US2017369883A1PendingUtilityA1

Modulation of hepatitis b virus (hbv) expression

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Assignee: IONIS PHARMACEUTICALS INCPriority: Apr 21, 2011Filed: May 5, 2017Published: Dec 28, 2017
Est. expiryApr 21, 2031(~4.7 yrs left)· nominal 20-yr term from priority
Inventors:Eric E. SwayzeSusan M. FreierMichael L. Mccaleb
A61P 37/02A61P 7/00A61P 35/00A61P 29/00A61P 31/14A61P 31/20A61P 1/16C12N 2320/30C12N 2310/344C12N 2310/341C12N 2310/346C12N 2310/11C12N 2310/3341C12N 2310/315C12N 15/1131C12N 2310/313C12N 2310/321C12N 2310/3231C07H 21/02A61K 31/712
63
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Claims

Abstract

Disclosed herein are antisense compounds and methods for decreasing HBV mRNA, DNA and protein expression. Such methods, compounds, and compositions are useful to treat, prevent, or ameliorate HBV-related diseases, disorders or conditions.

Claims

exact text as granted — not AI-modified
1 - 72 . (canceled) 
     
     
         73 . A single stranded modified oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of SEQ ID NO: 789, 802, or 1335, wherein the modified oligonucleotide comprises a modified sugar and is at least 95% complementary to SEQ ID NO: 1. 
     
     
         74 . The single stranded modified oligonucleotide of  claim 73 , further comprising a conjugate group. 
     
     
         75 . The single stranded modified oligonucleotide of  claim 74 , wherein the conjugate group comprises a carbohydrate. 
     
     
         76 . The single stranded modified oligonucleotide of  claim 73 , wherein said modified oligonucleotide is 100% complementary to SEQ ID NO: 1. 
     
     
         77 . The single stranded modified oligonucleotide of  claim 73 , wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
         78 . The single stranded modified oligonucleotide of  claim 77 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         79 . The single stranded modified oligonucleotide of  claim 73 , wherein the modified sugar is a bicyclic sugar. 
     
     
         80 . The single stranded modified oligonucleotide of  claim 79 , wherein the modified sugar comprises a 4′-CH 2 —O-2′ group. 
     
     
         81 . The single stranded modified oligonucleotide of  claim 73 , wherein at least one nucleoside comprises a modified nucleobase. 
     
     
         82 . The single stranded modified oligonucleotide of  claim 81 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         83 . The single stranded modified oligonucleotide of  claim 73 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   a 3′ wing segment consisting of linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises the modified sugar.   
     
     
         84 . The single stranded modified oligonucleotide of  claim 83 , wherein the gap segment consists of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 linked nucleosides. 
     
     
         85 . The single stranded modified oligonucleotide of  claim 73 , wherein the modified oligonucleotide has a nucleobase sequence comprising at least 13 contiguous nucleobases of SEQ ID NO: 789, 802, or 1335. 
     
     
         86 . The single stranded modified oligonucleotide of  claim 85 , further comprising a conjugate group. 
     
     
         87 . The single stranded modified oligonucleotide of  claim 86 , wherein the conjugate group comprises a carbohydrate. 
     
     
         88 . The single stranded modified oligonucleotide of  claim 85 , wherein said modified oligonucleotide is 100% complementary to SEQ ID NO: 1. 
     
     
         89 . The single stranded modified oligonucleotide of  claim 85 , wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
         90 . The single stranded modified oligonucleotide of  claim 89 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         91 . The single stranded modified oligonucleotide of  claim 85 , wherein the modified sugar is a bicyclic sugar. 
     
     
         92 . The single stranded modified oligonucleotide of  claim 91 , wherein the modified sugar comprises a 4′-CH 2 —O-2′ group. 
     
     
         93 . The single stranded modified oligonucleotide of  claim 85 , wherein at least one nucleoside comprises a modified nucleobase. 
     
     
         94 . The single stranded modified oligonucleotide of  claim 93 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         95 . The single stranded modified oligonucleotide of  claim 85 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   a 3′ wing segment consisting of linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises the modified sugar.   
     
     
         96 . The single stranded modified oligonucleotide of  claim 95 , wherein the gap segment consists of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 linked nucleosides. 
     
     
         97 . The single stranded modified oligonucleotide of  claim 73 , wherein the modified oligonucleotide has a nucleobase sequence comprising at least 15 contiguous nucleobases of SEQ ID NO: 802, or 1335. 
     
     
         98 . The single stranded modified oligonucleotide of  claim 97 , further comprising a conjugate group. 
     
     
         99 . The single stranded modified oligonucleotide of  claim 98 , wherein the conjugate group comprises a carbohydrate. 
     
     
         100 . The single stranded modified oligonucleotide of  claim 97 , wherein said modified oligonucleotide is 100% complementary to SEQ ID NO: 1. 
     
     
         101 . The single stranded modified oligonucleotide of  claim 97 , wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
         102 . The single stranded modified oligonucleotide of  claim 101 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         103 . The single stranded modified oligonucleotide of  claim 97 , wherein the modified sugar is a bicyclic sugar. 
     
     
         104 . The single stranded modified oligonucleotide of  claim 103 , wherein the modified sugar comprises a 4′-CH 2 —O-2′ group. 
     
     
         105 . The single stranded modified oligonucleotide of  claim 97 , wherein at least one nucleoside comprises a modified nucleobase. 
     
     
         106 . The single stranded modified oligonucleotide of  claim 105 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         107 . The single stranded modified oligonucleotide of  claim 97 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   a 3′ wing segment consisting of linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises the modified sugar.   
     
     
         108 . The single stranded modified oligonucleotide of  claim 107 , wherein the gap segment consists of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 linked nucleosides. 
     
     
         109 . A composition comprising the single stranded modified oligonucleotide of  claim 73  or salt thereof and at least one of a pharmaceutically acceptable carrier or diluent. 
     
     
         110 . A composition comprising the single stranded modified oligonucleotide of  claim 85  or salt thereof and at least one of a pharmaceutically acceptable carrier or diluent. 
     
     
         111 . A composition comprising the single stranded modified oligonucleotide of  claim 97  or salt thereof and at least one of a pharmaceutically acceptable carrier or diluent. 
     
     
         112 . A method of preventing, treating, ameliorating, or slowing progression of a HBV-related disease, disorder or condition in an animal comprising administering the single stranded modified oligonucleotide of  claim 73  to the animal, thereby preventing, treating, ameliorating, or slowing progression the HBV-related disease, disorder or condition. 
     
     
         113 . A method of preventing, treating, ameliorating, or slowing progression of a HBV-related disease, disorder or condition in an animal comprising administering the single stranded modified oligonucleotide of  claim 85  to the animal, thereby preventing, treating, ameliorating, or slowing progression the HBV-related disease, disorder or condition. 
     
     
         114 . A method of preventing, treating, ameliorating, or slowing progression of a HBV-related disease, disorder or condition in an animal comprising administering the single stranded modified oligonucleotide of  claim 97  to the animal, thereby preventing, treating, ameliorating, or slowing progression the HBV-related disease, disorder or condition. 
     
     
         115 . The method of  claim 112 , wherein administering the single stranded modified oligonucleotide of  claim 73  to the animal reduces HBsAG antigen levels in the animal. 
     
     
         116 . The method of  claim 113 , wherein administering the single stranded modified oligonucleotide of  claim 83  to the animal reduces HBsAG antigen levels in the animal. 
     
     
         117 . The method of  claim 114 , wherein administering the single stranded modified oligonucleotide of  claim 93  to the animal reduces HBsAG antigen levels in the animal.

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