Granted Patent
B2
US 12,509,684 · App. 18/417,807 · Granted Dec 30, 2025
Compositions and methods for modulating apolipoprotein C-III expression
Inventors:
Thazha P. Prakash (Carlsbad, CA); Punit P. Seth (Carlsbad, CA); Eric E. Swayze (Encinitas, CA); Mark J. Graham (San Clemente, 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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Abstract
Provided herein are oligomeric compounds with conjugate groups targeting apoplipoprotein C-III (ApoCIII). In certain embodiments, the ApoCIII targeting oligomeric compounds are conjugated to N-Acetylgalactosamine. Also disclosed herein are conjugated oligomeric compounds targeting ApoCIII for use in decreasing ApoCIII to treat, prevent, or ameliorate diseases, disorders or conditions related to ApoCIII. Certain diseases, disorders or conditions related to ApoCIII include inflammatory, cardiovascular and/or metabolic diseases, disorders or conditions. The conjugated oligomeric compounds disclosed herein can be used to treat such diseases, disorders or conditions in an individual in need thereof.
Claims (39)
1 . A method of reducing expression of apolipoprotein C3 in a subject comprising administering a compound comprising a modified oligonucleotide and a conjugate group, or a pharmaceutically acceptable salt thereof, to a subject having familial chylomicronemia syndrome (FCS), wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides, comprises a nucleobase sequence comprising a portion of at least 20 contiguous nucleobases complementary to an equal length portion of nucleobases 3533 to 3552 of SEQ ID NO: 3, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 3, and wherein the modified oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
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; and wherein the conjugate group comprises:
2 . The method of claim 1 , wherein the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide.
3 . The method of claim 1 , wherein the conjugate group is linked to the modified oligonucleotide at the 3′ end of the modified oligonucleotide.
4 . The method of claim 1 , wherein each internucleoside linkage of the modified oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage.
5 . The method of claim 4 , wherein the modified oligonucleotide comprises at least 5 phosphodiester internucleoside linkages.
6 . The method of claim 4 , wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage.
7 . The method of claim 6 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment.
8 . The method of claim 1 , wherein the modified oligonucleotide comprises the nucleoside sequence of SEQ ID NO: 244, and wherein the modified oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
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, wherein each internucleoside linkage in the gap segment is a phosphorothioate linkage and in each wing segment at least one internucleoside linkage is a phosphorothioate internucleoside linkage; and wherein each cytosine residue is a 5-methylcytosine.
9 . The method of claim 1 , wherein the compound has the formula:
or a pharmaceutically acceptable salt thereof;
wherein either R 1 is —OCH 2 CH 2 OCH 3 and R 2 is H;
and for each pair of R 3 and R 4 on the same ring, independently for each ring: either R 3 is selected from H and —OCH 2 CH 2 OCH 3 and R 4 is H; or R 3 and R 4 together form a bridge, wherein R 3 is —O—, and R 4 is —CH 2 , —CH(CH 3 )—, or —CH 2 CH 2 — and R 3 and R 4 are directly connected such that the resulting bridge is selected from —O—CH 2 , —O—CH(CH 3 )—, and —O—CH 2 CH 2 ;
R 5 is selected from H and —CH 3 ;
and Z is selected from S − and O − .
10 . The method of claim 9 , wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.
11 . The method of claim 1 , wherein the compound has the formula:
or a pharmaceutically acceptable salt thereof.
12 . The method of claim 1 , wherein said pharmaceutically acceptable salt is a sodium salt or a potassium salt.
13 . The method of claim 1 , comprising administering to the subject a composition comprising the pharmaceutically acceptable salt of the compound, wherein the composition further comprises a pharmaceutically acceptable diluent or carrier.
14 . The method of claim 1 , wherein the compound or the pharmaceutically acceptable salt thereof is administered by parenteral administration.
15 . The method of claim 1 , wherein the compound or the pharmaceutically acceptable salt thereof is administered by subcutaneous administration.
16 . The method of claim 1 , wherein the administration reduces triglyceride levels in the subject.
17 . The method of claim 1 , wherein the administration increases HDL levels in the subject.
18 . The method of claim 1 , wherein the administration increases chylomicron clearance in the subject, whereby the increase in chylomicron clearance treats, prevents, delays or ameliorates pancreatitis in the subject.
19 . A method of treating hypertriglyceridemia in a subject comprising administering to the subject having hypertriglyceridemia a compound comprising a modified oligonucleotide and a conjugate group, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides, comprises a nucleobase sequence comprising a portion of at least 20 contiguous nucleobases complementary to an equal length portion of nucleobases 3533 to 3552 of SEQ ID NO: 3, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 3, and wherein the modified oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
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; and wherein the conjugate group comprises:
20 . A method of treating familial chylomicronemia syndrome (FCS) in a subject comprising administering to the subject having FCS a compound comprising a modified oligonucleotide and a conjugate group, or a pharmaceutically acceptable salt thereof, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides, comprises a nucleobase sequence comprising a portion of at least 20 contiguous nucleobases complementary to an equal length portion of nucleobases 3533 to 3552 of SEQ ID NO: 3, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 3, and wherein the modified oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
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; and wherein the conjugate group comprises:
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 21, 2025
From: PRAKASH, THAZHA P.; SETH, PUNIT P.; SWAYZE, ERIC E.; GRAHAM, MARK J.
To: ISIS PHARMACEUTICALS, INC.
Reel/Frame 070583/0438 →
CHANGE OF NAME
Recorded Mar 21, 2025
From: ISIS PHARMACEUTICALS, INC.
To: IONIS PHARMACEUTICALS, INC.
Reel/Frame 070588/0710 →
Continuity (13)
Continuation
PCTUS2014036462
· 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
References Cited (400)
US 3687808A
· Merigan et al.
· 1972
[cited by applicant]
US 4469863A
· Ts'o et al.
· 1984
[cited by applicant]
US 4751219A
· Kempen et al.
· 1988
[cited by applicant]
US 4845205A
· Huynh Dinh et al.
· 1989
[cited by applicant]
US 4981957A
· Lableu 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 5134066A
· Rogers 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 5177198A
· Spielvogel et al.
· 1993
[cited by applicant]
US 5185444A
· Summerton et al.
· 1993
[cited by applicant]
US 5223618A
· Cook et al.
· 1993
[cited by applicant]
US 5256775A
· Froehler
· 1993
[cited by applicant]
US 5264562A
· Matteucci
· 1993
[cited by applicant]
US 5264564A
· Matteucci
· 1993
[cited by applicant]
US 5319080A
· Leumann
· 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 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 5457187A
· Gmelner et al.
· 1995
[cited by applicant]
US 5459255A
· Cook et al.
· 1995
[cited by applicant]
US 5466786A
· Buhr 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 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 5519134A
· Acevedo et al.
· 1996
[cited by applicant]
US 5525711A
· Hawkins et al.
· 1996
[cited by applicant]
US 5552540A
· Haralambidis
· 1996
[cited by applicant]
US 5567811A
· Mistura et al.
· 1996
[cited by applicant]
US 5576427A
· Cook et al.
· 1996
[cited by applicant]
US 5587469A
· 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 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 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 5625050A
· Beaton et al.
· 1997
[cited by applicant]
US 5627053A
· Usman 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 5670633A
· Cook 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 5750692A
· Cook et al.
· 1998
[cited by applicant]
US 5763588A
· Matteucci et al.
· 1998
[cited by applicant]
US 5792847A
· Buhr et al.
· 1998
[cited by applicant]
US 5801154A
· Baracchini et al.
· 1998
[cited by applicant]
US 5830653A
· Froehler et al.
· 1998
[cited by applicant]
US 5994517A
· Ts'o et al.
· 1999
[cited by applicant]
US 5998203A
· Matulic-Adamic
· 1999
[cited by applicant]
US 6005096A
· Matteucci et al.
· 1999
[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 6525031B2
· Manoharan
· 2003
[cited by applicant]
US 6525191B1
· Ramasamy
· 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 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 7034133B2
· Wengel et al.
· 2006
[cited by applicant]
US 7053207B2
· Wengel
· 2006
[cited by applicant]
US 7259150B2
· Crooke et al.
· 2007
[cited by applicant]
US 7262177B2
· Ts'o et al.
· 2007
[cited by applicant]
US 7267819B2
· Ferrara et al.
· 2007
[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 7569686B1
· Bhat et al.
· 2009
[cited by applicant]
US 7582744B2
· Manoharan et al.
· 2009
[cited by applicant]
US 7598227B2
· Crooke et al.
· 2009
[cited by applicant]
US 7723509B2
· Manoharan et al.
· 2010
[cited by applicant]
US 7741457B2
· Swayze et al.
· 2010
[cited by applicant]
US 7750141B2
· Crooke et al.
· 2010
[cited by applicant]
US 7851615B2
· Manoharan et al.
· 2010
[cited by applicant]
US 7935796B2
· Lee et al.
· 2011
[cited by applicant]
US 8106022B2
· Manoharan et al.
· 2012
[cited by applicant]
US 8137695B2
· Rozema et al.
· 2012
[cited by applicant]
US 8158601B2
· Chen 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 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 8530439B2
· Crooke et al.
· 2013
[cited by applicant]
US 8530640B2
· Seth et al.
· 2013
[cited by applicant]
US 8541376B2
· Ferrara 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 8653047B2
· Crooke et al.
· 2014
[cited by applicant]
US 8673632B2
· Crooke et al.
· 2014
[cited by applicant]
US 8742075B2
· Lee et al.
· 2014
[cited by applicant]
US 9127276B2
· Prakash et al.
· 2015
[cited by applicant]
US 9157082B2
· Mullick et al.
· 2015
[cited by applicant]
US 9163239B2
· Prakash
· 2015
[cited by examiner]
US 9181550B2
· Prakash et al.
· 2015
[cited by applicant]
US 9365848B2
· Crooke et al.
· 2016
[cited by applicant]
US 9550988B2
· Swayze et al.
· 2017
[cited by applicant]
US 9593333B2
· Alexander et al.
· 2017
[cited by applicant]
US 9624496B2
· Crooke et al.
· 2017
[cited by applicant]
US 9909124B2
· Crooke et al.
· 2018
[cited by applicant]
US 9932581B2
· Prakash et al.
· 2018
[cited by applicant]
US 20010053519A1
· Fodor et al.
· 2001
[cited by applicant]
US 20030017488A1
· Koishi et al.
· 2003
[cited by applicant]
US 20030077829A1
· MacLachlan
· 2003
[cited by applicant]
US 20030119724A1
· Ts'o et al.
· 2003
[cited by applicant]
US 20030170249A1
· Hakomori et al.
· 2003
[cited by applicant]
US 20030228597A1
· Cowsert et al.
· 2003
[cited by applicant]
US 20040171570A1
· Allerson et al.
· 2004
[cited by applicant]
US 20040242516A1
· Crooke et al.
· 2004
[cited by applicant]
US 20050009088A1
· Crooke et al.
· 2005
[cited by applicant]
US 20050130923A1
· Bhat et al.
· 2005
[cited by applicant]
US 20050164235A1
· Manoharan et al.
· 2005
[cited by applicant]
US 20050255487A1
· Khvorova et al.
· 2005
[cited by applicant]
US 20060148740A1
· Platenburg
· 2006
[cited by applicant]
US 20060183886A1
· Tso et al.
· 2006
[cited by applicant]
US 20060264395A1
· Crooke et al.
· 2006
[cited by applicant]
US 20070031844A1
· Khvorova et al.
· 2007
[cited by applicant]
US 20070054856A1
· Gerber 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 20080108801A1
· Manoharan et al.
· 2008
[cited by applicant]
US 20080113351A1
· Nalto et al.
· 2008
[cited by applicant]
US 20080177045A1
· Lee et al.
· 2008
[cited by applicant]
US 20080206869A1
· Smith et al.
· 2008
[cited by applicant]
US 20080255030A1
· Yu 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 20090306180A1
· Bhanot et al.
· 2009
[cited by applicant]
US 20090318536A1
· Freier et al.
· 2009
[cited by applicant]
US 20090326040A1
· Geary et al.
· 2009
[cited by applicant]
US 20100240730A1
· Beigelman et al.
· 2010
[cited by applicant]
US 20100331390A1
· Crooke et al.
· 2010
[cited by applicant]
US 20110039910A1
· Crooke et al.
· 2011
[cited by applicant]
US 20110060030A1
· Crooke et al.
· 2011
[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 20110201798A1
· Manoharan et al.
· 2011
[cited by applicant]
US 20110207799A1
· Rozema et al.
· 2011
[cited by applicant]
US 20110243948A1
· Lee et al.
· 2011
[cited by applicant]
US 20110269814A1
· Manoharan 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 20120122958A1
· Dawson 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 20120270929A1
· Crooke et al.
· 2012
[cited by applicant]
US 20130004427A1
· El-Sayed et al.
· 2013
[cited by applicant]
US 20130017250A1
· Ginsberg et al.
· 2013
[cited by applicant]
US 20130023579A1
· Crooke 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 20130178512A1
· Manoharan et al.
· 2013
[cited by applicant]
US 20130236968A1
· Manoharan et al.
· 2013
[cited by applicant]
US 20130281511A1
· Bettencourt et al.
· 2013
[cited by applicant]
US 20130317085A1
· Crooke et al.
· 2013
[cited by applicant]
US 20140343123A1
· Prakash et al.
· 2014
[cited by applicant]
US 20150057329A1
· Bhanot et al.
· 2015
[cited by applicant]
US 20210395734A1
· Prakash et al.
· 2021
[cited by applicant]
CA 2450022
· 2002
[cited by applicant]
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 WO1998039352
· 1998
[cited by applicant]
WO WO1999014226
· 1999
[cited by applicant]
WO WO2000014048
· 2000
[cited by applicant]
WO WO2000063364
· 2000
[cited by applicant]
WO WO2001005825
· 2001
[cited by applicant]
WO WO2001049687
· 2001
[cited by applicant]
WO WO2002043771
· 2002
[cited by applicant]
WO WO2003004602
· 2003
[cited by applicant]
WO WO2003044172
· 2003
[cited by applicant]
WO WO2004035765
· 2003
[cited by applicant]
WO WO2004024757
· 2004
[cited by applicant]
WO WO2004044181
· 2004
[cited by applicant]
WO WO2004063208
· 2004
[cited by applicant]
WO WO2004093783
· 2004
[cited by applicant]
WO WO2004101619
· 2004
[cited by applicant]
WO WO2004106356
· 2004
[cited by applicant]
WO WO2005000201
· 2005
[cited by applicant]
WO WO2005021570
· 2005
[cited by applicant]
WO WO2005028628
· 2005
[cited by applicant]
WO WO2005097155
· 2005
[cited by applicant]
WO WO2005121371
· 2005
[cited by applicant]
WO WO2006014729
· 2006
[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 WO2007146511
· 2007
[cited by applicant]
WO WO2008073300
· 2008
[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 WO2009134487
· 2009
[cited by applicant]
WO WO2009143369
· 2009
[cited by applicant]
WO WO2010036696
· 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 WO2010083615
· 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 WO2010148013
· 2010
[cited by applicant]
WO WO2011005860
· 2011
[cited by applicant]
WO WO2011005861
· 2011
[cited by applicant]
WO WO2011038356
· 2011
[cited by applicant]
WO WO2011085271
· 2011
[cited by applicant]
WO WO2011100131
· 2011
[cited by applicant]
WO WO2011115818
· 2011
[cited by applicant]
WO WO2011120053
· 2011
[cited by applicant]
WO WO2011123401
· 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 WO2012142458
· 2012
[cited by applicant]
WO WO2012145674
· 2012
[cited by applicant]
WO WO2012145697
· 2012
[cited by applicant]
WO WO2012149495
· 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 WO2013142571
· 2013
[cited by applicant]
WO WO2013165816
· 2013
[cited by applicant]
WO WO2013166121
· 2013
[cited by applicant]
WO WO2013173789
· 2013
[cited by applicant]
WO WO2013177468
· 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 WO2014127268
· 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 WO2014207232
· 2014
[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]
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]
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]
Biessen et al., “Synthesis of Cluster Galactosides with High Affinity for the Hepatic Asialoglycoprotein Receptor” J. Med. Chem. (1995) 38:1538-1546.
[cited by applicant]
Biessen et al., “The Cholesterol Derivative of a Triantennary Galactoside with High Affinity for the Hepatic Asialoglycoprotein Receptor: a Potent Cholesterol Lowering Agent” J. Med. Chem. (1995) 38:1846-1852.
[cited by applicant]
Braasch et al., “Locked nucleic acid (LNA): fine-tuning the recognition of DNA and RNA” Chem. Biol. (2001) 8:1-7.
[cited by applicant]
Braasch et al., “Novel Antisense and Peptide Nucleic Acid Strategies for Controlling Gene Expression” Biochemistry (2002) 41(14): 4503-4510.
[cited by applicant]
Branda et al., “Amplification of antibody production by phosphorothioate oligodeoxynucleotides” J Lab Clin Med. (1996) 128(3): 329-338.
[cited by applicant]
Coltart et al., “Principles of Mucin Architecture: Structural Studies on Synthetic Glycopeptides Bearing Clustered Mono-, Di-, Tri-, and Hexasaccharide Glycodomains” J. Am. Chem. Soc. (2002) 124: 9833-9844.
[cited by applicant]
Connolly et al., “Binding and Endocytosis of Cluster Glycosides by Rabbit Hepatocytes” J Biol Chem (1982) 257: 939-945.
[cited by applicant]
Crooke et al., “Pharmacokinetic Properties of Several Novel Oligonucleotide Analogs in mice” J. Pharmacol. Exp. Ther. (1996) 277(2):923-937.
[cited by applicant]
Crooke et al., “Pharmacological Properties of 2′-O-Methoxyethyl Modified Oligonucleotides” in Antisense a Drug Technology, Chapter 10, pp. 273-303, Crooke, S.T., ed., 2008.
[cited by applicant]
Crooke et al., “Toxicologic Properties of 2-O-Methoxyethyl Chimeric Antisense Inhibitors in Animals and Man” in Antisense a Drug Technology, Chapter 12, pp. 342-351, Crooke, S.T., ed., 2008.
[cited by applicant]
Czech et al. “RNAi-based therapeutic strategies for metabolic disease” Nature Reviews Endocrinology (2011) 7: 473-484.
[cited by applicant]
Davidson et al., “Apolipoprotein B: mRNA Editing, Lipoprotein Assembly, and Presecretory Degradation” Annu. Rev. Nutr. (2000) 20: 169-193.
[cited by applicant]
Dellinger et al., “Solid-Phase Chemical Synthesis of Phosphonoacetate and Thiophosphonoacetate Oligodeoxynucleotides” J. Am .Chem. Soc. (2003) 125: 940-950.
[cited by applicant]
Duff et al., “Intrabody Tissue-Specific Delivery of Antisense Conjugates in Animals: Ligand-Linker-Antisense Oligomer Conjugates” Methods in Enzymology (1999) 313: 297-321.
[cited by applicant]
Dupouy et al., “Watson—Crick Base-Pairing Properties of Nucleic Acid Analogues with Stereocontrolled a and b Torsion Angles (a,b-D-CNAs)” Angew. Chem. Int. Ed. (2006) 45: 3623-3627.
[cited by applicant]
Elayadi et al., “Application of PNA and LNA oligomers to chemotherapy” Curr. Opinion Invens. Drugs (2001) 2:558-561.
[cited by applicant]
Englisch et al., “Chemically Modified Oligonucleotides as Probes and Inhibitors” Agnew Chem. Int. Ed. Engl. (1991) 30:613-629.
[cited by applicant]
Freier et al., “The ups and downs of nucleic acid duplex stability: structure-stability studies on chemically-modified DNA:RNA duplexes” Nucleic Acids Research (1997) 25(22):4429-4443.
[cited by applicant]
Frieden et al., “Expanding the design horizon of antisense oligonucleotides with alpha-L-LNA” Nucleic Acids Research (2003) 31(21):6365-6372.
[cited by applicant]
Geary et al., “Pharmacokinetic Properties of 2′-O-(2-Methoxyethyl)-Modified Oligonucleotide Analogs in Rats” The Journal of Pharmacology and Experimental Therapeutics (2001) 296:890-897.
[cited by applicant]
Hoffman et al., “‘Brain-type’ N-glycosylation of asialo-transferrin from human cerebrospinal fluid” FEBS Letters (1995) 359: 164-168.
[cited by applicant]
Horn et al., “Chemical synthesis and characterization of branched oligodeoxyribonucleotides (bDNA) for use as signal amplifiers in nucleic acid quantification assays.” Nucleic Acids Research (1997) 25: 4842-4849.
[cited by applicant]
International Search Report for Application PCT/US12/52884 dated Nov. 20, 2012.
[cited by applicant]
International Search Report for Application PCT/US14/36460 dated Oct. 10, 2014.
[cited by applicant]
International Search Report for Application PCT/US14/36462 dated Dec. 23, 2014.
[cited by applicant]
International Search Report for Application PCT/US14/36463 dated Dec. 30, 2014.
[cited by applicant]
International Search Report for Application PCT/US14/36466 dated Dec. 1, 2014.
[cited by applicant]
International Search Report for Application PCT/US14/43731 dated Dec. 10, 2014.
[cited by applicant]
International Search Report for Application PCT/US14/56630 dated Dec. 24, 2014.
[cited by applicant]
Jayaprakash et al., “Non-Nucleoside Building Blocks for Copper-Assisted and Copper-Free Click Chemistry for the Efficient Synthesis of RNA Conjugates” Organic Letters (2010) 12(23): 5410-5413.
[cited by applicant]
Jiang et al., “The Design and Synthesis of Highly Branched and Spherically Symmetric Fluorinated Oils and Amphiles.” Tetrahedron (2007) 63(19): 3982-3988.
[cited by applicant]
Jin et al., “Use of α-N,N-bis[Carboxymethyl]lysine-Modified Peroxidase in Immunoassays” Analytical Biochemistry (1995) 229: 54-60.
[cited by applicant]
Kanasty et al., “Delivery Materials for siRNA Therapeutics” Nature Materials (2013) 12: 967-977.
[cited by applicant]
Kassim et al., “Gene therapy for dyslipidemia: a review of gene replacement and gene inhibition strategies” Clinical Lipidology (2010) 5(6): 793-809.
[cited by applicant]
Kato et al., “N-acetylgalactosamine incorporation into a peptide containing consecutive threonine residues by UDP-N-acetyl-D-galactosaminide:polypeptide N-acetylgalactosaminyltransferases” Glyobiology (2001) 11: 821-829.
[cited by applicant]
Khorev et al., “Trivalent, Gal/GalNAc-containing ligands designed for the asialoglycoprotein receptor” Bioorganic & Medicinal Chemistry (2008) 16: 5216-5231.
[cited by applicant]
Kim et al., “Oligomeric Glycopeptidomimetics Bearing the Cancer Related TN-Antigen” Tetrahedron Letters (1997) 38(20): 3487-3490.
[cited by applicant]
Kim et al., “Synthesis of Novel Phosphoramidite Building Blocks from Pentaerythritol” Synlett (2003) 12: 1838-1840.
[cited by applicant]
Koller et al., “Mechanisms of single-stranded phosphorothioate modified antisense oligonucleotide accumulation in hepatocytes.” Nucleic Acids Res. (2011) 39(11): 4795-4807.
[cited by applicant]
Kornilova et al., “Development of a fluorescence polarization binding assay for asialoglycoprotein receptor” Analytical Biochemistry (2012) 425: 43-46.
[cited by applicant]
Koshkin et al., “LNA (locked nucleic acids): Synthesis of the adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil bicyclonucleoside monomers, oligomerisation, and unprecedented nucleic acid recognition” Tet…
[cited by applicant]
Kroschwitz, “Polynucleotides” Concise Encyclopedia of Polymer Science and Engineering (1990) John Wiley & Sons, NY pp. 858-859.
[cited by applicant]
Kumar et al., “The first analogues of LNA (locked nucleic acids): phosphorothioate-LNA and 2′-thio-LNA” Bioorg Med Chem Lett. (1998) 8:2219-2222.
[cited by applicant]
Lazaris-Karatzas et al., “Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′ cap” Nature (1990) 345: 544-547.
[cited by applicant]
Lee et al., “Antisense Technology: An Emerging Platform for Cardiovascular Disease Therapeutics” J of Cardiovasc Trans Res (2013) 6: 969-980.
[cited by applicant]
Lee et al., “Facile Synthesis of a High-Affinity Ligand for Mammalian Hepatic Lectin Containing Three Terminal N-Acetylgalactosamine Residues” Bioconjugate Chem. (1997) 8: 762-765.
[cited by applicant]
Lee et al., “New and more efficient multivalent glyco-ligands for asialoglycoprotein receptor of mammalian hepatocytes” Bioorganic & Medicinal Chemistry (2011) 19:2494-2500.
[cited by applicant]
Lee et al., “New synthetic cluster ligands for galactose/N-acetylgalactosamine-specific lectin of mammalian liver” Biochem (1984) 23: 4255-4261.
[cited by applicant]
Lee et al., “Preparation of Cluster Glycosides of Nacetylgalactosamine That Have Subnanomolar Binding Constants Towards the Mammalian Hepatic Gal/GalNAc-specific Receptor” Glycoconjugate J. (1987) 4: 317-328.
[cited by applicant]
Lee et al., “Protein microarrays to study carbohydrate-recognition events” Bioorg Med Chem Lett (2006) 16(19): 5132-5135.
[cited by applicant]
Lee et al., “Synthesis of multivalent neoglyconjugates of MUC1 by the conjugation of carbohydrate-centered, triazole-linked glycoclusters to MUC1 peptides using click chemistry.” J Org Chem (2012) 77: 7564-7571.
[cited by applicant]
Lee et al., “Synthesis of Peptide-Based Trivalent Scaffold for Preparation of Cluster Glycosides” Methods in Enzymology (2003) 362: 38-43.
[cited by applicant]
Lee et al., “Synthesis of some cluster glycosides suitable for attachment to proteins or solid matrices” Carbohydrate Research (1978) 67: 509-514.
[cited by applicant]
Letsinger et al., “Cholesteryl-conjugated oligonucleotides: Synthesis, properties, and activity as inhibitors of replication of human immunodeficiency virus in cell culture” PNAS (1989) 86:6553-6556.
[cited by applicant]
Leumann et al., “DNA Analogues: From Supramolecular Principles to Biological Properties” Bioorganic & Medicinal Chemistry (2002) 10:841-854.
[cited by applicant]
Link, “Pharmacological regulation of hepatic glucose production” Curr Opin Investig Drugs (2003) 4: 421-429.
[cited by applicant]
Maier et al., “Synthesis of Antisense Oligonucleotides Conjugated to a Multivalent Carbohydrate Cluster for Cellular Targeting” Bioconjugate Chem. (2003) 14: 18-29.
[cited by applicant]
Maierhofer et al., “Probing multivalent carbohydrate—lectin interactions by an enzyme-linked lectin assay employing covalently immobilized carbohydrates” Bioorganic & Medicinal Chemistry (2007) 15: 7661-7676.
[cited by applicant]
Manoharan et al., “Chemical Modifications to Improve Uptake and Bioavailability of Antisense Oligonucleotides” Ann. N.Y. Acad. Sci. (1992) 660: 306-309.
[cited by applicant]
Manoharan et al., “Cholic Acid-Oligonucleotide Conjugates for Antisense Applications” Bioorg. Med. Chem. Lett. (1994) 4:1053-1060.
[cited by applicant]
Manoharan et al., “Introduction of a Lipophilic Thioether Tether in the Minor Groove of Nucleic Acids for Antisense Applications” Bioorg. Med. Chem. Lett. (1993) 3(12):2765-2770.
[cited by applicant]
Manoharan et al., “Lipidic Nucleic Acids” Tetrahedron Lett. (1995) 36(21):3651-3654.
[cited by applicant]
Manoharan et al., “N-(2-Cyanoethoxycarbonyloxy)succinimide: A New Reagent for Protection of Amino Groups in Oligonucleotides” J. Org. Chem. (1999) 64: 6468-6472.
[cited by applicant]
Manoharan et al., “Oligonucleotide Conjugates: Alteration of the Pharmacokinetic Properties of Antisense Agents” Nucleosides & Nucleotides (1995) 14(3-5):969-973.
[cited by applicant]
Manoharan, “Oligonucleotide Conjugates as Potential Antisense Drugs with Improved Uptake, Biodistribution, Targeted Delivery, and Mechanism of Action” Antisense & Nucleic Acid Drug Development (2002) 12: 103-128.
[cited by applicant]
Marcaurelle et al., “Synthesis of Oxime-Linked Mucin Mimics Containing the Tumor-Related TN and Sialyl TN Antigens” Organic Letters (2001) 3(23): 3691-3694.
[cited by applicant]
Merwin et al., “Targeted delivery of DNA using YEE(GalNAcAH)3, a synthetic glycopeptide ligand for the asialoglycoprotein receptor.” Bioconjug Chem (1994) 5(6): 612-620.
[cited by applicant]
Mishra et al., “Improved leishmanicidal effect of phosphorotioate antisense oligonucleotides by LDL-mediated delivery” Biochim. Biophys. Acta (1995) 1264:229-237.
[cited by applicant]
Miura et al., “Fluorometric determination of total mRNA with oligo(dT) immobilized on microtiter plates” Clin. Chem. (1996) 42:1758-1764.
[cited by applicant]
Oberhauser et al., “Effective incorporation of 2′-O-methyl-oligoribonucleotides into liposomes and enhanced cell association through modifications with thiocholesterol” Nucl. Acids Res. (1992) 20(3):533-538.
[cited by applicant]
Orum et al., “Locked nucleic acids: A promising molecular family for gene-function analysis and antisense drug development” Curr. Opinion Mol. Ther. (2001) 3:239-243.
[cited by applicant]
Park et al., “The asialoglycoprotein receptor clears glycoconjugates terminating with sialic acid a2,6GalNAc” PNAS (2005) 102(47): 17125-17129.
[cited by applicant]
Pavia et al., “Synthetic TN glycopeptide related to human glycophorin AM. High-field proton and carbon-13 nuclear magnetic resonance study.” Int J Pep Protein Res (1983) 22: 539-548.
[cited by applicant]
Petrova et al., “Carrier-free cellular uptake and the gene-silencing activity of the lipophilic siRNAs is strongly affected by the length of the linker between siRNA and lipophilic group” Nucleic Acids Research (2012) 4…
[cited by applicant]
Pujol et al., “A Sulfur Tripod Glycoconjugate that Releases a High-Affinity Copper Chelator in Hepatocytes” Angew. Chem. Int. Ed. (2012) 51: 7445-7448.
[cited by applicant]
Rajur et al., “Covalent Protein-Oligonucleotide Conjugates for Efficient Delivery of Antisense Molecules” Bioconjugate Chem. (1997) 8: 935-940.
[cited by applicant]
Raouane et al., “Synthesis, Characterization, and in Vivo Delivery of siRNA-Squalene Nanoparticles Targeting Fusion Oncogene in Papillary Thyroid Carcinoma” J. Med. Chem. (2011) 54: 4067-4076.
[cited by applicant]
Rensen et al., “Design and Synthesis of Novel N-Acetylgalactosamine-Terminated Glycolipids for Targeting of Lipoproteins to the Hepatic Asialoglycoprotein Receptor” J. Med. Chem. (2004) 47:5798-5808.
[cited by applicant]
Rensen et al., “Determination of the Upper Size Limit for Uptake and Processing of Ligands by the Asialoglycoprotein Receptor on Hepatocytes in Vitro and in Vivo” J. Biol. Chem. (2001) 276(40):37577-37584.
[cited by applicant]
Rensen et al., “Stimulation of Liver-Directed Cholesterol Flux in Mice by Novel N-Acetylgalactosamine-Terminated Glycolipids With High Affinity for the Asialoglycoprotein Receptor” Arterioscler Thromb Vasc Biol (2006) 2…
[cited by applicant]
Rossenberg et al., “Stable polyplexes based on arginine-containing oligopeptides for in vivo gene delivery” Gene Therapy (2004) 11: 457-464.
[cited by applicant]
Rouchaud et al., “A New and Efficient Synthesis of Derivatives of Octahydro-4H-pyrrolo[1,2-c]pyrido[1′,2′-a]imidazole” Eur. J. Org. Chem. (2011) 12: 2346-2353.
[cited by applicant]
Sanghvi, Chapter 15, Antisense Research and Applications, Crooke and Lebleu ed., CRC Press (1993).
[cited by applicant]
Sato et al., “Glycoinsulins: Dendritic Sialyloligosaccharide-Displaying Insulins Showing a Prolonged Blood-Sugar-Lowering Activity” J. Am. Chem. Soc. (2004) 126: 14013-14022.
[cited by applicant]
Seth et al., “Design, Synthesis And Evaluation Of Constrained Methoxyethyl (cMOE) and Constrained Ethyl (cEt) Nucleoside Analogs” Nucleic Acids Symposium Series (2008) 52(1): 553-554.
[cited by applicant]
Seth et al., “Synthesis and biophysical characterization of R-6′-Me-α-L-LNA modified oligonucleotides.” Bioorg. Med. Chem. (2011) 21(4): 1122-1125.
[cited by applicant]
Seth et al., “Synthesis and Biophysical Evaluation of 2′,4′-Constrained 2′O-Methoxyethyl and 2′,4′-Constrained 2′O-Ethyl Nucleic Acid Analogues” J Org Chem. (2010) 75(5): 1569-1581.
[cited by applicant]
Shchepinov et al., “Oligonucleotide dendrimers: stable nano-structures” Nucleic Acids Research (1999) 27(15): 3035-3041.
[cited by applicant]