US2023355651A1PendingUtilityA1

Rnai agents for hepatitis b virus infection

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Assignee: ARROWHEAD PHARMACEUTICALS INCPriority: Aug 4, 2016Filed: Dec 2, 2022Published: Nov 9, 2023
Est. expiryAug 4, 2036(~10.1 yrs left)· nominal 20-yr term from priority
Inventors:Zhen LiRui ZhuChristine I. WooddellBruce D. GivenTao PeiDavid L. LewisLauren J. AlmeidaDavid B. RozemaDarren H. Wakefield
A61K 31/7105A61P 31/14A61K 9/0019A61K 31/675C12N 15/113A61P 31/20A61K 31/7088C12N 15/1131C12N 2310/11C12N 2310/14C12N 2310/314C12N 2310/315C12N 2310/3515C12N 2310/322C12N 2310/321A61P 1/16Y02A50/30A61K 48/00A61K 31/713C07H 21/02A61K 47/549A61K 45/06A61P 35/00A61P 31/18A61P 31/12
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Claims

Abstract

Described are compositions and methods for inhibition of Hepatitis B virus gene expression. RNA interference (RNAi) agents for inhibiting the expression of Hepatitis B virus gene are described. The HBV RNAi agents disclosed herein may be targeted to cells, such as hepatocytes, for example, by using conjugated targeting ligands. Pharmaceutical compositions comprising one or more HBV RNAi agents optionally with one or more additional therapeutics are also described. Delivery of the described HBV RNAi agents to infected liver in vivo provides for inhibition of HBV gene expression and treatment of diseases and conditions associated with HBV infection.

Claims

exact text as granted — not AI-modified
1 - 66 . (canceled) 
     
     
         67 . A combination comprising a first RNAi agent that targets the S open reading frame (ORF) of an HBV gene and a second RNAi agent that targets the X open reading frame (ORF) of an HBV gene. 
     
     
         68 . An RNAi agent comprising a sense strand comprising a nucleobase sequence according to any one of SEQ ID NO: 282-284, 286-290, 295-297, 300, 302, 306-315, and 319-321, and an antisense strand at least partially complementary to the sense strand. 
     
     
         69 . The RNAi agent of  claim 68 , wherein the antisense strand comprises a nucleobase sequence according to any one of SEQ ID NO: 152, 155-160, 165-171, 174-177, and 179-181. 
     
     
         70 . The RNAi agent of  claim 68 , wherein the sense strand comprises a modified nucleotide sequence according to any one of SEQ ID NO: 204-206, 208-212, 219-223, 226, 229, 234-247, 252-255, and 273. 
     
     
         71 . The RNAi agent of  claim 68 , wherein the antisense strand comprises a modified nucleotide sequence according to any one of SEQ ID NO: 72-76, 78, 79, 88-92, 98-100, 108-124, and 126-130. 
     
     
         72 . The RNAi agent of  claim 68 , wherein the RNAi agent comprises an antisense strand and a sense strand having modified nucleotide sequences, the RNAi agent having the duplex structure of AD04001 (SEQ ID NO: 72 and SEQ ID NO: 204); AD04002 (SEQ ID NO: 73 and SEQ ID NO: 204); AD04003 (SEQ ID NO: 74 and SEQ ID NO: 205); AD04004 (SEQ ID NO: 72 and SEQ ID NO: 206); AD04005 (SEQ ID NO: 75 and SEQ ID NO: 212); AD04008 (SEQ ID NO: 78 and SEQ ID NO: 208); AD04009 (SEQ ID NO: 76 and SEQ ID NO: 209); AD04010 (SEQ ID NO: 79 and SEQ ID NO: 211); AD04422 (SEQ ID NO: 74 and SEQ ID NO: 219); AD04423 (SEQ ID NO: 88 and SEQ ID NO: 205); AD04425 (SEQ ID NO: 89 and SEQ ID NO: 20); AD04426 (SEQ ID NO: 90 and SEQ ID NO: 221); AD04427 (SEQ ID NO: 90 and SEQ ID NO: 222); AD04428 (SEQ ID NO: 91 and SEQ ID NO: 221); AD04429 (SEQ ID NO: 91 and SEQ ID NO: 222); AD04430 (SEQ ID NO: 92 and SEQ ID NO: 223); AD04438 (SEQ ID NO: 98 and SEQ ID NO: 226); AD04439 (SEQ ID NO: 99 and SEQ ID NO: 226); AD04511 (SEQ ID NO: 100 and SEQ ID NO: 229); AD04581 (SEQ ID NO: 108 and SEQ ID NO: 211); AD04583 (SEQ ID NO: 109 and SEQ ID NO: 234); AD04584 (SEQ ID NO: 110 and SEQ ID NO: 234); AD04585 (SEQ ID NO: 111 and SEQ ID NO: 235); AD04586 (SEQ ID NO: 112 and SEQ ID NO: 234); AD04587 (SEQ ID NO: 109 and SEQ ID NO: 236); AD04588 (SEQ ID NO: 110 and SEQ ID NO: 237); AD04590 (SEQ ID NO: 113 and SEQ ID NO: 211); AD04591 (SEQ ID NO: 108 and SEQ ID NO: 238); AD04592 (SEQ ID NO: 74 and SEQ ID NO: 239); AD04593 (SEQ ID NO: 114 and SEQ ID NO: 240); AD04594 (SEQ ID NO: 115 and SEQ ID NO: 240); AD04595 (SEQ ID NO: 116 and SEQ ID NO: 241); AD04596 (SEQ ID NO: 117 and SEQ ID NO: 241; AD04597 (SEQ ID NO: 114 and SEQ ID NO: 242); AD04598 (SEQ ID NO: 115 and SEQ ID NO: 243); AD04599 (SEQ ID NO: 118 and SEQ ID NO: 220); AD04734 (SEQ ID NO: 119 and SEQ ID NO: 235); AD04771 (SEQ ID NO: 120 and SEQ ID NO: 244); AD04772 (SEQ ID NO: 121 and SEQ ID NO: 245); AD04773 (SEQ ID NO: 122 and SEQ ID NO: 244); AD04774 (SEQ ID NO: 123 and SEQ ID NO: 246); AD04775 (SEQ ID NO: 123 and SEQ ID NO: 247); AD04822 (SEQ ID NO: 124 and SEQ ID NO: 244); AD04872 (SEQ ID NO: 126 and SEQ ID NO: 252); AD04873 (SEQ ID NO: 127 and SEQ ID NO: 252); AD04874 (SEQ ID NO: 128 and SEQ ID NO: 253); AD04875 (SEQ ID NO: 129 and SEQ ID NO: 254); AD04876 (SEQ ID NO: 130 and SEQ ID NO: 255); AD04962 (SEQ ID NO: 111 and SEQ ID NO: 244) or AD05164 (SEQ ID NO: 126 and SEQ ID NO: 273). 
     
     
         73 . The RNAi agent of  claim 68 , wherein the RNAi agent comprises a sense strand linked at the 5′ terminal end to NAG37s and having the structure (NAG37)s-(invAb)sguggacuuCfUJfCfucaauuuucus(invAb) (SEQ ID NO: 252) and an antisense strand having the structure asGfsasAfaAfuUfgAfgAfgAfaGfuCfcasc (SEQ ID NO: 126). 
     
     
         74 . The RNAi agent of  claim 68 , wherein at least one nucleotide of the sense strand and/or at least one nucleotide of the antisense strand of the RNAi agent is a modified nucleotide and/or has a modified internucleoside linkage. 
     
     
         75 . The RNAi agent of  claim 68 , wherein the sense strand and the antisense strand are each 17 to 30 nucleotides in length. 
     
     
         76 . The RNAi agent of  claim 68 , wherein the RNAi agent is conjugated to a targeting ligand. 
     
     
         77 . The RNAi agent of  claim 76 , wherein the targeting ligand comprises N-acetyl-galactosamine. 
     
     
         78 . The RNAi agent of  claim 77 , wherein the targeting ligand is (NAG13), (NAG13)s, (NAG18), (NAG18)s, (NAG24), (NAG24)s, (NAG25), (NAG25)s, (NAG26), (NAG26)s, (NAG27), (NAG27)s, (NAG28), (NAG28)s, (NAG29), (NAG29)s, (NAG30), (NAG30)s, (NAG31), (NAG31)s, (NAG32), (NAG32)s, (NAG33), (NAG33)s, (NAG34), (NAG34)s, (NAG35), (NAG35)s, (NAG36), (NAG36)s, (NAG37), (NAG37)s, (NAG38), (NAG38)s, (NAG39), or (NAG39)s. 
     
     
         79 . The RNAi agent of  claim 77 , wherein the targeting ligand is conjugated to the sense strand of the RNAi agent. 
     
     
         80 . The RNAi agent of  claim 77 , wherein the targeting ligand is conjugated to the antisense strand of the RNAi agent. 
     
     
         81 . The RNAi agent of  claim 68 , wherein the RNAi agent is in a salt form. 
     
     
         82 . The RNAi agent of  claim 68 , wherein the RNAi agent is in a sodium salt form. 
     
     
         83 . An RNAi agent comprising an antisense strand comprising a nucleobase sequence according to any one of SEQ ID NO: 171, 152, 155-160, 165-170, and 174-181, and a sense strand at least partially complementary to the antisense sense strand. 
     
     
         84 . The RNAi agent of  claim 83 , wherein the sense strand comprises a nucleobase sequence according to any one of SEQ ID NO: 282-287, 289, 290, 294-302, 306-315, and 318-321. 
     
     
         85 . The RNAi agent of  claim 83 , wherein the antisense strand comprises a modified nucleotide sequence according to any one of SEQ ID NO: 65, 72-79, 88-100, and 108-130. 
     
     
         86 . The RNAi agent of  claim 83 , wherein the sense strand comprises a modified nucleotide sequence according to any one of SEQ ID NO: 204-209, 211, 212, 219-229, 234-248, 251-255, and 273.

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