US 11,685,921 B2
Molecules and agents for treating hepatitis B virus
Pattraranee Limphong, San Diego, CA (US); Kiyoshi Tachikawa, San Diego, CA (US); Christine Esau, San Diego, CA (US); and Padmanabh Chivukula, San Diego, CA (US)
Assigned to Arcturus Therapeutics, Inc., San Diego, CA (US)
Filed by Arcturus Therapeutics, Inc., San Diego, CA (US)
Filed on Dec. 20, 2019, as Appl. No. 16/724,122.
Application 16/724,122 is a continuation of application No. 15/410,984, filed on Jan. 20, 2017, abandoned.
Application 15/410,984 is a continuation in part of application No. 15/212,279, filed on Jul. 17, 2016, abandoned.
Claims priority of provisional application 62/193,997, filed on Jul. 17, 2015.
Prior Publication US 2020/0131516 A1, Apr. 30, 2020
This patent is subject to a terminal disclaimer.
Int. Cl. C12N 15/11 (2006.01); C12N 15/113 (2010.01); A61K 9/127 (2006.01); A61K 47/69 (2017.01)
CPC C12N 15/1131 (2013.01) [A61K 9/1271 (2013.01); A61K 47/6911 (2017.08); C12N 2310/14 (2013.01); C12N 2310/315 (2013.01); C12N 2310/321 (2013.01); C12N 2310/322 (2013.01); C12N 2310/323 (2013.01); C12N 2310/344 (2013.01); C12N 2310/3515 (2013.01); C12N 2320/32 (2013.01)] 11 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 sense strand for RNA interference and the second strand is an antisense strand for RNA interference, wherein the compound comprises a sequence of bases targeted to inhibit expression of an HBV genome, wherein the sense strand and the antisense strand are each independently selected from the group consisting of:
 
REF SEQ S/ HBV (Sense (S)-Antisense (AS))
POS ID NO AS (5′-3′)
 
 
1777 1182 S UNA-G/*/mArGmGrCmUrGmUrArGrGmCr
 
 
 
 AmUrAmArAmUrU/*/UNA-U/*/dT
 
1777 1183 AS mArAmUrUmUrAmUrGmCrCmUmAmCr
 
 
 
 AmGrCmCrUmC/UNA-U/*/dT
 
1777 1184 S UNA-G/*/rArGrGmCmUrGmUrArGrGm
 
 
 
 CrAmUrArArAmUmU/*/UNA-U/*/dT
 
1777 1185 AS mArA/*/mUrUmUrAmUrGmCrCmUmAm
 
 
 
 CrAmGrCmCrUmC/UNA-U/*/dT
 
1777 1186 S UNA-G/*/rArGrGmCmUrGmUrArGrGm
 
 
 
 CrAmUrArArAmUmU/*/UNA-U/*/dT
 
1777 1187 AS mArArUmUmUrArUrGmCrCmUrArCrAm
 
 
 
 GmCmCrUmC/UNA-U/*/dT
 
1777 1188 S UNA-G/*/rArGrGmCmUrGmUrArGrGmCr
 
 
 
 AmUrArArAmUmU/*/UNA-U/*/dT
 
1777 1189 AS mArAmUrUmU/*/rAmU/*/rGmCrCmU/
 
 
 
 */mAmC/*/rAmGrCmCrUmC/UNA-U/*/dT
 
1777 1190 S UNA-G/*/rArGrGmCmUrGmUrArGrGm
 
 
 
 CrAmUrArArAmUmU/*/UNA-U/*/dT
 
1777 1191 AS mArAmUrUmUrAmUrGmCrCmUmAmCrAm
 
 
 
 GrCmCrUmA/UNA-U/*/dT
 
1777 1192 S UNA-G/*/rArGrGmCmUrGmUrArGrGm
 
 
 
 CrAmUrArArAmUmU/*/UNA-U/*/dT
 
1777 1193 AS mArAmUrUdUrAmUrGmCrCmUmAmCr
 
 
 
 AdGrCmCrUmC/UNA-U/*/dT
 
1777 1194 S UNA-G/*/rArGrGmCmUrGmUrArGrGm
 
 
 
 CrAmUrArArAmUmU/*/UNA-U/*/dT
 
1777 1195 AS rArAmUmUmUrAmUrGmCmCmUrAmCr
 
 
 
 ArGmCmCmUmC/UNA-U/*/dT
 
1777 1196 S UNA-G/*/rArGrGfCfUrGfUrArGrGf
 
 
 
 CrAfUrArArAfUfU/*/UNA-U/*/dT
 
1777 1197 AS rArAfUrUfUrAfUrGfCfCfUrAfCr
 
 
 
 ArGfCfCfUfC/UNA-U/*/dT
 
1777 1198 S UNA-G/*/fArGfGrCfUrGfUrArGrGf
 
 
 
 CrAfUrAfArAfUrU/*/UNA-U/*/dT
 
1777 1199 AS fArAfUrUfUrAfUrGfCrCfUfAfCr
 
 
 
 AfGrCfCrUfC/UNA-U/*/dT
 
380 1200 S UNA-U/*/mGrUmCrUmGrCmGrGrCrGm
 
 
 
 UrUmUrUmArUmCrA/*/UNA-U/*/dT
 
380 1201 AS mUrGmArUmArAmArAmCrGmCmCmGr
 
 
 
 CmArGmArCmA/UNA-U/*/dT
 
380 1202 S UNA-U/*/rGmUmCmUrGmCrGrGmCrGm
 
 
 
 UmUmUmUrAmUmCrA/*/UNA-U/*/dT
 
380 1203 AS mUrG/*/mArUmArAmArAmCrGmCmCm
 
 
 
 GrCmArGmArCmA/UNA-U/*/dT
 
380 1204 S UNA-U/*/rGmUmCmUrGmCrGrGmCrGm
 
 
 
 UmUmUmUrAmUmCrA/*/UNA-U/*/dT
 
380 1205 AS mUrGrAmUmArArArAmCrGmCrCrGr
 
 
 
 CmAmGmArCmA/UNA-U/*/dT
 
380 1206 S UNA-U/*/rGmUmCmUrGmCrGrGmCr
 
 
 
 GmUmUmUmUrAmUmCrA/*/UNA-U/*/dT
 
380 1207 AS mU/*/rGmArU/*/mArAmArAmCrGm
 
 
 
 CmCmGrC/*/mArGmArC/*/mA/UNA-U/*/dT
 
380 1208 S UNA-U/*/rGmUmCmUrGmCrGrGmCr
 
 
 
 GmUmUmUmUrAmUmCrA/*/UNA-U/*/dT
 
380 1209 AS mUrGmArUmArAmArAmCrGmCmCm
 
 
 
 GrCmArGmArCmC/UNA-U/*/dT
 
380 1210 S UNA-U/*/rGmUmCmUrGmCrGrGmCr
 
 
 
 GmUmUmUmUrAmUmCrA/*/UNA-U/*/dT
 
380 1211 AS mUrGmArUdArAmArAmCrGmCmCm
 
 
 
 GrCdArGmArCmA/UNA-U/*/dT
 
380 1212 S UNA-U/*/rGmUmCmUrGmCrGrGmCr
 
 
 
 GmUmUmUmUrAmUmCrA/*/UNA-U/*/dT
 
380 1213 AS mUrGrAmUrArArArAmCrGmCmCrGm
 
 
 
 CrArGrAmCrA/UNA-U/*/dT
 
380 1214 S UNA-U/*/rGfUfCfUrGfCrGrGfCr
 
 
 
 GfUfUfUfUrAfUfCrA/*/UNA-U/*/dT
 
380 1215 AS fUrGrAfUrArArArAfCrGfCfCrGf
 
 
 
 CrArGrAfCrA/UNA-U/*/dT
 
380 1216 S UNA-U/*/fGrUfCrUfGrCfGrGrCrGf
 
 
 
 UrUfUrUfArUfCrA/*/UNA-U/*/dT
 
380 1217 AS fUrGfArUfArAfArAfCrGfCfCfGr
 
 
 
 CfArGfArCfA/UNA-U/*/dT
 
1575 1218 S UNA-C/*/mCrGmUrGmUrGmCrArCr
 
 
 
 UmUrCmGrCmUrUmCrA/*/UNA-U/*/dT
 
1575 1219 AS mUrGmArAmGrCmGrAmArGmUmGm
 
 
 
 CrAmCrAmCrGmG/UNA-U/*/dT
 
1575 1220 S UNA-C/*/mCrGmUrGmUrGmCrAmCm
 
 
 
 UrUrCmGmCmUmUmCrA/*/UNA-U/*/dT
 
1575 1221 AS mUrG/*/mArAmGrCmGrAmArGmUm
 
 
 
 GmCrAmCrAmCrGmG/UNA-U/*/dT
 
1575 1222 S UNA-C/*/mCrGmUrGmUrGmCrAmCm
 
 
 
 UrUrCmGmCmUmUmCrA/*/UNA-U/*/dT
 
1575 1223 AS mUrGrAmAmGrCrGrAmArGmUrGrCr
 
 
 
 AmCmAmCrGmG/UNA-U/*/dT
 
1575 1224 S UNA-C/*/mCrGmUrGmUrGmCrAmCmUr
 
 
 
 UrCmGmCmUmUmCrA/*/UNA-U/*/dT
 
1575 1225 AS mU/*/rGmArAmGrCmGrAmArGmU/*/
 
 
 
 mGmC/*/rAmC/*/rAmCrGmG/UNA-U/*/dT
 
 
 
 U/*/dT
 
1575 1226 S UNA-C/*/mCrGmUrGmUrGmCrAmCmUr
 
 
 
 UrCmGmCmUmUmCrA/*/UNA-U/*/dT
 
1575 1227 AS mUrGmArAmGrCmGrAmArGmUmGmCr
 
 
 
 AmCrAmCrGmA/UNA-U/*/dT
 
1575 1228 S UNA-C/*/mCrGmUrGmUrGmCrAmCmUr
 
 
 
 UrCmGmCmUmUmCrA/*/UNA-U/*/dT
 
1575 1229 AS mUrGmArAdGrCmGrAmArGmUmGmCr
 
 
 
 AdCrAmCrGmG/UNA-U/*/dT
 
1575 1230 S UNA-C/*/mCrGmUrGmUrGmCrAmCm
 
 
 
 UrUrCmGmCmUmUmCrA/*/UNA-U/*/dT
 
1575 1231 AS mUrGrArArGmCrGrArArGmUrGmCr
 
 
 
 AmCrAmCrGrG/UNA-U/*/dT
 
1575 1232 S UNA-C/*/fCrGfUrGfUrGfCrAfCfUf
 
 
 
 UfCrGfCfUrUfCrA/*/UNA-U/*/dT
 
1575 1233 AS fUrGrArArGfCrGrArArGfUrGfCr
 
 
 
 AfCrAfCrGrG/UNA-U/*/dT
 
1575 1234 S UNA-C/*/fCrGfUrGfUrGfCrArCr
 
 
 
 UfUrCfGrCfUrUfCrA/*/UNA-U/*/dT
 
1575 1235 AS fUrGfArAfGrCfGrAfArGfUfGfCr
 
 
 
 AfCrAfCrGfG/UNA-U/*/dT
 
1575 1236 S UNA-U/*/mGrUmGrCmArCmUrUrCr
 
 
 
 GmCrUmUrCmArCmCrU/*/UNA-U/*/dT
 
1575 1237 AS mArGmGrUmGrAmArGmCrGmAmAmGr
 
 
 
 UmGrCmArCmA/UNA-U/*/dT
 
1578 1238 S UNA-U/*/mGrUmGrCmArCmUrUrCrGm
 
 
 
 CrUmUrCmArCmCrU/*/UNA-U/*/dT
 
1578 1239 AS mArGmGrUmGrAmArGmCrGmAmAmGr
 
 
 
 UmGrCmArCmA/UNA-U/*/dT
 
1578 1240 S UNA-U/*/rGmUrGmCrAmCmUmUmCrGm
 
 
 
 CmUmUmCrAmCmCmU/*/UNA-U/*/dT
 
1578 1241 AS mArG/*/mGrUmGrAmArGmCrGmAmAm
 
 
 
 GrUmGrCmArCmA/UNA-U/*/dT
 
1578 1242 S UNA-U/*/rGmUrGmCrAmCmUmUmCrGm
 
 
 
 CmUmUmCrAmCmCmU/*/UNA-U/*/dT
 
1578 1243 AS mArGrGmUmGrArArGmCrGmArArGrUm
 
 
 
 GmCmArCmA/UNA-U/*/dT
 
1578 1244 S UNA-U/*/rGmUrGmCrAmCmUmUmCrGmCm
 
 
 
 UmUmCrAmCmCmU/*/UNA-U/*/dT
 
1578 1245 AS mArGmGrU/*/mGrAmArGmCrGmAmAmGr
 
 
 
 U/*/mGrC/*/mArC/*/mA/UNA-U/*/dT
 
1578 1246 S UNA-U/*/rGmUrGmCrAmCmUmUmCrGm
 
 
 
 CmUmUmCrAmCmCmU/*/UNA-U/*/dT
 
1578 1247 AS mArGmGrUmGrAmArGmCrGmAmAmGr
 
 
 
 UmGrCmArCmC/UNA-U/*/dT
 
1578 1248 S UNA-U/*/rGmUrGmCrAmCmUmUmCrGm
 
 
 
 CmUmUmCrAmCmCmU/*/UNA-U/*/dT
 
1578 1249 AS mArGmGrUdGrAmArGmCrGmAmAmGrUd
 
 
 
 GrCmArCmA/UNA-U/*/dT
 
1578 1250 S UNA-U/*/rGmUrGmCrAmCmUmUmCrGm
 
 
 
 CmUmUmCrAmCmCmU/*/UNA-U/*/dT
 
1578 1251 AS rArGrGmUrGrArArGmCrGrArArGmUr
 
 
 
 GmCrAmCrA/UNA-U/*/dT
 
1578 1252 S UNA-U/*/rGfUrGfCrAfCfUfUfCrGf
 
 
 
 CfUfUfCrAfCfCfU/*/UNA-U/*/dT
 
1578 1253 AS rArGrGfUrGrArArGfCrGrArArGf
 
 
 
 UrGfCrAfCrA/UNA-U/*/dT
 
1578 1254 S UNA-U/*/fGrUfGrCfArCfUrUrCrGf
 
 
 
 CrUfUrCfArCfCrU/*/UNA-U/*/dT
 
1578 1255 AS fArGfGrUfGrAfArGfCrGfAfAfGr
 
 
 
 UfGrCfArCfA/UNA-U/*/dT
 
1576 1256 S UNA-C/*/rGmUrGmUrGmCrAmCmUmUm
 
 
 
 CrGmCmUmUrCrAmC/*/UNA-U/*/dT
 
1576 1257 AS mGrU/*/mGrAmArGmC/UNA-G/mArAm
 
 
 
 GmUmGrCmArCmArCmG/UNA-U/*/dT
 
1576 1258 S UNA-C/*/rGmUrGmUrGmCrAmCmUmUm
 
 
 
 CrGmCmUmUrCrAmC/*/UNA-U/*/dT
 
1576 1259 AS mGrU/*/rGmAmArGrC/UNA-G/mAr
 
 
 
 AmGrUrGrCmAmCmArCmG/UNA-U/*/dT
 
1576 1260 S UNA-C/*/rGmUrGmUrGmCrAmCmUmUm
 
 
 
 CrGmCmUmUrCrAmC/*/UNA-U/*/dT
 
1576 1261 AS mGrU/*/mGrAmArGmC/UNA-G/mArAmGmU/
 
 
 
 */mGrC/*/mArC/*/mArCmG/UNA-U/*/dT
 
1576 1262 S UNA-C/*/rGmUrGmUrGmCrAmCmUm
 
 
 
 UmCrGmCmUmUrCrAmC/*/UNA-U/*/dT
 
1576 1263 AS mGrUmGrAmArGmC/UNA-G/mArAmGm
 
 
 
 UmGrCmArCmArCmA/UNA-U/*/dT
 
1576 1264 S UNA-C/*/rGmUrGmUrGmCrAmCmUmUm
 
 
 
 CrGmCmUmUrCrAmC/*/UNA-U/*/dT
 
1576 1265 AS mGrU/*/rGmAdArGrC/UNA-G/mArAm
 
 
 
 GrUrGrCdAmCmArCmG/UNA-U/*/dT
 
1576 1266 S UNA-C/*/rGmUrGmUrGmCrAmCmUmUm
 
 
 
 CrGmCmUmUrCrAmC/*/UNA-U/*/dT
 
1576 1267 AS rGmUrGrArArGmC/UNA-G/rArArGmUr
 
 
 
 GmCrAmCrAmCrG/UNA-U/*/dT
 
1576 1268 S UNA-C/*/rGfUrGfUrGfCrAfCfUfUfCr
 
 
 
 GfCfUfUfCrAfC/*/UNA-U/*/dT
 
1576 1269 AS rGfUrGrArArGfC/UNA-G/rArArGfUr
 
 
 
 GfCrAfCrAfCrG/UNA-U/*/dT
 
1576 1270 S UNA-C/*/fGrUfGrUfGrCfArCrUrUfCr
 
 
 
 GfCrUfUrCfArC/*/UNA-U/*/dT
 
1576 1271 AS fGrUfGrAfArGfC/UNA-G/fArAfGfUf
 
 
 
 GrCfArCfArCfG/UNA-U/*/dT
 
1578 1274 S UNA-U/mGrUmGrCmArCmUrUrCrGmCrUm
 
 
 
 UrCmArCmCrU/UNA-U/mU
 
1578 1275 AS mArGmGrUmGrAmArGmCrGmAmAmGrUm
 
 
 
 GrCmArCmA/UNA-U/mU
 
1578 1276 S UNA-U/mGrUmGrCmArCmUrUrCrGmCrUm
 
 
 
 UrCmArCmCrU/UNA-U/mU
 
1578 1277 AS 5Phos/mArGmGrUmGrAmArGmCrGmAmAm
 
 
 
 GrUmGrCmArCmA/UNA-U/mU
 
1777 1278 S UNA-G/mArGmGrCmUrGmUrArGrGmCrAmUr
 
 
 
 AmArAmUrU/UNA-U/mU
 
1777 1279 AS mArAmUrUmUrAmUrGmCrCmUmAmCrAmGr
 
 
 
 CmCrUmC/UNA-U/mU
 
1777 1280 S UNA-G/mArGmGrCmUrGmUrArGrGmCrAmUr
 
 
 
 AmArAmUrU/UNA-U/mU
 
1777 1281 AS 5Phos/mArAmUrUmUrAmUrGmCrCmUmAmCr
 
 
 
 AmGrCmCrUmC/UNA-U/mU
 
380 1282 S UNA-U/mGrUmCrUmGrCmGrGrCrGmUrUmUr
 
 
 
 UmArUmCrA/UNA-U/mU
 
380 1283 AS mUrGmArUmArAmArAmCrGmCmCmGrCm
 
 
 
 ArGmArCmA/UNA-U/mU
 
380 1284 S UNA-U/mGrUmCrUmGrCmGrGrCrGmUrUm
 
 
 
 UrUmArUmCrA/UNA-U/mU
 
380 1285 AS 5Phos/mUrGmArUmArAmArAmCrGmCmCm
 
 
 
 GrCmArGmArCmA/UNA-U/mU,
 
SEQ ID NO:1107 (UNA-U*/mGrUmCrUmGrCmGrGrCrGmUrUmUrUmArUmCrA*/UNA-U*/mU) and SEQ ID NO:1108 (mUrGmArUmArAmArAmCrGmCmCmGrCmArGmArCmA/UNA-U*/mU);
and wherein “m” before a nucleotide denotes a chemically-modified 2′-OMe ribonucleotide, “r” before a nucleotide denotes a ribonucleotide, an asterisk * between characters refers to a phosphorothioate linkage, “d” before a nucleotide denotes a deoxyribonucleotide, “UNA” before a nucleotide denotes an unlocked nucleotide, and “f” before a nucleotide denotes a 2′-deoxy-2′-fluoro ribonucleotide.