US 12,077,757 B2
Modified oligonucleotides and methods of use
Sergei Gryaznov, San Mateo, CA (US); Leonid Beigelman, San Mateo, CA (US); Antitsa Dimitrova Stoycheva, Half Moon Bay, CA (US); Saul Martinez Montero, Gijón (ES); Jin Hong, San Mateo, CA (US); Rajendra K. Pandey, Foster City, CA (US); Vivek Kumar Rajwanshi, Cupertino, CA (US); Lakshmipathi Pandarinathan, Boston, MA (US); Yi Jin, Carlsbad, CA (US); and Bharat Baral, Vacaville, CA (US)
Assigned to Janssen Pharmaceutica NV, Beerse (BE)
Filed by Janssen Biopharma, Inc., South San Francisco, CA (US)
Filed on Oct. 5, 2020, as Appl. No. 17/063,080.
Application 17/063,080 is a continuation of application No. 15/705,137, filed on Sep. 14, 2017, granted, now 10,793,859.
Claims priority of provisional application 62/394,739, filed on Sep. 14, 2016.
Claims priority of provisional application 62/394,738, filed on Sep. 14, 2016.
Prior Publication US 2021/0040483 A1, Feb. 11, 2021
This patent is subject to a terminal disclaimer.
Int. Cl. C07H 21/02 (2006.01); A61K 31/712 (2006.01); A61K 31/7125 (2006.01); A61K 47/54 (2017.01); A61P 31/20 (2006.01); C12N 15/11 (2006.01); C12N 15/113 (2010.01)
CPC C12N 15/1131 (2013.01) [A61K 31/712 (2013.01); A61K 31/7125 (2013.01); A61K 47/549 (2017.08); A61P 31/20 (2018.01); C07H 21/02 (2013.01); C12N 15/111 (2013.01); C12N 2310/11 (2013.01); C12N 2310/314 (2013.01); C12N 2310/3145 (2013.01); C12N 2310/315 (2013.01); C12N 2310/3231 (2013.01); C12N 2310/341 (2013.01); C12N 2310/344 (2013.01); C12N 2310/351 (2013.01); C12N 2320/32 (2013.01)] 15 Claims
 
1. A chimeric antisense oligonucleotide represented by Formula (A):
5′-X-Y-Z3′  (A),
wherein
X-Y-Z is a chimeric oligonucleotide comprising a sequence of 18 to 22 nucleosides, optionally conjugated at the 5′ and/or 3′ end to a ligand targeting group;
X is a domain comprising a sequence of modified nucleosides that is 3 to 10 nucleosides in length;
Z is a domain comprising a sequence of modified nucleosides that is 3 to 10 nucleosides in length; and
Y is a domain comprising a sequence of 2 to 10 2′-deoxy-nucleosides linked through thiophosphate intersubunit linkages,
each modified nucleoside in the X domain and each modified nucleoside in the Z domain are nucleosides of Formula (1)

OG Complex Work Unit Chemistry
wherein
R is H or a positively charged counter ion,
B is a nucleobase independently selected from the group consisting of adenine, guanine, thymine, cytosine, uracil, 5-methylcytosine, 2,6-diaminopurine, and 5-methyluracil,
R1 is —CR′3, —CR′2OCR′3, —(CR′2)3OCR′3, —(CR′2)1-2CR′3, —(CR′2)2OCR′3, or —Et, and
R′ is independently in each instance H or F, and
wherein the oligonucleotide comprises a nucleobase sequence that is complementary or hybridizes to a target RNA.