagcugugc 1988319RNAHepatitis B virus 883caagccucca agcugugcc 1988419RNAHepatitis B virus 884aagccuccaa gcugugccu 1988519RNAHepatitis B virus 885gaugugucug cggcguuuu 1988619RNAHepatitis B virus 886ugugucugcg gcguuuuau 1988719RNAHepatitis B virus 887ugucugcggc guuuuauca 1988819RNAHepatitis B virus 888aacuuuuuca ccucugccu 1988919RNAHepatitis B virus 889gagucuagac ucguggugg 1989019RNAHepatitis B virus 890agucuagacu cguggugga 1989119RNAHepatitis B virus 891gucuagacuc gugguggac 1989219RNAHepatitis B virus 892cauccugcug cuaugccuc 1989319RNAHepatitis B virus 893uccugcugcu augccucau 1989419RNAHepatitis B virus 894ccugcugcua ugccucauc 1989519RNAHepatitis B virus 895cugcugcuau gccucaucu 1989619RNAHepatitis B virus 896ugcugcuaug ccucaucuu 1989719RNAHepatitis B virus 897acucguggug gacuucucu 1989819RNAHepatitis B virus 898cucguggugg acuucucuc 1989919RNAHepatitis B virus 899cgugugcacu ucgcuucac 1990019RNAHepatitis B virus 900ugcacuucgc uucaccucu 1990119RNAHepatitis B virus 901cacuucgcuu caccucugc 1990219RNAHepatitis B virus 902ccgcguaaag agaggugcg 1990319RNAHepatitis B virus 903gagaagucca ccacgaguc 1990419RNAHepatitis B virus 904ugagagaagu ccaccacga 1990519RNAHepatitis B virus 905aacgccgcag acacaucca 1990619RNAHepatitis B virus 906ugaagcgaag ugcacacgg 1990719RNAHepatitis B virus 907ggugaagcga agugcacac 1990819RNAHepatitis B virus 908aggugaagcg aagugcaca 1990919RNAHepatitis B virus 909gaggugaagc gaagugcac 1991019RNAHepatitis B virus 910cagaggugaa gcgaagugc 1991119RNAHepatitis B virus 911aguccaccac gagucuaga 1991219RNAHepatitis B virus 912aaguccacca cgagucuag 1991319RNAHepatitis B virus 913gaaguccacc acgagucua 1991419RNAHepatitis B virus 914agaaguccac cacgagucu 1991519RNAHepatitis B virus 915auuuaugccu acagccucc 1991619RNAHepatitis B virus 916aauuuaugcc uacagccuc 1991719RNAHepatitis B virus 917ccaauuuaug ccuacagcc 1991819RNAHepatitis B virus 918accaauuuau gccuacagc 1991919RNAHepatitis B virus 919gaccaauuua ugccuacag 1992019RNAHepatitis B virus 920agaccaauuu augccuaca 1992119RNAHepatitis B virus 921auugagagaa guccaccac 1992219RNAHepatitis B virus 922cacagcuugg aggcuugaa 1992319RNAHepatitis B virus 923gcacagcuug gaggcuuga 1992419RNAHepatitis B virus 924ggcacagcuu ggaggcuug 1992519RNAHepatitis B virus 925aggcacagcu uggaggcuu 1992619RNAHepatitis B virus 926aaaacgccgc agacacauc 1992719RNAHepatitis B virus 927auaaaacgcc gcagacaca 1992819RNAHepatitis B virus 928ugauaaaacg ccgcagaca 1992919RNAHepatitis B virus 929aggcagaggu gaaaaaguu 1993019RNAHepatitis B virus 930ccaccacgag ucuagacuc 1993119RNAHepatitis B virus 931uccaccacga gucuagacu 1993219RNAHepatitis B virus 932guccaccacg agucuagac 1993319RNAHepatitis B virus 933gaggcauagc agcaggaug 1993419RNAHepatitis B virus 934augaggcaua gcagcagga 1993519RNAHepatitis B virus 935gaugaggcau agcagcagg 1993619RNAHepatitis B virus 936agaugaggca uagcagcag 1993719RNAHepatitis B virus 937aagaugaggc auagcagca 1993819RNAHepatitis B virus 938agagaagucc accacgagu 1993919RNAHepatitis B virus 939gagagaaguc caccacgag 1994019RNAHepatitis B virus 940gugaagcgaa gugcacacg 1994119RNAHepatitis B virus 941agaggugaag cgaagugca 1994219RNAHepatitis B virus 942gcagagguga agcgaagug 1994321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 943gagucuagac ucgugguggu u 2194421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 944ccaccacgag ucuagacucu u 2194521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 945agucuagacu cgugguggau u 2194621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 946uccaccacga gucuagacuu u 2194721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 947gucuagacuc gugguggacu u 2194821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 948guccaccacg agucuagacu u 2194921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 949ucuagacucg ugguggacuu u 2195021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 950aguccaccac gagucuagau u 2195121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 951cuagacucgu gguggacuuu u 2195221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 952aaguccacca cgagucuagu u 2195321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 953uagacucgug guggacuucu u 2195421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 954gaaguccacc acgagucuau u 2195521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 955agacucgugg uggacuucuu u 2195621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 956agaaguccac cacgagucuu u 2195721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 957gacucguggu ggacuucucu u 2195821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 958gagaagucca ccacgagucu u 2195921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 959acucguggug gacuucucuu u 2196021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 960agagaagucc accacgaguu u 2196121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 961cucguggugg acuucucucu u 2196221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 962gagagaaguc caccacgagu u 2196321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 963ucguggugga cuucucucau u 2196421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 964ugagagaagu ccaccacgau u 2196521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 965gugguggacu ucucucaauu u 2196621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 966auugagagaa guccaccacu u 2196721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 967uggauguguc ugcggcguuu u 2196821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 968aacgccgcag acacauccau u 2196921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 969gaugugucug cggcguuuuu u 2197021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 970aaaacgccgc agacacaucu u 2197121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 971ugugucugcg gcguuuuauu u 2197221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 972auaaaacgcc gcagacacau u 2197321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 973ugucugcggc guuuuaucau u 2197421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 974ugauaaaacg ccgcagacau u 2197521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 975cauccugcug cuaugccucu u 2197621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 976gaggcauagc agcaggaugu u 2197721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 977uccugcugcu augccucauu u 2197821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 978augaggcaua gcagcaggau u 2197921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 979ccugcugcua ugccucaucu u 2198021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 980gaugaggcau agcagcaggu u 2198121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 981cugcugcuau gccucaucuu u 2198221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 982agaugaggca uagcagcagu u 2198321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 983ugcugcuaug ccucaucuuu u 2198421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 984aagaugaggc auagcagcau u 2198521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 985cgcaccucuc uuuacgcggu u 2198621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 986ccgcguaaag agaggugcgu u 2198721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 987ccgugugcac uucgcuucau u 2198821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 988ugaagcgaag ugcacacggu u 2198921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 989cgugugcacu ucgcuucacu u 2199021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 990gugaagcgaa gugcacacgu u 2199121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 991gugugcacuu cgcuucaccu u 2199221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 992ggugaagcga agugcacacu u

2199321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 993ugugcacuuc gcuucaccuu u 2199421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 994aggugaagcg aagugcacau u 2199521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 995gugcacuucg cuucaccucu u 2199621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 996gaggugaagc gaagugcacu u 2199721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 997ugcacuucgc uucaccucuu u 2199821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 998agaggugaag cgaagugcau u 2199921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 999gcacuucgcu ucaccucugu u 21100021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1000cagaggugaa gcgaagugcu u 21100121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1001cacuucgcuu caccucugcu u 21100221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1002gcagagguga agcgaagugu u 21100321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1003ggaggcugua ggcauaaauu u 21100421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1004auuuaugccu acagccuccu u 21100521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1005gaggcuguag gcauaaauuu u 21100621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1006aauuuaugcc uacagccucu u 21100721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1007ggcuguaggc auaaauuggu u 21100821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1008ccaauuuaug ccuacagccu u 21100921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1009gcuguaggca uaaauugguu u 21101021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1010accaauuuau gccuacagcu u 21101121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1011cuguaggcau aaauuggucu u 21101221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1012gaccaauuua ugccuacagu u 21101321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1013uguaggcaua aauuggucuu u 21101421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1014agaccaauuu augccuacau u 21101521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1015aacuuuuuca ccucugccuu u 21101621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1016aggcagaggu gaaaaaguuu u 21101721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1017uucaagccuc caagcugugu u 21101821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1018cacagcuugg aggcuugaau u 21101921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1019ucaagccucc aagcugugcu u 21102021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1020gcacagcuug gaggcuugau u 21102121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1021caagccucca agcugugccu u 21102221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1022ggcacagcuu ggaggcuugu u 21102321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1023aagccuccaa gcugugccuu u 21102421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1024aggcacagcu uggaggcuuu u 21102521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1025cgugugcacu ucgcuucacu u 21102621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1026gugaagcgaa gugcacacgu u 21102721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1027cgugugcacu ucgcuucacu u 21102821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1028gugaagcgaa gugcacacgu u 21102921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1029cgugugcacu ucgcuucacu u 21103021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1030gugaagcgaa gugcacacgu u 21103121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1031cgugugcacu ucgcuucacu u 21103221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1032gugaagcgaa gugcacacgu u 21103321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1033cgugugcacu ucgcuucacu u 21103421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1034gugaagcgaa gugcacacgu u 21103521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1035cgugugcacu ucgcuucacu u 21103621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1036gugaagcgaa gugcacacgu u 21103721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1037cgugugcacu ucgcuucacu u 21103821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1038gugaagcgaa gugcacacgu u 21103921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1039cgugugcacu ucgcuucacu u 21104021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1040gugaagcgaa gugcacacgu u 21104121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1041ccgugugcac uucgcuucau u 21104221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1042ugaagcgaag ugcacacggu u 21104321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1043ccgugugcac uucgcuucau u 21104421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1044ugaagcgaag ugcacacggu u 21104521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1045ccgugugcac uucgcuucau u 21104621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1046ugaagcgaag ugcacacggu u 21104721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1047ugugcacuuc gcuucaccuu u 21104821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1048aggugaagcg aagugcacau u 21104921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1049ugugcacuuc gcuucaccuu u 21105021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1050aggugaagcg aagugcacau u 21105121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1051ugugcacuuc gcuucaccuu u 21105221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1052aggugaagcg aagugcacau u 21105321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1053aacuuuuuca ccucugccuu u 21105421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1054aggcagaggu gaaaaaguuu u 21105521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1055aacuuuuuca ccucugccuu u 21105621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1056aggcagaggu gaaaaaguuu u 21105721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1057aacuuuuuca ccucugccuu u 21105821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1058aggcagaggu gaaaaaguuu u 21105921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1059agucuagacu cgugguggau u 21106021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1060uccaccacga gucuagacuu u 21106121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1061ugcacuucgc uucaccucuu u 21106221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1062agaggugaag cgaagugcau u 21106321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1063ugcacuucgc uucaccucuu u 21106421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1064agaggugaag cgaagugcau u 21106521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1065ugcacuucgc uucaccucuu u 21106621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1066agaggugaag cgaagugcau u 21106721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1067ugcacuucgc uucaccucuu u 21106821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1068agaggugaag cgaagugcau u 21106921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1069ugugcacuuc gcuucaccuu u 21107021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1070aggugaagcg aagugcacau u 21107121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1071ugugcacuuc gcuucaccuu u 21107221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1072aggugaagcg aagugcacau u 21107321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1073ugugcacuuc gcuucaccuu u 21107421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1074aggugaagcg aagugcacau u 21107521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1075ugugcacuuc gcuucaccuu u 21107621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1076aggugaagcg aagugcacau u 21107721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1077ugugcacuuc gcuucaccuu u 21107821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1078aggugaagcg aagugcacau u 21107921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1079ugugcacuuc gcuucaccuu u 21108021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1080aggugaagcg aagugcacau u 21108121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1081ugugcacuuc gcuucaccuu u 21108221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1082aggugaagcg aagugcacau u 21108321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1083ugugcacuuc gcuucaccuu u 21108421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1084aggugaagcg aagugcacau u 21108521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1085ugugcacuuc gcuucaccuu u 21108621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1086aggugaagcg aagugcacau u 21108721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1087ugugcacuuc gcuucaccuu u 21108821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1088aggugaagcg aagugcacau u 21108921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1089ugugcacuuc gcuucaccuu u 21109021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1090aggugaagcg aagugcacau u 21109121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1091ugugcacuuc gcuucaccuu u 21109221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1092aggugaagcg aagugcacau u 21109321RNAArtificial SequenceDescription of Artificial Sequence

Synthetic oligonucleotide 1093ugugcacuuc gcuucaccuu u 21109421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1094aggugaagcg aagugcacau u 21109521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1095ugugcacuuc gcuucaccuu u 21109621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1096aggugaagcg aagugcacau u 21109721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1097ugugcacuuc gcuucaccuu u 21109821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1098aggugaagcg aagugcacau u 21109921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1099ugugcacuuc gcuucaccuu u 21110021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1100aggugaagcg aagugcacau u 21110121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1101gaggcuguag gcauaaauuu u 21110221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1102aauuuaugcc uacagccucu u 21110321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1103gaggcuguag gcauaaauuu u 21110421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1104aauuuaugcc uacagccucu u 21110521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1105gaggcuguag gcauaaauuu u 21110621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1106aauuuaugcc uacagccucu u 21110721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1107ugucugcggc guuuuaucau u 21110821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1108ugauaaaacg ccgcagacau u 21110921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1109ugucugcggc guuuuaucau u 21111021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1110ugauaaaacg ccgcagacau u 21111121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1111ugucugcggc guuuuaucau u 21111221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1112ugauaaaacg ccgcagacau u 21111321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1113ugucugcggc guuuuaucau u 21111421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1114ugauaaaacg ccgcagacau u 21111521RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1115cgugugcacu ucgcuucacu u 21111621RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1116gugaagcgaa gugcacacgu u 21111721RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1117ccgugugcac uucgcuucau u 21111821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1118ugaagcgaag ugcacacggu u 21111921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1119ugcacuucgc uucaccucuu u 21112021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1120agaggugaag cgaagugcau u 21112121DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1121ugugcacuuc gcuucaccuu t 21112221DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1122aggugaagcg aagugcacau t 21112321DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1123ugugcacuuc gcuucaccuu t 21112421DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1124aggugaagcg aagugcacau t 21112521DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1125ugugcacuuc gcuucaccuu t 21112621DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1126aggugaagcg aagugcacau t 21112721DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1127ugugcacuuc gcuucaccuu t 21112821DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1128aggugaagcg aagugcacau t 21112921DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1129gaggcuguag gcauaaauuu t 21113021DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1130gaggcuguag gcauaaauuu t 21113121DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1131gaggcuguag gcauaaauuu t 21113221DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1132aauuuaugcc uacagccucu t 21113321DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1133gaggcuguag gcauaaauuu t 21113421DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1134aauuuaugcc uacagccucu t 21113521DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1135gaggcuguag gcauaaauuu t 21113621DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1136gaggcuguag gcauaaauuu t 21113721DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1137gaggcuguag gcauaaauuu t 21113821RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1138ugauaaaacg ccgcagacau u 21113921RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1139ugucugcggc guuuuaucau u 21114021RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1140ugauaaaacg ccgcagacau u 21114121RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1141ugucugcggc guuuuaucau u 21114221RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1142ugauaaaacg ccgcagacau u 21114321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1143ugucugcggc guuuuaucau u 21114421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1144ugucugcggc guuuuaucau u 21114521DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1145ccgugugcac uucgcuucau t 21114621DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1146ugaagcgaag ugcacacggu t 21114721DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1147cgugugcacu ucgcuucacu t 21114821DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1148gugaagcgaa gugcacacgu t 21114921DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1149gcacuucgcu ucaccucugu t 21115021DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1150cagaggugaa gcgaagugcu t 21115121DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1151ugcacuucgc uucaccucuu t 21115221DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1152agaggugaag cgaagugcau t 21115321DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1153gaugugucug cggcguuuuu t 21115421DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1154aaaacgccgc agacacaucu t 21115521DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1155ugugucugcg gcguuuuauu t 21115621DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1156auaaaacgcc gcagacacau t 21115721DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1157ugucugcggc guuuuaucau t 21115821DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1158ugauaaaacg ccgcagacau t 21115921DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1159cugcugcuau gccucaucuu t 21116021DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1160agaugaggca uagcagcagu t 21116121DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1161uccugcugcu augccucauu t 21116221DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1162augaggcaua gcagcaggau t 21116321DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1163gaggcuguag gcauaaauuu t 21116421DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1164aauuuaugcc uacagccucu t 21116521DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1165gcuguaggca uaaauugguu t 21116621DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1166accaauuuau gccuacagcu t 21116721DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1167cuguaggcau aaauuggucu t 21116821DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1168gaccaauuua ugccuacagu t 21116921DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1169uguaggcaua aauuggucuu t 21117021DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1170agaccaauuu augccuacau t 21117121DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1171ugugcacuuc gcuucaccuu t 21117221DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1172aggugaagcg aagugcacau t 21117321RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1173ugucugcggc guuuuaucau u 21117421RNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1174ugauaaaacg ccgcagacau u 21117521DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1175ugugcacuuc gcuucaccuu t 21117621DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1176aggugaagcg aagugcacau t 21117721DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1177ugucugcggc guuuuaucau t 21117821DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1178ugauaaaacg ccgcagacau t 21117921DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1179gaggcuguag gcauaaauuu t 21118021DNAArtificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide 1180aauuuaugcc uacagccucu t 2111813221DNAHepatitis B virus 1181ttccactgcc ttccaccaag ctctgcagga tcccagagtc aggggtctgt attttcctgc 60tggtggctcc agttcaggaa cagtaaaccc tgctccgaat attgcctctc acatctcgtc 120aatctccgcg aggactgggg accctgtgac gaacatggag aacatcacat caggattcct 180aggacccctg ctcgtgttac aggcggggtt tttcttgttg acaagaatcc tcacaatacc 240gcagagtcta gactcgtggt ggacttctct caattttcta gggggatcac ccgtgtgtct 300tggccaaaat tcgcagtccc caacctccaa tcactcacca acctcctgtc ctccaatttg 360tcctggttat cgctggatgt gtctgcggcg ttttatcata ttcctcttca tcctgctgct 420atgcctcatc ttcttattgg ttcttctgga ttatcaaggt atgttgcccg tttgtcctct 480aattccagga tcaacaacaa ccagtacggg accatgcaaa acctgcacga ctcctgctca 540aggcaactct atgtttccct catgttgctg tacaaaacct acggatggaa attgcacctg 600tattcccatc ccatcgtcct gggctttcgc aaaataccta tgggagtggg cctcagtccg 660tttctcttgg ctcagtttac tagtgccatt tgttcagtgg ttcgtagggc tttcccccac 720tgtttggctt tcagctatat ggatgatgtg gtattggggg ccaagtctgt acagcatcgt 780gagtcccttt ataccgctgt taccaatttt cttttgtctc tgggtataca tttaaaccct 840aacaaaacaa aaagatgggg ttattcccta aacttcatgg gttacataat tggaagttgg 900ggaactttgc cacaggatca tattgtacaa aagatcaaac actgttttag aaaacttcct 960gttaacaggc ctattgattg gaaagtatgt caaagaattg tgggtctttt gggctttgct 1020gctccattta cacaatgtgg atatcctgcc ttaatgcctt tgtatgcatg tatacaagct 1080aaacaggctt tcactttctc gccaacttac aaggcctttc taagtaaaca gtacatgaac 1140ctttaccccg ttgctcggca acggcctggt ctgtgccaag tgtttgctga cgcaaccccc 1200actggctggg gcttggccat aggccatcag cgcatgcgtg gaacctttgt ggctcctctg 1260ccgatccata ctgcggaact cctagccgct tgttttgctc gcagccggtc tggagcaaag 1320ctcatcggaa ctgacaattc tgtcgtcctc tcgcggaaat atacatcgtt tccatggctg 1380ctaggctgta ctgccaactg gatccttcgc gggacgtcct ttgtttacgt cccgtcggcg 1440ctgaatcccg cggacgaccc ctctcggggc cgcttgggac tctctcgtcc ccttctccgt 1500ctgccgttcc agccgaccac ggggcgcacc tctctttacg cggtctcccc gtctgtgcct 1560tctcatctgc cggtccgtgt gcacttcgct tcacctctgc acgttgcatg gagaccaccg 1620tgaacgccca tcagatcctg cccaaggtct tacataagag gactcttgga ctcccagcaa 1680tgtcaacgac cgaccttgag gcctacttca aagactgtgt gtttaaagac tgggaggagc 1740tgggggagga gattaggtta aaggtctttg tattaggagg ctgtaggcat aaattggtct 1800gcgcaccagc accatgcaac tttttcacct ctgcctaatc atctcttgta catgtcccac 1860tgttcaagcc tccaagctgt gccttgggtg

gctttggggc atggacattg acccttataa 1920agaatttgga gctactgtgg agttactctc gtttttgcct tctgacttct ttccttccgt 1980cagagatctc ctagacaccg cctcagctct gtatcgagaa gccttagaat ctcctgagca 2040ttgctcacct caccatactg cactcaggca agccattctc tgctgggggg aattgatgac 2100tctagctacc tgggtgggta ataatttgga agatccagca tccagggatc tagtagtcaa 2160ttatgttaat actaacatgg gtttaaagat caggcaacta ttgtggtttc atatatcttg 2220ccttactttt ggaagagaga ctgtacttga atatttggtc tctttcggag tgtggattcg 2280cactcctcca gcctatagac caccaaatgc ccctatctta tcaacacttc cggaaactac 2340tgttgttaga cgacgggacc gaggcaggtc ccctagaaga agaactccct cgcctcgcag 2400acgcagatct caatcgccgc gtcgcagaag atctcaatct cgggaatctc aatgttagta 2460ttccttggac tcataaggtg ggaaacttta cggggcttta ttcctctaca gtacctatct 2520ttaatcctga atggcaaact ccttcctttc ctaagattca tttacaagag gacattatta 2580ataggtgtca acaatttgtg ggccctctca ctgtaaatga aaagagaaga ttgaaattaa 2640ttatgcctgc tagattctat cctactcaca ctaaatattt gcccttagac aaaggaatta 2700aaccttatta tccagatcag gtagttaatc attacttcca aaccagacat tatttacata 2760ctctttggaa ggctggtatt ctatataaga gggaaaccac acgtagcgca tcattttgtg 2820ggtcaccata ttcttgggaa caagagctac agcatgggag gttggtcatc aaaacctcgc 2880aaaggcatgg ggacgaatct ttctgttccc aaccctctgg gattctttcc cgatcatcag 2940ttggaccctg cattcggagc caactcaaac aatccagatt gggacttcaa ccccatcaag 3000gaccactggc cagcagccaa ccaggtagga gcgggagcat tcgggccagg gctcacccct 3060ccacacggcg gtattctggg gtggagccct caggctcagg gcatattgac cacagtgtca 3120acaattcctc ctcctgcctc caccaatcgg cagtcaggaa ggcagcctac tcccatctct 3180ccacctctaa gagacagtca tcctcaggcc atgcagtgga a 3221

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