	US 12,290,573 B2
	Modified RNAi agents
Kallanthottathil G. Rajeev, Cambridge, MA (US); Tracy Zimmermann, Cambridge, MA (US); Muthiah Manoharan, Cambridge, MA (US); Martin Maier, Cambridge, MA (US); Satyanarayana Kuchimanchi, Cambridge, MA (US); and Klaus Charisse, Cambridge, MA (US)
Assigned to Alnylam Pharmaceuticals, Inc., Cambridge, MA (US)
Filed by Alnylam Pharmaceuticals, Inc., Cambridge, MA (US)
Filed on Jun. 24, 2022, as Appl. No. 17/848,850.
Application 17/848,850 is a continuation of application No. 16/850,555, filed on Apr. 16, 2020, granted, now 11,406,716.
Application 16/850,555 is a continuation of application No. 16/165,343, filed on Oct. 19, 2018, granted, now 10,668,170, issued on Jun. 2, 2020.
Application 16/165,343 is a continuation of application No. 15/706,389, filed on Sep. 15, 2017, abandoned.
Application 15/706,389 is a continuation of application No. 14/358,009, granted, now 9,796,974, issued on Oct. 24, 2017, previously published as PCT/US2012/065601, filed on Nov. 16, 2012.
Claims priority of provisional application 61/561,710, filed on Nov. 18, 2011.
Prior Publication US 2022/0331446 A1, Oct. 20, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 48/00 (2006.01); C07H 21/02 (2006.01); C12N 15/113 (2010.01); C12N 15/85 (2006.01)

CPC A61K 48/00 (2013.01) [C07H 21/02 (2013.01); C12N 15/113 (2013.01); C12N 15/85 (2013.01); C12N 2310/315 (2013.01); C12N 2310/321 (2013.01); C12N 2310/322 (2013.01); C12N 2310/343 (2013.01); C12N 2310/346 (2013.01); C12N 2320/51 (2013.01)]

20 Claims

1. A double-stranded RNAi agent capable of inhibiting the expression of a target gene, comprising a sense strand and an antisense strand, each strand having 14 to 30 nucleotides, wherein the sense strand sequence is represented by formula (I):

5′n_p-N_a-(XXX)_i-N_b-YYY-N_b-(ZZZ)_j-N_a-n_q3′ (I)

wherein:

i is 1 and j is 0; or i is 0 and j is 1; or both i and j are 1;

p and q are each independently 0-6;

each N_aindependently represents an oligonucleotide sequence comprising 2-25 modified nucleotides, each sequence comprising at least two differently modified nucleotides;

each N_bindependently represents an oligonucleotide sequence comprising 1, 2, 3, 4, 5, or 6 modified nucleotides;

each n_pand n_qindependently represent an overhang nucleotide;

XXX, YYY and ZZZ each independently represent one motif of three identical modifications on three consecutive nucleotides; and

YYY represents three 2′-F modified nucleotides, and the YYY motif occurs at the 9, 10 and 11 positions of the sense strand from the 5′-end;

the modification of each nucleotide next to a XXX, YYY or ZZZ motif is a different modification than the modification of the motif that the nucleotide is next to; and

at least one of the sense strand and antisense strand contains at least one phosphorothioate internucleotide modification within the first 5 nucleotides, counting from the 5′-end of the strand.