IP Library › Granted Patent US 12,516,319
Granted Patent B2
US 12,516,319 · App. 17/970,887 · Granted Jan 6, 2026

Compositions and methods for modulating TTR expression

Inventors: Thazha P. Prakash (Carlsbad, CA); Punit P. Seth (Carlsbad, CA); Eric E. Swayze (Encinitas, CA)
Assignee: IONIS PHARMACEUTICALS, INC.
C12N15/113A61K31/7088A61K31/713A61K47/549C07H21/04C12N15/111C12N2310/11C12N2310/113C12N2310/17C12N2310/31C12N2310/315C12N2310/321C12N2310/322C12N2310/3231C12N2310/3341C12N2310/341C12N2310/346C12N2310/351C12N2310/3511C12N2310/3513C12N2310/3515C12N2310/3525C12N2310/353C12N2320/32
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Quick Facts
Patent No.
US 12,516,319
App. No.
17/970,887
Granted
Jan 6, 2026
Kind
B2
Abstract

Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.

Claims (21)

1 . A compound comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides, and is at least 95% complementary to an equal length portion of nucleobases of SEQ ID NO: 2 over the entire length, wherein the nucleobase sequence of the modified oligonucleotide comprises at least 8 contiguous nucleobases of SEQ ID NO: 12; and wherein the conjugate group is linked to the modified oligonucleotide by a conjugate linker; wherein the conjugate group comprises:

wherein each n is, independently, from 1 to 20; and

wherein the conjugate linker comprises:

2 . The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO: 2.

3 . The compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

4 . The compound of claim 3 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

5 . The compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified sugar.

6 . The compound of claim 5 , wherein at least one modified sugar is selected from a bicyclic sugar, a 2′-O-methoxyethyl modified sugar, a constrained ethyl modified sugar, a 3′-fluoro-HNA or a 4′-(CH 2 )n-O-2′ bridge, wherein n is 1 or 2.

7 . The compound of claim 1 , wherein at least one nucleoside comprises a modified nucleobase.

8 . The compound of claim 7 , wherein the modified nucleobase is a 5-methylcytosine.

9 . The compound claim 1 , wherein the modified oligonucleotide consists of 20 linked nucleosides having a nucleobase sequence consisting of SEQ ID NO: 12, and wherein the modified oligonucleotide comprises:

a gap segment consisting of ten linked deoxynucleosides;

a 5′ wing segment consisting of five linked nucleosides; and

a 3′ wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, and wherein each cytosine residue is a 5-methylcytosine.

10 . The compound of claim 9 , wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage.

11 . The compound of claim 1 , wherein the conjugate group comprises:

and the conjugate linker has the following structure:

12 . The compound of claim 1 , wherein the conjugate group comprises a cleavable moiety selected from a phosphodiester, an amide, and an ester.

13 . The compound of claim 1 , wherein the conjugate group together with the linker comprise:

14 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 13, 2022
From: PRAKASH, THAZHA P; SETH, PUNIT P.; SWAYZE, ERIC E.
To: ISIS PHARMACEUTICALS, INC.
Reel/Frame 062070/0586 →
CHANGE OF NAME Recorded Dec 13, 2022
From: ISIS PHARMACEUTICALS, INC.
To: IONIS PHARMACEUTICALS, INC.
Reel/Frame 062117/0339 →
Continuity (13)
Continuation 16790557 · Feb 13, 2020
Continuation 15687306 · Aug 25, 2017
Continuation 14822493 · Aug 10, 2015
Continuation 14633491 · Feb 27, 2015
Continuation PCTUS2014036463 · May 1, 2014
Provisional Application 61986867 · Apr 30, 2014
Provisional Application 61976991 · Apr 8, 2014
Provisional Application 61880790 · Sep 20, 2013
Provisional Application 61871673 · Aug 29, 2013
Provisional Application 61843887 · Jul 8, 2013
Provisional Application 61823826 · May 15, 2013
Provisional Application 61818442 · May 1, 2013
Related Publication 20230151365A1 · May 18, 2023
References Cited (400)
US 3687808A · Merigan et al. · 1972 [cited by applicant]
US 4415732A · Caruthers et al. · 1983 [cited by applicant]
US 4458066A · Caruthers et al. · 1984 [cited by applicant]
US 4469863A · Ts'o et al. · 1984 [cited by applicant]
US 4476301A · Imbach et al. · 1984 [cited by applicant]
US 4500707A · Caruthers et al. · 1985 [cited by applicant]
US 4668777A · Caruthers et al. · 1987 [cited by applicant]
US 4725677A · Koster et al. · 1988 [cited by applicant]
US 4751219A · Kempen et al. · 1988 [cited by applicant]
US 4845205A · Huynh Dinh et al. · 1989 [cited by applicant]
US 4973679A · Caruthers et al. · 1990 [cited by applicant]
US 4981957A · Lebleu et al. · 1991 [cited by applicant]
US 5013830A · Ohutsuka et al. · 1991 [cited by applicant]
US 5023243A · Tullis · 1991 [cited by applicant]
US 5034506A · Summerton et al. · 1991 [cited by applicant]
US 5118800A · Smith et al. · 1992 [cited by applicant]
US 5130302A · Spielvogel et al. · 1992 [cited by applicant]
US 5132418A · Caruthers et al. · 1992 [cited by applicant]
US 5134066A · Rogers et al. · 1992 [cited by applicant]
US RE34036E · McGeehan · 1992 [cited by applicant]
US 5149797A · Pederson et al. · 1992 [cited by applicant]
US 5166315A · Summerton et al. · 1992 [cited by applicant]
US 5175273A · Bischofberger et al. · 1992 [cited by applicant]
US 5177196A · Meyer, Jr. et al. · 1993 [cited by applicant]
US 5177198A · Spielvogel et al. · 1993 [cited by applicant]
US 5185444A · Summerton et al. · 1993 [cited by applicant]
US 5188897A · Suhadolnik et al. · 1993 [cited by applicant]
US 5194599A · Froehler · 1993 [cited by applicant]
US 5214134A · Weis et al. · 1993 [cited by applicant]
US 5216141A · Benner · 1993 [cited by applicant]
US 5220007A · Pederson et al. · 1993 [cited by applicant]
US 5223618A · Cook et al. · 1993 [cited by applicant]
US 5235033A · Summerton et al. · 1993 [cited by applicant]
US 5256775A · Froehler · 1993 [cited by applicant]
US 5264423A · Cohen et al. · 1993 [cited by applicant]
US 5264562A · Matteucci · 1993 [cited by applicant]
US 5264564A · Matteucci · 1993 [cited by applicant]
US 5276019A · Cohen et al. · 1994 [cited by applicant]
US 5278302A · Caruthers et al. · 1994 [cited by applicant]
US 5286717A · Cohen et al. · 1994 [cited by applicant]
US 5319080A · Leumann · 1994 [cited by applicant]
US 5321131A · Agrawal et al. · 1994 [cited by applicant]
US 5359044A · Cook et al. · 1994 [cited by applicant]
US 5366878A · Pederson et al. · 1994 [cited by applicant]
US 5367066A · Urdea et al. · 1994 [cited by applicant]
US 5378825A · Cook et al. · 1995 [cited by applicant]
US 5386023A · Sanghvi et al. · 1995 [cited by applicant]
US 5393878A · Leumann · 1995 [cited by applicant]
US 5399676A · Froehler · 1995 [cited by applicant]
US 5403711A · Walder et al. · 1995 [cited by applicant]
US 5405938A · Sumerton et al. · 1995 [cited by applicant]
US 5405939A · Suhadolnik et al. · 1995 [cited by applicant]
US 5432272A · Benner · 1995 [cited by applicant]
US 5434257A · Matteucci et al. · 1995 [cited by applicant]
US 5446137A · Maag et al. · 1995 [cited by applicant]
US 5453496A · Caruthers et al. · 1995 [cited by applicant]
US 5455233A · Spielvogel et al. · 1995 [cited by applicant]
US 5457187A · Gmelner et al. · 1995 [cited by applicant]
US 5457191A · Cook et al. · 1995 [cited by applicant]
US 5459255A · Cook et al. · 1995 [cited by applicant]
US 5466677A · Baxter et al. · 1995 [cited by applicant]
US 5466786A · Burh et al. · 1995 [cited by applicant]
US 5470967A · Huie et al. · 1995 [cited by applicant]
US 5476925A · Letsinger et al. · 1995 [cited by applicant]
US 5484908A · Froehler et al. · 1996 [cited by applicant]
US 5489677A · Sanghvi et al. · 1996 [cited by applicant]
US 5491133A · Walder et al. · 1996 [cited by applicant]
US 5502177A · Matteucci et al. · 1996 [cited by applicant]
US 5508270A · Baxter et al. · 1996 [cited by applicant]
US 5514785A · Van Ness et al. · 1996 [cited by applicant]
US 5519126A · Hecht · 1996 [cited by applicant]
US 5519134A · Acevedo et al. · 1996 [cited by applicant]
US 5525711A · Hawkins et al. · 1996 [cited by applicant]
US 5527899A · Froehler · 1996 [cited by applicant]
US 5536821A · Agrawal et al. · 1996 [cited by applicant]
US 5541306A · Agrawal et al. · 1996 [cited by applicant]
US 5541307A · Cook et al. · 1996 [cited by applicant]
US 5550111A · Suhadolnik et al. · 1996 [cited by applicant]
US 5552540A · Haralambidis · 1996 [cited by applicant]
US 5561225A · Maddry et al. · 1996 [cited by applicant]
US 5563253A · Agrawal et al. · 1996 [cited by applicant]
US 5565350A · Kmiec · 1996 [cited by applicant]
US 5565555A · Froehler et al. · 1996 [cited by applicant]
US 5567811A · Mistura et al. · 1996 [cited by applicant]
US 5571799A · Tkachuk et al. · 1996 [cited by applicant]
US 5576427A · Cook et al. · 1996 [cited by applicant]
US 5587361A · Cook et al. · 1996 [cited by applicant]
US 5587469A · Cook et al. · 1996 [cited by applicant]
US 5587470A · Cook et al. · 1996 [cited by applicant]
US 5591722A · Montgomery et al. · 1997 [cited by applicant]
US 5594121A · Froehler et al. · 1997 [cited by applicant]
US 5596086A · Matteucci · 1997 [cited by applicant]
US 5596091A · Switzer · 1997 [cited by applicant]
US 5597909A · Urdea et al. · 1997 [cited by applicant]
US 5602240A · De Mesmaeker et al. · 1997 [cited by applicant]
US 5608046A · Cook et al. · 1997 [cited by applicant]
US 5610289A · Cook et al. · 1997 [cited by applicant]
US 5610300A · Altmann et al. · 1997 [cited by applicant]
US 5614617A · Cook et al. · 1997 [cited by applicant]
US 5618704A · Sanghvi et al. · 1997 [cited by applicant]
US 5623065A · Cook et al. · 1997 [cited by applicant]
US 5623070A · Cook et al. · 1997 [cited by applicant]
US 5625050A · Beaton et al. · 1997 [cited by applicant]
US 5627053A · Usman et al. · 1997 [cited by applicant]
US 5633360A · Bishofberger et al. · 1997 [cited by applicant]
US 5639873A · Barascut et al. · 1997 [cited by applicant]
US 5645985A · Froehler et al. · 1997 [cited by applicant]
US 5646265A · McGee · 1997 [cited by applicant]
US 5646269A · Matteucci · 1997 [cited by applicant]
US 5652355A · Metelev et al. · 1997 [cited by applicant]
US 5652356A · Agrawal · 1997 [cited by applicant]
US 5663312A · Chaturvedula · 1997 [cited by applicant]
US 5670633A · Cook et al. · 1997 [cited by applicant]
US 5672697A · Buhr et al. · 1997 [cited by applicant]
US 5677437A · Teng et al. · 1997 [cited by applicant]
US 5677439A · Weis et al. · 1997 [cited by applicant]
US 5681941A · Cook et al. · 1997 [cited by applicant]
US 5698685A · Summerton et al. · 1997 [cited by applicant]
US 5700920A · Altmann et al. · 1997 [cited by applicant]
US 5700922A · Cook · 1997 [cited by applicant]
US 5721218A · Froehler · 1998 [cited by applicant]
US 5750692A · Cook et al. · 1998 [cited by applicant]
US 5763588A · Matteucci et al. · 1998 [cited by applicant]
US 5792608A · Swaminathan et al. · 1998 [cited by applicant]
US 5792847A · Burh et al. · 1998 [cited by applicant]
US 5801154A · Baracchini et al. · 1998 [cited by applicant]
US 5808027A · Cook et al. · 1998 [cited by applicant]
US 5830653A · Froehler et al. · 1998 [cited by applicant]
US 5859221A · Cook et al. · 1999 [cited by applicant]
US 5948903A · Cook et al. · 1999 [cited by applicant]
US 5994517A · Ts'o et al. · 1999 [cited by applicant]
US 5998203A · Matulic-Adamic · 1999 [cited by applicant]
US 6005087A · Cook et al. · 1999 [cited by applicant]
US 6005096A · Matteucci et al. · 1999 [cited by applicant]
US 6166199A · Cook et al. · 2000 [cited by applicant]
US 6268490B1 · Imanishi et al. · 2001 [cited by applicant]
US 6300319B1 · Manoharan · 2001 [cited by applicant]
US 6383812B1 · Chen et al. · 2002 [cited by applicant]
US 6426220B1 · Bennett et al. · 2002 [cited by applicant]
US 6525031B2 · Manoharan · 2003 [cited by applicant]
US 6525191B1 · Ramasamy · 2003 [cited by applicant]
US 6531584B1 · Cook et al. · 2003 [cited by applicant]
US 6582908B2 · Fodor et al. · 2003 [cited by applicant]
US 6600032B1 · Manoharan et al. · 2003 [cited by applicant]
US 6620916B1 · Takahara et al. · 2003 [cited by applicant]
US 6660720B2 · Manoharan et al. · 2003 [cited by applicant]
US 6670461B1 · Wengel et al. · 2003 [cited by applicant]
US 6673661B1 · Liu et al. · 2004 [cited by applicant]
US 6770748B2 · Imanishi et al. · 2004 [cited by applicant]
US 6794499B2 · Wengel et al. · 2004 [cited by applicant]
US 6906182B2 · Ts'o et al. · 2005 [cited by applicant]
US 6908903B1 · Theodore et al. · 2005 [cited by applicant]
US 7015315B1 · Cook et al. · 2006 [cited by applicant]
US 7034133B2 · Wengel et al. · 2006 [cited by applicant]
US 7053199B2 · Imanishi et al. · 2006 [cited by applicant]
US 7053207B2 · Wengel · 2006 [cited by applicant]
US 7060809B2 · Wengel et al. · 2006 [cited by applicant]
US 7101993B1 · Cook et al. · 2006 [cited by applicant]
US 7217805B2 · Imanishi et al. · 2007 [cited by applicant]
US 7262177B2 · Ts'o et al. · 2007 [cited by applicant]
US 7314923B2 · Kaneko et al. · 2008 [cited by applicant]
US 7399845B2 · Seth et al. · 2008 [cited by applicant]
US 7427672B2 · Imanishi et al. · 2008 [cited by applicant]
US 7439043B2 · DeFrees et al. · 2008 [cited by applicant]
US 7491805B2 · Vargeese et al. · 2009 [cited by applicant]
US 7547684B2 · Seth et al. · 2009 [cited by applicant]
US 7569686B1 · Bhat et al. · 2009 [cited by applicant]
US 7572582B2 · Wengel et al. · 2009 [cited by applicant]
US 7582744B2 · Manoharan et al. · 2009 [cited by applicant]
US 7666854B2 · Seth et al. · 2010 [cited by applicant]
US 7696344B2 · Khvorova et al. · 2010 [cited by applicant]
US 7696345B2 · Allerson et al. · 2010 [cited by applicant]
US 7723509B2 · Manoharan et al. · 2010 [cited by applicant]
US 7741457B2 · Swayze et al. · 2010 [cited by applicant]
US 7750131B2 · Seth et al. · 2010 [cited by applicant]
US 7851615B2 · Manoharan et al. · 2010 [cited by applicant]
US 7875733B2 · Bhat et al. · 2011 [cited by applicant]
US 7939677B2 · Bhat et al. · 2011 [cited by applicant]
US 8022193B2 · Swayze et al. · 2011 [cited by applicant]
US 8030467B2 · Seth et al. · 2011 [cited by applicant]
US 8034909B2 · Wengel et al. · 2011 [cited by applicant]
US 8080644B2 · Wengel et al. · 2011 [cited by applicant]
US 8088746B2 · Seth et al. · 2012 [cited by applicant]
US 8088904B2 · Swayze et al. · 2012 [cited by applicant]
US 8101743B2 · Brown-Driver et al. · 2012 [cited by applicant]
US 8106022B2 · Manoharan et al. · 2012 [cited by applicant]
US 8124745B2 · Allerson et al. · 2012 [cited by applicant]
US 8137695B2 · Rozema et al. · 2012 [cited by applicant]
US 8153365B2 · Wengel et al. · 2012 [cited by applicant]
US 8158601B2 · Chen et al. · 2012 [cited by applicant]
US 8268980B2 · Seth et al. · 2012 [cited by applicant]
US 8278283B2 · Seth et al. · 2012 [cited by applicant]
US 8278425B2 · Prakash et al. · 2012 [cited by applicant]
US 8278426B2 · Seth et al. · 2012 [cited by applicant]
US 8313772B2 · Rozema et al. · 2012 [cited by applicant]
US 8344125B2 · Manoharan et al. · 2013 [cited by applicant]
US 8349308B2 · Yurkovetskiy et al. · 2013 [cited by applicant]
US 8404862B2 · Manoharan et al. · 2013 [cited by applicant]
US 8435491B2 · Wang et al. · 2013 [cited by applicant]
US 8440803B2 · Swayze et al. · 2013 [cited by applicant]
US 8450467B2 · Manoharan et al. · 2013 [cited by applicant]
US 8501805B2 · Seth et al. · 2013 [cited by applicant]
US 8501930B2 · Rozema et al. · 2013 [cited by applicant]
US 8530640B2 · Seth et al. · 2013 [cited by applicant]
US 8541548B2 · Rozema · 2013 [cited by applicant]
US 8546556B2 · Seth et al. · 2013 [cited by applicant]
US 8552163B2 · Lee et al. · 2013 [cited by applicant]
US 8575123B2 · Manoharan et al. · 2013 [cited by applicant]
US 8604192B2 · Seth et al. · 2013 [cited by applicant]
US RE44779E · Imanishi et al. · 2014 [cited by applicant]
US 8642752B2 · Swayze et al. · 2014 [cited by applicant]
US 8697860B1 · Monia et al. · 2014 [cited by applicant]
US 8809514B2 · Yamada et al. · 2014 [cited by applicant]
US 8828956B2 · Manoharan et al. · 2014 [cited by applicant]
US 8993738B2 · Prakash et al. · 2015 [cited by applicant]
US 9005906B2 · Swayze et al. · 2015 [cited by applicant]
US 9012421B2 · Migawa et al. · 2015 [cited by applicant]
US 9061044B2 · Freier · 2015 [cited by applicant]
US 9102938B2 · Rajeev et al. · 2015 [cited by applicant]
US 9127276B2 · Prakash et al. · 2015 [cited by applicant]
US 9181549B2 · Prakash et al. · 2015 [cited by applicant]
US 9290760B2 · Rajeev et al. · 2016 [cited by applicant]
US 9399774B2 · Monia et al. · 2016 [cited by applicant]
US 9816092B2 · Monia et al. · 2017 [cited by applicant]
US 10150965B2 · Brown et al. · 2018 [cited by applicant]
US 20010053519A1 · Fodor et al. · 2001 [cited by applicant]
US 20020082227A1 · Henry et al. · 2002 [cited by applicant]
US 20030077829A1 · MacLachlan · 2003 [cited by applicant]
US 20030082807A1 · Wengel · 2003 [cited by applicant]
US 20030119724A1 · Ts'o et al. · 2003 [cited by applicant]
US 20030158403A1 · Manoharan et al. · 2003 [cited by applicant]
US 20030170249A1 · Hakomori et al. · 2003 [cited by applicant]
US 20030175906A1 · Manoharan et al. · 2003 [cited by applicant]
US 20030207841A1 · Kaneko et al. · 2003 [cited by applicant]
US 20030224377A1 · Wengel et al. · 2003 [cited by applicant]
US 20030228597A1 · Cowsert et al. · 2003 [cited by applicant]
US 20040143114A1 · Imanishi et al. · 2004 [cited by applicant]
US 20040171570A1 · Allerson et al. · 2004 [cited by applicant]
US 20040192918A1 · Imanishi et al. · 2004 [cited by applicant]
US 20040249178A1 · Vargeese et al. · 2004 [cited by applicant]
US 20050107319A1 · Bansal · 2005 [cited by applicant]
US 20050130923A1 · Bhat et al. · 2005 [cited by applicant]
US 20050164235A1 · Manoharan et al. · 2005 [cited by applicant]
US 20050244869A1 · Brown-Driver et al. · 2005 [cited by applicant]
US 20060148740A1 · Platenburg · 2006 [cited by applicant]
US 20060183886A1 · Tso et al. · 2006 [cited by applicant]
US 20070031844A1 · Khvorova et al. · 2007 [cited by applicant]
US 20070287831A1 · Seth et al. · 2007 [cited by applicant]
US 20080039618A1 · Allerson et al. · 2008 [cited by applicant]
US 20080085869A1 · Yamada et al. · 2008 [cited by applicant]
US 20080108801A1 · Manoharan et al. · 2008 [cited by applicant]
US 20080206869A1 · Smith et al. · 2008 [cited by applicant]
US 20080281041A1 · Rozema et al. · 2008 [cited by applicant]
US 20080281044A1 · Manoharan et al. · 2008 [cited by applicant]
US 20090012281A1 · Swayze et al. · 2009 [cited by applicant]
US 20090203132A1 · Swayze et al. · 2009 [cited by applicant]
US 20090203135A1 · Forst et al. · 2009 [cited by applicant]
US 20090286973A1 · Manoharan et al. · 2009 [cited by applicant]
US 20100093085A1 · Yamada et al. · 2010 [cited by applicant]
US 20100120665A1 · Kaleko et al. · 2010 [cited by applicant]
US 20100190837A1 · Migawa et al. · 2010 [cited by applicant]
US 20100197762A1 · Swayze et al. · 2010 [cited by applicant]
US 20100240730A1 · Beigelman et al. · 2010 [cited by applicant]
US 20110077386A1 · Lee et al. · 2011 [cited by applicant]
US 20110097264A1 · Wang et al. · 2011 [cited by applicant]
US 20110097265A1 · Wang et al. · 2011 [cited by applicant]
US 20110123520A1 · Manoharan et al. · 2011 [cited by applicant]
US 20110124853A1 · Chen et al. · 2011 [cited by applicant]
US 20110201798A1 · Manoharan et al. · 2011 [cited by applicant]
US 20110207799A1 · Rozema et al. · 2011 [cited by applicant]
US 20110269814A1 · Manoharan et al. · 2011 [cited by applicant]
US 20110294868A1 · Monia et al. · 2011 [cited by applicant]
US 20120035115A1 · Manoharan et al. · 2012 [cited by applicant]
US 20120095075A1 · Manoharan et al. · 2012 [cited by applicant]
US 20120101148A1 · Aking et al. · 2012 [cited by applicant]
US 20120128760A1 · Manoharan et al. · 2012 [cited by applicant]
US 20120136042A1 · Manoharan et al. · 2012 [cited by applicant]
US 20120157509A1 · Hadwiger et al. · 2012 [cited by applicant]
US 20120165393A1 · Rozema et al. · 2012 [cited by applicant]
US 20120183602A1 · Chen et al. · 2012 [cited by applicant]
US 20120225927A1 · Sah et al. · 2012 [cited by applicant]
US 20120230938A1 · Rozema et al. · 2012 [cited by applicant]
US 20130004427A1 · El-Sayed et al. · 2013 [cited by applicant]
US 20130035366A1 · Swayze et al. · 2013 [cited by applicant]
US 20130109817A1 · Yurkovetskiy et al. · 2013 [cited by applicant]
US 20130121954A1 · Wakefield et al. · 2013 [cited by applicant]
US 20130130378A1 · Manoharan et al. · 2013 [cited by applicant]
US 20130178512A1 · Manoharan et al. · 2013 [cited by applicant]
US 20130203836A1 · Rajeev et al. · 2013 [cited by applicant]
US 20130236968A1 · Manoharan et al. · 2013 [cited by applicant]
US 20140107184A1 · Swayze et al. · 2014 [cited by applicant]
US 20140107330A1 · Freier et al. · 2014 [cited by applicant]
US 20140256797A1 · Monia et al. · 2014 [cited by applicant]
US 20140357701A1 · Swayze et al. · 2014 [cited by applicant]
US 20150018540A1 · Prakash et al. · 2015 [cited by applicant]
US 20150184153A1 · Freier et al. · 2015 [cited by applicant]
US 20150191727A1 · Migawa et al. · 2015 [cited by applicant]
US 20150267195A1 · Seth et al. · 2015 [cited by applicant]
US 20150275212A1 · Albaek et al. · 2015 [cited by applicant]
JP WO2015105083 · 2016 [cited by examiner]
WO WO1994002499 · 1994 [cited by applicant]
WO WO1994017093 · 1994 [cited by applicant]
WO WO1997020563 · 1997 [cited by applicant]
WO WO1997046098 · 1997 [cited by applicant]
WO WO1998013381 · 1998 [cited by applicant]
WO WO1999014226 · 1999 [cited by applicant]
WO WO2000014048 · 2000 [cited by applicant]
WO WO2000063364 · 2000 [cited by applicant]
WO WO2001049687 · 2001 [cited by applicant]
WO WO2002043771 · 2002 [cited by applicant]
WO WO2003004602 · 2003 [cited by applicant]
WO WO2004011624 · 2004 [cited by applicant]
WO WO2004024757 · 2004 [cited by applicant]
WO WO2004035765 · 2004 [cited by applicant]
WO WO2004045543 · 2004 [cited by applicant]
WO WO2004063208 · 2004 [cited by applicant]
WO WO2004101619 · 2004 [cited by applicant]
WO WO2004106356 · 2004 [cited by applicant]
WO WO2005021570 · 2005 [cited by applicant]
WO WO2005097155 · 2005 [cited by applicant]
WO WO2005121371 · 2005 [cited by applicant]
WO WO2006031461 · 2006 [cited by applicant]
WO WO2006047842 · 2006 [cited by applicant]
WO WO2007035759 · 2007 [cited by applicant]
WO WO2007090071 · 2007 [cited by applicant]
WO WO2007134181 · 2007 [cited by applicant]
WO WO2008098788 · 2008 [cited by applicant]
WO WO2008101157 · 2008 [cited by applicant]
WO WO2008150729 · 2008 [cited by applicant]
WO WO2008154401 · 2008 [cited by applicant]
WO WO2009003009 · 2008 [cited by applicant]
WO WO2009006478 · 2009 [cited by applicant]
WO WO2009073809 · 2009 [cited by applicant]
WO WO2009082607 · 2009 [cited by applicant]
WO WO2009126933 · 2009 [cited by applicant]
WO WO2009143369 · 2009 [cited by applicant]
WO WO2010017509 · 2010 [cited by applicant]
WO WO2010036698 · 2010 [cited by applicant]
WO WO2010048549 · 2010 [cited by applicant]
WO WO2010048585 · 2010 [cited by applicant]
WO WO2010054406 · 2010 [cited by applicant]
WO WO2010077578 · 2010 [cited by applicant]
WO WO2010088537 · 2010 [cited by applicant]
WO WO2010101951 · 2010 [cited by applicant]
WO WO2010103204 · 2010 [cited by applicant]
WO WO2010129709 · 2010 [cited by applicant]
WO WO2010144740 · 2010 [cited by applicant]
WO WO2011005860 · 2011 [cited by applicant]
WO WO2011005861 · 2011 [cited by applicant]
WO WO2011038356 · 2011 [cited by applicant]
WO WO2011047312 · 2011 [cited by applicant]
WO WO2011100131 · 2011 [cited by applicant]
WO WO2011115818 · 2011 [cited by applicant]
WO WO2011120053 · 2011 [cited by applicant]
WO WO2011133871 · 2011 [cited by applicant]
WO WO2011139702 · 2011 [cited by applicant]
WO WO2011139917 · 2011 [cited by applicant]
WO WO2011163121 · 2011 [cited by applicant]
WO WO2012037254 · 2012 [cited by applicant]
WO WO2012068187 · 2012 [cited by applicant]
WO WO2012083046 · 2012 [cited by applicant]
WO WO2012083185 · 2012 [cited by applicant]
WO WO2012089352 · 2012 [cited by applicant]
WO WO2012089602 · 2012 [cited by applicant]
WO WO2012135736 · 2012 [cited by applicant]
WO WO2012145674 · 2012 [cited by applicant]
WO WO2012145697 · 2012 [cited by applicant]
WO WO2012177784 · 2012 [cited by applicant]
WO WO2012177947 · 2012 [cited by applicant]
WO WO2013033230 · 2013 [cited by applicant]
WO WO2013075035 · 2013 [cited by applicant]
WO WO2013119979 · 2013 [cited by applicant]
WO WO2013165816 · 2013 [cited by applicant]
WO WO2013166121 · 2013 [cited by applicant]
WO WO2013173789 · 2013 [cited by applicant]
WO WO2014076195 · 2014 [cited by applicant]
WO WO2014076196 · 2014 [cited by applicant]
WO WO2014118267 · 2014 [cited by applicant]
WO WO2014118272 · 2014 [cited by applicant]
WO WO2014179620 · 2014 [cited by applicant]
WO WO2014179625 · 2014 [cited by applicant]
WO WO2014179626 · 2014 [cited by applicant]
WO WO2014179627 · 2014 [cited by applicant]
WO WO2014179629 · 2014 [cited by applicant]
WO WO2014205451 · 2014 [cited by applicant]
WO WO2014207232 · 2014 [cited by applicant]
WO WO2015006740 · 2015 [cited by applicant]
WO WO2008036825 · 2018 [cited by applicant]
Akinc et al., “Targeted Delivery of RNAi Therapeutics with Endogenous and Exogenous Ligand-Based Mechanisms” Molecular Therapy (2010) 18(7): 1357-1364. [cited by applicant]
Albaek et al., “Analogues of a Locked Nucleic Acid with Three-Carbon 2′,4′-Linkages: Synthesis by Ring-Closing Metathesis and Influence of Nucleic Acid Duplex Stability” J. Org. Chem. (2006) 71:7731-7740. [cited by applicant]
Allshire, “RNAi and Heterochromatin—a Hushed-Up Affair” Science (2002) 297: 1818-1819. [cited by applicant]
Altmann et al., “Second generation antisense oligonucleotides—inhibition of PKC-a an c-RAF kinase expression by chimeric oligonucleotides incorporating 5′-substitute carbocyclic nucleosides and 2′-O-ethylene glycol subs… [cited by applicant]
Altmann et al., “Second Generation of Antisense Oligonucleotides: From Nuclease Resistance to Biological Efficacy in Animals” Chimia (1996) 50: 168-176. [cited by applicant]
Altmann et al., “Second-generation antisense oligonucleotides: structure-activity relationships and the design of improved signal-transduction inhibitors” Biochem. Soc. Trans. (1996) 24: 630-637. [cited by applicant]
Andre et al., “Determination of modulation of ligand properties of synthetic complex-type biantennary N-glycans by introduction of bisecting GlcNAc in silico, in vitro and in vivo” Eur. J. Biochem. (2004) 271: 118-134. [cited by applicant]
Asseline et al., “Modification of the 5′ Terminus of Oligodeoxyribonucleotides for Conjugation with Ligands” in Current Protocols in Nucleic Acid Chemistry, 2001, Supplement 5, Chapter 4: Unit 4.9 (4.9.1-4.9.28); John W… [cited by applicant]
Atsma et al., “Partial characterization of low density lipoprotein preparations isolated from fresh and frozen plasma after radiolabeling by seven different methods.” J Lipid Res. (1991) 32(1): 173-181. [cited by applicant]
Baker et al., “2′-O-(2-Methoxy)ethyl-modified Anti-intercellular Adhesion Molecule 1 (ICAM-1) Oligonucleotides Selectively Increase the ICAM-1 mRNA Level and Inhibit Formation of the ICAM-1 Translation Initiation Comple… [cited by applicant]
Beaucage et al., “The functionalization of oligonucleotides via phosphoramidate derivatives” Tetrahedron (1993) 49(10): 1925-1963. [cited by applicant]
Biessen et al., “Novel hepatotrophic prodrugs of the antiviral nucleoside 9-(2-phosphonylmethoxyethyl)adenine with improved pharmacokinetics and antiviral activity” FASEB J. (2000) 14: 1784-1792. [cited by applicant]