US 12,275,938 B2
Modified RNA agents with reduced off-target effect
Shigeo Matsuda, Cambridge, MA (US); Mark K. Schlegel, Cambridge, MA (US); Maja Janas, Cambridge, MA (US); Vasant R. Jadhav, Cambridge, MA (US); Martin Maier, Cambridge, MA (US); Klaus Charisse, Cambridge, MA (US); Muthiah Manoharan, Cambridge, MA (US); Kallanthottathil Rajeev, Cambridge, MA (US); and Jayaprakash K. Nair, Cambridge, MA (US)
Assigned to ALNYLAM PHARMACEUTICALS, INC., Cambridge, MA (US)
Filed by Alnylam Pharmaceuticals, Inc., Cambridge, MA (US)
Filed on May 13, 2022, as Appl. No. 17/743,663.
Application 17/743,663 is a continuation of application No. 17/055,710, previously published as PCT/US2019/032633, filed on May 16, 2019.
Claims priority of provisional application 62/672,405, filed on May 16, 2018.
Claims priority of provisional application 62/719,291, filed on Aug. 17, 2018.
Prior Publication US 2022/0290145 A1, Sep. 15, 2022
Int. Cl. C07H 21/04 (2006.01); C12N 15/113 (2010.01)
CPC C12N 15/113 (2013.01) [C12N 2310/14 (2013.01); C12N 2310/318 (2013.01); C12N 2310/323 (2013.01); C12N 2310/33 (2013.01); C12N 2310/344 (2013.01); C12N 2310/53 (2013.01)] 38 Claims
 
1. A double-stranded RNA (dsRNA) molecule comprising a sense strand and an antisense strand, each strand having 18 to 35 nucleotides, wherein
the dsRNA molecule has a duplex region of 17-30 nucleotide pairs in length;
the antisense strand has sufficient complementarity to a target sequence to mediate RNA interference;
the antisense strand comprises a thermally destabilizing modification at position 7 of the antisense strand, counting from the 5′-end of the antisense strand; and
the thermally destabilizing modification is of the formula,

OG Complex Work Unit Chemistry
wherein Base is an optionally modified nucleobase;
the dsRNA molecule is optionally conjugated to a ligand.