P
USRE48345EActiveUtilityPatentIndex 72

Compositions and methods for inhibiting gene expression of hepatitis B virus

Assignee: ARROWHEAD PHARMACEUTICALS INCPriority: Jun 30, 2011Filed: Aug 19, 2016Granted: Dec 8, 2020
Est. expiryJun 30, 2031(~5 yrs left)· nominal 20-yr term from priority
Inventors:CHIN DANIEL JDECKERT JOCHENHOSSBACH MARKUSJOHN MATTHIAS
A61K 31/713C12N 15/1131C12N 2310/335C12N 2310/3521C12N 2310/321C12N 2310/315C12N 2310/14A61K 2300/00C12N 2310/351C12N 15/11A61P 31/20A61P 35/00A61P 31/12A61P 1/16A61P 29/00
72
PatentIndex Score
3
Cited by
242
References
69
Claims

Abstract

The invention relates to a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a Hepatitis B Virus gene. The invention also relates to a pharmaceutical composition comprising the dsRNA or nucleic acid molecules or vectors encoding the same together with a pharmaceutically acceptable carrier; methods for treating diseases caused by Hepatitis B Virus infection using said pharmaceutical composition; and methods for inhibiting the expression of a Hepatitis B Virus gene in a cell.

Claims

exact text as granted — not AI-modified
The invention claimed is: 
     
       1. A double-stranded ribonucleic acid molecule capable of inhibiting the expression of a Hepatitis B Virus gene in vitro wherein said double-stranded ribonucleic acid molecule comprises a sense strand comprising, in order, nucleotides 1-19 of SEQ ID 2, or 6 and an antisense strand at least partially complementary to the sense strand, wherein said sense strand and said antisense strand are each less than 30 nucleotides in length. 
     
     
       2. The double-stranded ribonucleic acid molecule of  claim 1 , wherein said antisense strand comprises in order nucleotides 1-19 of SEQ ID 158 or 163. 
     
     
       3. The double-stranded ribonucleic acid molecule of  claim 2 , wherein said double-stranded ribonucleic acid molecule comprises sequence pairs selected from the group consisting of SEQ ID NOs: 2/158 and 6/163. 
     
     
       4. The double-stranded ribonucleic acid molecule of  claim 1 , wherein the sense strand or the antisense strand further comprises a 3′ overhang of 1-5 nucleotides in length. 
     
     
       5. The double-stranded ribonucleic acid molecule of  claim 4 , wherein the 3′ overhang of the antisense strand comprises uracil or nucleotides which are complementary to the pregenomic RNA and/or the mRNA encoding the protein necessary for replication or pathogenesis of Hepatitis B Virus. 
     
     
       6. The double-stranded ribonucleic acid molecule of  claim 4 , wherein the 3′ overhang of the sense strand comprises uracil or nucleotides which that are identical to the pregenomic RNA and/or the mRNA encoding the protein necessary for replication or pathogenesis of Hepatitis B Virus. 
     
     
       7. The double-stranded ribonucleic acid molecule of  claim 1 , wherein said double-stranded ribonucleic acid molecule comprises at least one modified nucleotide selected from the group consisting of: 2′-O-methyl modified nucleotide, nucleotide comprising a 5′-phosphorothioate group, terminal nucleotide linked to a cholesteryl derivative, terminal nucleotide linked to a dodecanoic acid bisdecylamide group, 2′-deoxy- 2′-fluoro modified nucleotide, 2-deoxy-nucleotide 2′-deoxy-nucleotide, locked nucleotide, abasic nucleotide, deoxythymidine, inverted deoxythymidine, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, phosphoramidate, and non-natural base comprising nucleotide. 
     
     
       8. The double-stranded ribonucleic acid molecule of  claim 7 , wherein said double-stranded ribonucleic acid molecule contains a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphomthioate 5′-phosphorothioate group, and a deoxythymidine. 
     
     
       9. The double-stranded ribonucleic acid molecule of  claim 8 , wherein said sense strand or said antisense strand further comprises an overhang of 1-2 deoxythymidines. 
     
     
       10. The double-stranded ribonucleic acid molecule of  claim 9 , wherein said double-stranded ribonucleic acid molecule comprises the sequence pairs a sequence pair selected from the group consisting of SEQ ID NOs: 322/486 and 327/491. 
     
     
       11. The double-stranded ribonucleic acid molecule of  claim 1 , wherein said double-stranded ribonucleic acid molecule comprises a nucleic acid sequence encoding said sense strand or said antisense strand. 
     
     
       12. A pharmaceutical composition comprising:
 a) a first and a second double-stranded ribonucleic acid molecules each as defined in  claim 1 ; 
 b) at least one nucleic acid sequence encoding sense strands or antisense strands comprising a first and a second double-stranded ribonucleic acid molecules each as defined in  claim 1 ; or, 
 c) a cell, tissue or non-human organism comprising a first and a second double-stranded ribonucleic acid molecules each as defined in  claim 1 . 
 
     
     
       13. The A pharmaceutical composition of  claim 12  wherein comprising:
 a) said a first double stranded double-stranded ribonucleic acid has comprising a sense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 2 and said a second double-stranded ribonucleic acid has comprising a sense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 4 or 6; or 
 b) said a first double stranded double-stranded ribonucleic acid has comprising a sense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 6 and said a second double-stranded ribonucleic acid has comprising a sense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 2 or 7. 
 
     
     
       14. The pharmaceutical composition of  claim 12 , further comprising a pharmaceutically acceptable carrier, stabilizer, and/or diluent. 
     
     
       15. A method for inhibiting the expression of a Hepatitis B Virus gene in a cell, a tissue, or an organism, the method comprising:
 a) introducing into the cell, tissue, or organism the double-stranded ribonucleic acid molecule as defined in  claim 1 ; and 
 b) maintaining the cell, tissue, or organism produced in step a) for a time sufficient to obtain degradation of the mRNA transcript of a the Hepatitis B Virus gene, thereby inhibiting expression of a Hepatitis B Virus gene in the cell, tissue, or organism. 
 
     
     
       16. The method of  claim 15 , wherein inhibiting the expression of the Hepatitis B Virus gene in an organism treats or manages a pathological condition or disease caused by infection with the Hepatitis B Virus. 
     
     
       17. The method of  claim 16 , wherein the pathological condition and disease caused by the infection with the Hepatitis B Virus is selected from the group consisting of: chronic liver disorder, inflammation, fibrotic condition, and proliferative disorder. 
     
     
       18. The double-stranded ribonucleic acid molecule of claim 1, wherein the sense strand comprises, in order, nucleotides 1-19 of SEQ ID NO: 2, wherein the antisense strand is at least partially complementary to the sense strand, and wherein the sense strand and the antisense strand are each less than 30 nucleotides in length. 
     
     
       19. The double-stranded ribonucleic acid molecule of claim 18, wherein the double-stranded ribonucleic acid molecule contains at least one modified nucleotide. 
     
     
       20. The double-stranded ribonucleic acid molecule of claim 19, wherein the one or more modified nucleotides are independently selected from the group consisting of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, a terminal nucleotide linked to a cholesteryl derivative, a terminal nucleotide linked to a dodecanoic acid bisdecylamide group, a 2′-deoxy-2′-fluoro-modified nucleotide, a 2′-deoxy-nucleotide, a locked nucleotide, an abasic nucleotide, a deoxythymidine, an inverted deoxythymidine, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoroamidate, and a non-natural base comprising a nucleotide. 
     
     
       21. The double-stranded ribonucleic acid molecule of claim 19, wherein the double-stranded ribonucleic acid molecule comprises at least one 2′-O-methyl-modified nucleotide, at least one nucleotide comprising a 5′-phosphorothioate group, and at least one deoxythymidine. 
     
     
       22. The double-stranded ribonucleic acid molecule of claim 21, wherein the sense strand or the antisense strand further comprises an overhang of 1 or 2 deoxythymidine(s). 
     
     
       23. The double-stranded ribonucleic acid molecule of claim 18, wherein the double-stranded ribonucleic acid molecule comprises the sequence pair of SEQ ID NOs: 2/158. 
     
     
       24. The double-stranded ribonucleic acid molecule of claim 19, wherein the sense strand, or the antisense strand, or both the sense strand and the antisense strand, further comprises a 3′ overhang of 1-5 nucleotides in length. 
     
     
       25. A pharmaceutical composition comprising:
 a) a double-stranded ribonucleic acid molecule of claim 19; or   b) a cell, tissue, or non-human organism comprising a double-stranded ribonucleic acid molecule of claim 19.   
     
     
       26. A pharmaceutical composition comprising:
 a) a first double-stranded ribonucleic acid molecule of claim 19 and a second double-stranded ribonucleic acid molecule that is different from the first double-stranded ribonucleic acid molecule and inhibits the expression of a Hepatitis B Virus gene; or   b) a cell, tissue, or non-human organism comprising a first double-stranded ribonucleic acid molecule of claim 19 and a second double-stranded ribonucleic acid molecule that is different from the first double-stranded ribonucleic acid molecule and inhibits the expression of a Hepatitis B Virus gene.   
     
     
       27. The pharmaceutical composition of claim 26, wherein the second double-stranded ribonucleic acid has a sense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 3. 
     
     
       28. The pharmaceutical composition of claim 26, wherein the second double-stranded ribonucleic acid has a sense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 6. 
     
     
       29. The pharmaceutical composition of claim 27, wherein the first double-stranded ribonucleic acid molecule and the second double-stranded ribonucleic acid molecule each comprise at least one 2′-O-methyl modified nucleotide and at least one nucleotide comprising a 5′-phosphorothioate group. 
     
     
       30. The pharmaceutical composition of claim 26, wherein the first double-stranded ribonucleic acid molecule comprises the sequence pair of SEQ ID NOs: 322/486; and the second double-stranded ribonucleic acid molecule comprises the sequence pair of SEQ ID NOs: 323/487, 324/488, or 327/491. 
     
     
       31. The pharmaceutical composition of claim 25, wherein the double-stranded ribonucleic acid molecule comprises the sequence pair of SEQ ID NOs: 322/486. 
     
     
       32. The pharmaceutical composition of claim 26, wherein the first double-stranded ribonucleic acid molecule comprises the sequence pair of SEQ ID NOs: 322/486. 
     
     
       33. A method for inhibiting the expression of a Hepatitis B Virus gene in a cell, a tissue, or an organism, the method comprising:
 a) introducing into the cell, tissue, or organism a double-stranded ribonucleic acid molecule of claim 19; and   b) maintaining the cell, tissue or organism produced in step a) for a time sufficient to obtain degradation of an mRNA transcript of the Hepatitis B Virus gene in the cell, tissue, or organism.   
     
     
       34. The method of claim 33, wherein the double-stranded ribonucleic acid molecule comprises the sequence pair of SEQ ID NOs: 2/158. 
     
     
       35. The method of claim 33, wherein inhibiting expression of a Hepatitis B Virus gene in an organism treats or manages a pathological condition or disease caused by infection with a Hepatitis B Virus. 
     
     
       36. The method of claim 35, wherein the pathological condition and disease caused by the infection with a Hepatitis B Virus is selected from the group consisting of: chronic liver disorder, inflammation, fibrotic condition, and proliferative disorder. 
     
     
       37. A method of treating a subject having a pathological condition or disease caused by infection with a Hepatitis B Virus, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 12. 
     
     
       38. The method of claim 37, wherein the pathological condition or disease caused by infection with a Hepatitis B Virus is selected from the group consisting of: chronic liver disorder, inflammation, fibrotic condition, and proliferative disorder. 
     
     
       39. A method of treating a subject having a pathological condition or disease caused by infection with a Hepatitis B Virus, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 13. 
     
     
       40. The method of claim 39, wherein the pathological condition or disease caused by infection with a Hepatitis B Virus is selected from the group consisting of: chronic liver disorder, inflammation, fibrotic condition, and proliferative disorder. 
     
     
       41. A method of treating a subject having a pathological condition or disease caused by infection with a Hepatitis B Virus, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 25. 
     
     
       42. The method of claim 41, wherein the pathological condition or disease caused by infection with a Hepatitis B Virus is selected from the group consisting of: chronic liver disorder, inflammation, fibrotic condition, and proliferative disorder. 
     
     
       43. A method of treating a subject having a pathological condition or disease caused by infection with a Hepatitis B Virus, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 26. 
     
     
       44. The method of claim 43, wherein the first double-stranded ribonucleic acid in the pharmaceutical composition has a sense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 2 and the second double-stranded ribonucleic acid in the pharmaceutical composition has a sense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 3. 
     
     
       45. The method of claim 43, wherein the first double-stranded ribonucleic acid in the pharmaceutical composition has a sense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 2 and the second double-stranded ribonucleic acid in the pharmaceutical composition has a sense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 6. 
     
     
       46. The method of claim 43, wherein the pathological condition or disease caused by infection with a Hepatitis B Virus is selected from the group consisting of: chronic liver disorder, inflammation, fibrotic condition, and proliferative disorder. 
     
     
       47. The method of claim 43, further comprising administering to the subject a different second pharmaceutical composition. 
     
     
       48. A double-stranded ribonucleic acid molecule that inhibits the expression of a Hepatitis B Virus gene, wherein the double-stranded ribonucleic acid molecule comprises an antisense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 158 and a sense strand at least partially complementary to the antisense strand, wherein the sense strand and the antisense strand are each less than 30 nucleotides in length. 
     
     
       49. The double-stranded ribonucleic acid molecule of claim 48, wherein the double-stranded ribonucleic acid molecule contains at least one modified nucleotide. 
     
     
       50. The double-stranded ribonucleic acid molecule of claim 49, wherein the one or more modified nucleotides are independently selected from the group consisting of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, a terminal nucleotide linked to a cholesteryl derivative, a terminal nucleotide linked to a dodecanoic acid bisdecylamide group, a 2′-deoxy-2′-fluoro-modified nucleotide, a 2′-deoxy-nucleotide, a locked nucleotide, an abasic nucleotide, a deoxythymidine, an inverted deoxythymidine, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoroamidate, and a non-natural base comprising nucleotide. 
     
     
       51. The double-stranded ribonucleic acid molecule of claim 40, wherein the double-stranded ribonucleic acid molecule comprises at least one 2′-O-methyl-modified nucleotide, at least one nucleotide comprising a 5′-phosphorothioate group, and at least one deoxythymidine. 
     
     
       52. The double-stranded ribonucleic acid molecule of claim 51, wherein the sense strand or the antisense strand further comprises an overhang of 1 or 2 deoxythymidine(s). 
     
     
       53. The double-stranded ribonucleic acid molecule of claim 49, wherein the sense strand, or the antisense strand, or both the sense strand and the antisense strand, further comprises a 3′ overhang of 1-5 nucleotides in length. 
     
     
       54. A pharmaceutical composition comprising:
 a) a double-stranded ribonucleic acid molecule of claim 49; or   b) a cell, tissue, or non-human organism comprising a double-stranded ribonucleic acid molecule of claim 49.   
     
     
       55. A pharmaceutical composition comprising:
 a) a first double-stranded ribonucleic acid molecule of claim 49 and a second double-stranded ribonucleic acid molecule that is different from the first double-stranded ribonucleic acid molecule and inhibits the expression of a Hepatitis B Virus gene; or   b) a cell, tissue, or non-human organism comprising a first double-stranded ribonucleic acid molecule of claim 49 and a second double-stranded ribonucleic acid molecule that is different from the first double-stranded ribonucleic acid molecule and inhibits the expression of a Hepatitis B Virus gene.   
     
     
       56. The pharmaceutical composition of claim 55, wherein the first double-stranded ribonucleic acid has an antisense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 158 and the second double-stranded ribonucleic acid has an antisense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 159 or 160. 
     
     
       57. The pharmaceutical composition of claim 55, wherein the first double-stranded ribonucleic acid has an antisense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 158 and the second double-stranded ribonucleic acid has an antisense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 163. 
     
     
       58. The pharmaceutical composition of claim 56, wherein the first double-stranded ribonucleic acid molecule and the second double-stranded ribonucleic acid molecule each comprise at least one 2′-O-methyl modified nucleotide and at least one nucleotide comprising a 5′-phosphorothioate group. 
     
     
       59. The pharmaceutical composition of claim 57, wherein the first double-stranded ribonucleic acid molecule and the second double-stranded ribonucleic acid molecule each comprise at least one 2′-O-methyl modified nucleotide and at least one nucleotide comprising a 5′-phosphorothioate group. 
     
     
       60. A method for inhibiting the expression of a Hepatitis B Virus gene in a cell, a tissue, or an organism, the method comprising:
 a) introducing into the cell, tissue, or organism the double-stranded ribonucleic acid molecule of claim 49; and   b) maintaining the cell, tissue or organism produced in step a) for a time sufficient to obtain degradation of the mRNA transcript of the Hepatitis B Virus gene in the cell, tissue, or organism.   
     
     
       61. The method of claim 60, wherein inhibiting the expression of the Hepatitis B Virus gene in an organism treats a pathological condition or disease caused by infection with the Hepatitis B Virus. 
     
     
       62. The method of claim 61, wherein the pathological condition and disease caused by the infection with the Hepatitis B Virus is selected from the group consisting of: chronic liver disorder, inflammation, fibrotic condition, and proliferative disorder. 
     
     
       63. A method of treating a subject having a pathological condition or disease caused by infection with a Hepatitis B Virus, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 54. 
     
     
       64. The method of claim 63, wherein the pathological condition or disease caused by infection with a Hepatitis B Virus is selected from the group consisting of: chronic liver disorder, inflammation, fibrotic condition, and proliferative disorder. 
     
     
       65. A method of treating a subject having a pathological condition or disease caused by infection with a Hepatitis B Virus, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 55. 
     
     
       66. The method of claim 65, wherein the first double-stranded ribonucleic acid in the pharmaceutical composition has an antisense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 158 and the second double-stranded ribonucleic acid in the pharmaceutical composition has an antisense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 159 or 160. 
     
     
       67. The method of claim 65, wherein the first double-stranded ribonucleic acid in the pharmaceutical composition has an antisense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 158 and the second double-stranded ribonucleic acid in the pharmaceutical composition has an antisense strand comprising, in order, nucleotides 1-19 of SEQ ID NO: 163. 
     
     
       68. The method of claim 65, wherein the pathological condition or disease caused by infection with a Hepatitis B Virus is selected from the group consisting of: chronic liver disorder, inflammation, fibrotic condition, and proliferative disorder. 
     
     
       69. The method of claim 65, further comprising administering to the subject a different second pharmaceutical composition for treating a subject having a pathological condition or disease caused by infection with a Hepatitis B Virus.

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