IP Library › Granted Patent US 12,365,894
Granted Patent B2
US 12,365,894 · App. 17/022,678 · Granted Jul 22, 2025

Branched lipid conjugates of siRNA for specific tissue delivery

Inventors: Anastasia Khvorova (Westborough, MA); Annabelle Biscans (Cambridge, MA)
Assignee: UNIVERSITY OF MASSACHUSETTS
C12N15/113A61K31/713C12N2310/315C12N2310/321C12N2310/322C12N2310/3515
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Quick Facts
Patent No.
US 12,365,894
App. No.
17/022,678
Granted
Jul 22, 2025
Kind
B2
Abstract

This disclosure relates to an siRNA-lipid conjugate of formula Y-L-(H) n . Y is an siRNA molecule, L is a linker covalently bonded to Y and H, each H is independently a hydrophobic chain comprising 5 to 50 carbon atoms, n is 1, 2, or 3, and linker L is bonded to the 3′ end of the sense strand of the siRNA.

Claims (29)

1. An siRNA-lipid conjugate represented by the following formula:

Y-L-(H) 2

wherein:

Y is an siRNA molecule comprising a sense strand and an antisense strand,

L is a linker, and Y-L comprise the structure:

wherein each m and n comprises 1, 2, 3, 4, or 5,

each H is independently a hydrophobic chain comprising 5 to 50 carbon atoms, and

linker L is bonded to the 3′ end of the sense strand of the siRNA.

2. The siRNA-lipid conjugate according to claim 1 , wherein the hydrophobic chain of at least one H is a linear or branched aliphatic chain comprising 10 to 30 carbon atoms.

3. The siRNA-lipid conjugate according to claim 1 , wherein the hydrophobic chain of at least one H is derived from a linear or branched fatty acid and the carbonyl group of the fatty acid is attached to the linker by an amide bond.

4. The siRNA-lipid conjugate according to claim 3 , wherein the fatty acid is selected from the group consisting of myristic, docosahexaenoic, and eicosapentaenoic.

5. The siRNA-lipid conjugate according to claim 1 , wherein each H is independently an aliphatic chain comprising 12 to 26 carbon atoms.

6. The siRNA-lipid conjugate according to claim 1 , wherein each H is a branched chain comprising 24 to 48 carbon atoms.

7. The siRNA-lipid conjugate according to claim 1 , wherein the linker is attached to an H by a bond selected from the group consisting of an ester bond, an amide bond, an ether bond, a thioether bond, a nitrogen-carbon covalent bond, and combinations thereof.

8. The siRNA-lipid conjugate according to claim 1 , wherein the linker L is covalently bonded to Y and each H.

9. The siRNA-lipid conjugate according to claim 1 , wherein said siRNA comprises at least one modified nucleotide.

10. The siRNA-lipid conjugate according to claim 9 , wherein said modified nucleotide comprises a 2′-O-methyl modified nucleotide, a 2′-deoxy-2′-fluoro modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, or a terminal nucleotide linked to an E-vinylphosphate group.

11. The siRNA-lipid conjugate according to claim 9 , wherein said modified nucleotide comprises a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, or a non-natural base comprising nucleotide.

12. The siRNA-lipid conjugate according to claim 1 , wherein the siRNA comprises at least one 2′-O-methyl modified nucleotide, at least one 2′-deoxy-2′-fluoro modified nucleotide, and at least one nucleotide comprising a 5′-phosphorothioate group.

13. The siRNA-lipid conjugate according to claim 1 , wherein at least 80% of the nucleotides of the siRNA are chemically modified.

14. The siRNA-lipid conjugate according to claim 1 , wherein all the nucleotides of the siRNA are chemically modified.

15. The siRNA-lipid conjugate according to claim 1 , wherein:

(1) the sense strand of the siRNA molecule comprises alternating 2′-methoxy-ribonucleotides and 2′-fluoro-ribonucleotides;

(2) the antisense strand of the siRNA molecule comprises alternating 2′-methoxy-ribonucleotides and 2′-fluoro-ribonucleotides;

(3) the nucleotides of the sense strand are connected via phosphodiester or phosphorothioate linkages; and

(4) the nucleotides of the antisense strand are connected via phosphodiester or phosphorothioate linkages.

16. A pharmaceutical composition for inhibiting the expression of a gene in an organism, comprising

the siRNA-lipid conjugate according to claim 1 and a pharmaceutically acceptable carrier.

17. The siRNA-lipid conjugate according to claim 1 , wherein n and m are 1.

Assignments (3)
CONFIRMATORY ASSIGNMENT Recorded Mar 15, 2024
From: KHVOROVA, ANASTASIA; BISCANS, ANNABELLE
To: UNIVERSITY OF MASSACHUSETTS
Reel/Frame 066800/0085 →
CONFIRMATORY LICENSE Recorded Jan 19, 2024
From: UNIVERSITY OF MASSACHUSETTS CHAN MEDICAL SCHOOL
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 066356/0237 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 21, 2021
From: KHVOROVA, ANASTASIA; BISCANS, ANNABELLE
To: UNIVERSITY OF MASSACHUSETTS
Reel/Frame 055984/0080 →
Continuity (2)
Provisional Application 62900971 · Sep 16, 2019
Related Publication 20210108200A1 · Apr 15, 2021
References Cited (400)
US 4522811A · Eppstein et al. · 1985 [cited by applicant]
US 5194596A · Tischer et al. · 1993 [cited by applicant]
US 5219739A · Tischer et al. · 1993 [cited by applicant]
US 5240848A · Keck et al. · 1993 [cited by applicant]
US 5328470A · Nabel et al. · 1994 [cited by applicant]
US 5332671A · Ferrara et al. · 1994 [cited by applicant]
US 5684143A · Grayaznov et al. · 1997 [cited by applicant]
US 5814014A · Elsberry et al. · 1998 [cited by applicant]
US 5858988A · Wang · 1999 [cited by applicant]
US 5939402A · Weis et al. · 1999 [cited by applicant]
US 6025335A · Weis et al. · 2000 [cited by applicant]
US 6093180A · Elsberry et al. · 2000 [cited by applicant]
US 6107094A · Crooke · 2000 [cited by applicant]
US 6168587B1 · Bellhouse et al. · 2001 [cited by applicant]
US 6177403B1 · Stedman · 2001 [cited by applicant]
US 6194389B1 · Johnston et al. · 2001 [cited by applicant]
US 6291438B1 · Wang · 2001 [cited by applicant]
US 6312900B1 · Dean et al. · 2001 [cited by applicant]
US 6383814B1 · Lee et al. · 2002 [cited by applicant]
US 6447768B1 · van Zonneveld et al. · 2002 [cited by applicant]
US 6471996B1 · Sokoll et al. · 2002 [cited by applicant]
US 6472375B1 · Hoon et al. · 2002 [cited by applicant]
US 6489464B1 · Agrawal et al. · 2002 [cited by applicant]
US 7250496B2 · Bentwich · 2007 [cited by applicant]
US 7459547B2 · Zamore et al. · 2008 [cited by applicant]
US 7691997B2 · Khvorova et al. · 2010 [cited by applicant]
US 7723512B2 · Manoharan et al. · 2010 [cited by applicant]
US 7732593B2 · Zamore et al. · 2010 [cited by applicant]
US 7750144B2 · Zamore et al. · 2010 [cited by applicant]
US 7772203B2 · Zamore et al. · 2010 [cited by applicant]
US 7790867B2 · Bentwich · 2010 [cited by applicant]
US 7820809B2 · Khvorova et al. · 2010 [cited by applicant]
US 7834171B2 · Leake et al. · 2010 [cited by applicant]
US 8013136B2 · Manoharan et al. · 2011 [cited by applicant]
US 8097752B2 · Calogeropolou et al. · 2012 [cited by applicant]
US 8304530B2 · Zamore et al. · 2012 [cited by applicant]
US 8309704B2 · Zamore et al. · 2012 [cited by applicant]
US 8309705B2 · Zamore et al. · 2012 [cited by applicant]
US 8329892B2 · Zamore et al. · 2012 [cited by applicant]
US 8431544B1 · Agrawal et al. · 2013 [cited by applicant]
US 8501706B2 · Yamada et al. · 2013 [cited by applicant]
US 8507661B2 · Manoharan et al. · 2013 [cited by applicant]
US 8664189B2 · Khvorova et al. · 2014 [cited by applicant]
US 8703731B2 · Jimenez et al. · 2014 [cited by applicant]
US 8796443B2 · Khvorova et al. · 2014 [cited by applicant]
US 8815818B2 · Samarsky et al. · 2014 [cited by applicant]
US 8871774B2 · Charifson et al. · 2014 [cited by applicant]
US 8877439B2 · Butora et al. · 2014 [cited by applicant]
US 8906874B2 · Rao et al. · 2014 [cited by applicant]
US 8993738B2 · Prakash et al. · 2015 [cited by applicant]
US 9029389B2 · No et al. · 2015 [cited by applicant]
US 9074211B2 · Woolf et al. · 2015 [cited by applicant]
US 9080171B2 · Khvorova et al. · 2015 [cited by applicant]
US 9095504B2 · Libertine et al. · 2015 [cited by applicant]
US 9175289B2 · Khvorova et al. · 2015 [cited by applicant]
US 9198981B2 · Ambati et al. · 2015 [cited by applicant]
US 9303259B2 · Khvorova et al. · 2016 [cited by applicant]
US 9340786B2 · Khvorova et al. · 2016 [cited by applicant]
US 9493774B2 · Kamens et al. · 2016 [cited by applicant]
US 9745574B2 · Woolf et al. · 2017 [cited by applicant]
US 9796756B2 · Hadwiger et al. · 2017 [cited by applicant]
US 9809817B2 · Khvorova · 2017 [cited by examiner]
US 9862350B2 · Guerrero et al. · 2018 [cited by applicant]
US 9862952B2 · Khvorova et al. · 2018 [cited by applicant]
US 9867882B2 · Manoharan et al. · 2018 [cited by applicant]
US 10087210B2 · Prakash et al. · 2018 [cited by applicant]
US 10435688B2 · Khvorova et al. · 2019 [cited by applicant]
US 10478503B2 · Khvorova et al. · 2019 [cited by applicant]
US 10479992B2 · Woolf et al. · 2019 [cited by applicant]
US 10519451B2 · Khvorova et al. · 2019 [cited by applicant]
US 10633653B2 · Khvorova et al. · 2020 [cited by applicant]
US 10774327B2 · Khvorova et al. · 2020 [cited by applicant]
US 10799591B2 · Khvorova et al. · 2020 [cited by applicant]
US 10844377B2 · Khvorova et al. · 2020 [cited by applicant]
US 11230713B2 · Khvorova et al. · 2022 [cited by applicant]
US 11279930B2 · Khvorova et al. · 2022 [cited by applicant]
US 11345917B2 · Khvorova et al. · 2022 [cited by applicant]
US 11492619B2 · Khvorova et al. · 2022 [cited by applicant]
US 11667915B2 · Woolf et al. · 2023 [cited by applicant]
US 11702659B2 · Khvorova et al. · 2023 [cited by applicant]
US 11753638B2 · Khvorova et al. · 2023 [cited by applicant]
US 11827882B2 · Khvorova et al. · 2023 [cited by applicant]
US 11896669B2 · Khvorova et al. · 2024 [cited by applicant]
US 20010027251A1 · Cook et al. · 2001 [cited by applicant]
US 20030045705A1 · Cook · 2003 [cited by applicant]
US 20030143732A1 · Fosnaugh et al. · 2003 [cited by applicant]
US 20040121426A1 · Hsieh · 2004 [cited by applicant]
US 20040198640A1 · Leake et al. · 2004 [cited by applicant]
US 20040205839A1 · Doutriaux et al. · 2004 [cited by applicant]
US 20050096284A1 · McSwiggen · 2005 [cited by applicant]
US 20050220766A1 · Amalfitano et al. · 2005 [cited by applicant]
US 20050255487A1 · Khvorova et al. · 2005 [cited by applicant]
US 20060009409A1 · Woolf · 2006 [cited by applicant]
US 20060024715A1 · Liu et al. · 2006 [cited by applicant]
US 20060078542A1 · Mah et al. · 2006 [cited by applicant]
US 20060094032A1 · Fougerolles et al. · 2006 [cited by applicant]
US 20060105998A1 · Calogeropoulou et al. · 2006 [cited by applicant]
US 20070004664A1 · McSwiggen et al. · 2007 [cited by applicant]
US 20070004665A1 · McSwiggen et al. · 2007 [cited by applicant]
US 20070099860A1 · Sah et al. · 2007 [cited by applicant]
US 20070135372A1 · MacLachlan et al. · 2007 [cited by applicant]
US 20070160534A1 · Dennis et al. · 2007 [cited by applicant]
US 20070191273A1 · Ambat et al. · 2007 [cited by applicant]
US 20070259827A1 · Aronin et al. · 2007 [cited by applicant]
US 20080039415A1 · Stewart et al. · 2008 [cited by applicant]
US 20080108583A1 · Feinstein · 2008 [cited by applicant]
US 20080108801A1 · Manoharan · 2008 [cited by applicant]
US 20080119427A1 · Bhat et al. · 2008 [cited by applicant]
US 20080188429A1 · Iyer · 2008 [cited by applicant]
US 20080269149A1 · Bowles et al. · 2008 [cited by applicant]
US 20090143322A1 · Burkoth et al. · 2009 [cited by applicant]
US 20090234109A1 · Han et al. · 2009 [cited by applicant]
US 20090281299A1 · Manorahan et al. · 2009 [cited by applicant]
US 20090306178A1 · Bhat et al. · 2009 [cited by applicant]
US 20090318676A1 · Manoharan et al. · 2009 [cited by applicant]
US 20100015706A1 · Quay et al. · 2010 [cited by applicant]
US 20100093085A1 · Yamada et al. · 2010 [cited by applicant]
US 20100184209A1 · Vermeulen et al. · 2010 [cited by applicant]
US 20100186103A1 · Gao et al. · 2010 [cited by applicant]
US 20100240730A1 · Beigelman et al. · 2010 [cited by applicant]
US 20110039914A1 · Pavco et al. · 2011 [cited by applicant]
US 20110046206A1 · Bhat et al. · 2011 [cited by applicant]
US 20110086905A1 · Glazer · 2011 [cited by applicant]
US 20110097716A1 · Natt et al. · 2011 [cited by applicant]
US 20110201006A1 · Roehl et al. · 2011 [cited by applicant]
US 20110237522A1 · Khvorova et al. · 2011 [cited by applicant]
US 20110237648A1 · Khvorova et al. · 2011 [cited by applicant]
US 20110251258A1 · Samarsky et al. · 2011 [cited by applicant]
US 20110263680A1 · Khvorova et al. · 2011 [cited by applicant]
US 20120016005A1 · Samarsky et al. · 2012 [cited by applicant]
US 20120040459A1 · Khvorova et al. · 2012 [cited by applicant]
US 20120052487A9 · Khvorova et al. · 2012 [cited by applicant]
US 20120059046A1 · Woolf et al. · 2012 [cited by applicant]
US 20120065243A1 · Woolf et al. · 2012 [cited by applicant]
US 20120136039A1 · Aronin et al. · 2012 [cited by applicant]
US 20130065298A1 · Davidson et al. · 2013 [cited by applicant]
US 20130131141A1 · Khvorova et al. · 2013 [cited by applicant]
US 20130131142A1 · Libertine et al. · 2013 [cited by applicant]
US 20130178513A1 · Dobie et al. · 2013 [cited by applicant]
US 20130196434A1 · Maier et al. · 2013 [cited by applicant]
US 20130197055A1 · Kamens et al. · 2013 [cited by applicant]
US 20130345218A1 · Charifson et al. · 2013 [cited by applicant]
US 20140005192A1 · Charifson et al. · 2014 [cited by applicant]
US 20140005197A1 · Charifson et al. · 2014 [cited by applicant]
US 20140113950A1 · Khvorova et al. · 2014 [cited by applicant]
US 20140155387A1 · No et al. · 2014 [cited by applicant]
US 20140288148A1 · Biegelman et al. · 2014 [cited by applicant]
US 20140296486A1 · Gao et al. · 2014 [cited by applicant]
US 20140315974A1 · Khvorova et al. · 2014 [cited by applicant]
US 20140364482A1 · Khvorova et al. · 2014 [cited by applicant]
US 20150025122A1 · Smith · 2015 [cited by applicant]
US 20150190525A1 · Tatro · 2015 [cited by applicant]
US 20150209441A1 · Carell · 2015 [cited by applicant]
US 20150232840A1 · Aronin et al. · 2015 [cited by applicant]
US 20150247142A1 · Esau et al. · 2015 [cited by applicant]
US 20150267200A1 · McSwiggen et al. · 2015 [cited by applicant]
US 20150315584A1 · Macdonald et al. · 2015 [cited by applicant]
US 20160017323A1 · Prakash et al. · 2016 [cited by applicant]
US 20160115482A1 · Libertine et al. · 2016 [cited by applicant]
US 20160115484A1 · Woolf et al. · 2016 [cited by applicant]
US 20160130578A1 · Khvorova et al. · 2016 [cited by applicant]
US 20160130583A1 · Yokota et al. · 2016 [cited by applicant]
US 20160244765A1 · Khvorova et al. · 2016 [cited by applicant]
US 20160281148A1 · Greenlee et al. · 2016 [cited by applicant]
US 20160319278A1 · Khvorova et al. · 2016 [cited by applicant]
US 20160355808A1 · Khvorova et al. · 2016 [cited by applicant]
US 20160355826A1 · Khvorova et al. · 2016 [cited by applicant]
US 20160376598A1 · Lee et al. · 2016 [cited by applicant]
US 20170009239A1 · Khvorova et al. · 2017 [cited by applicant]
US 20170009304A1 · Zhou · 2017 [cited by applicant]
US 20170037456A1 · Kokoris et al. · 2017 [cited by applicant]
US 20170043024A1 · Khvorova et al. · 2017 [cited by applicant]
US 20170043204A1 · James · 2017 [cited by applicant]
US 20170051283A1 · Khvorova · 2017 [cited by applicant]
US 20170051286A1 · Smith · 2017 [cited by applicant]
US 20170067056A1 · Khvorova et al. · 2017 [cited by applicant]
US 20170183655A1 · Grabcysk et al. · 2017 [cited by applicant]
US 20170189541A1 · Foster · 2017 [cited by applicant]
US 20170281795A1 · Geall · 2017 [cited by applicant]
US 20170312367A1 · Khvorova et al. · 2017 [cited by applicant]
US 20170327524A1 · Nanna et al. · 2017 [cited by applicant]
US 20170369882A1 · Khvorova et al. · 2017 [cited by applicant]
US 20180023082A1 · Stanek et al. · 2018 [cited by applicant]
US 20180087052A1 · Hung et al. · 2018 [cited by applicant]
US 20180094263A1 · Khvorova et al. · 2018 [cited by applicant]
US 20180179546A1 · Khvorova et al. · 2018 [cited by applicant]
US 20180251764A1 · Albaek et al. · 2018 [cited by applicant]
US 20180264105A1 · Kugimiya · 2018 [cited by examiner]
US 20190002880A1 · Woolf et al. · 2019 [cited by applicant]
US 20190024082A1 · Khvorova et al. · 2019 [cited by applicant]
US 20190144860A1 · Konstantinova et al. · 2019 [cited by applicant]
US 20190185855A1 · Khvorova et al. · 2019 [cited by applicant]
US 20190225965A1 · Khvorova et al. · 2019 [cited by applicant]
US 20190247507A1 · Khvorova et al. · 2019 [cited by applicant]
US 20200087663A1 · Aronin · 2020 [cited by applicant]
US 20200095580A1 · Hauptmann et al. · 2020 [cited by applicant]
US 20200123543A1 · Khvorova et al. · 2020 [cited by applicant]
US 20200165618A1 · Khvorova et al. · 2020 [cited by applicant]
US 20200270605A1 · Khvorova et al. · 2020 [cited by applicant]
US 20200308578A1 · Woolf et al. · 2020 [cited by applicant]
US 20200308584A1 · Khvorova et al. · 2020 [cited by applicant]
US 20200339983A1 · Khvorova et al. · 2020 [cited by applicant]
US 20200362341A1 · Khvorova · 2020 [cited by applicant]
US 20200385737A1 · Khvorova · 2020 [cited by applicant]
US 20210024926A1 · Khvorova et al. · 2021 [cited by applicant]
US 20210071117A9 · Khvorova et al. · 2021 [cited by applicant]
US 20210071177A1 · Khvorova · 2021 [cited by applicant]
US 20210085793A1 · Khvorova et al. · 2021 [cited by applicant]
US 20210115442A1 · Khvorova et al. · 2021 [cited by applicant]
US 20210139901A1 · Khvorova et al. · 2021 [cited by applicant]
US 20210317460A1 · Khvorova et al. · 2021 [cited by applicant]
US 20210340535A1 · Khvorova · 2021 [cited by applicant]
US 20210355491A1 · Khvorova et al. · 2021 [cited by applicant]
US 20210363523A1 · Khvorova et al. · 2021 [cited by applicant]
US 20220010309A1 · Khvorova et al. · 2022 [cited by applicant]
US 20220042015A1 · Khvorova et al. · 2022 [cited by applicant]
US 20220090069A1 · Khvorova et al. · 2022 [cited by applicant]
US 20220228141A1 · Khvorova et al. · 2022 [cited by applicant]
US 20220251554A1 · Khvorova et al. · 2022 [cited by applicant]
US 20220251555A1 · Khvorova et al. · 2022 [cited by applicant]
US 20220364100A1 · Khvorova et al. · 2022 [cited by applicant]
US 20230021431A1 · Khvorova · 2023 [cited by applicant]
US 20230061751A1 · Khvorova et al. · 2023 [cited by applicant]
US 20230078622A1 · Khvorova et al. · 2023 [cited by applicant]
US 20230193281A1 · Khvorova et al. · 2023 [cited by applicant]
US 20230313198A1 · Khvorova et al. · 2023 [cited by applicant]
US 20230340475A1 · Khvorova et al. · 2023 [cited by applicant]
US 20230348907A1 · Khvorova et al. · 2023 [cited by applicant]
US 20230392146A1 · Khvorova et al. · 2023 [cited by applicant]
US 20230416735A1 · Khvorova et al. · 2023 [cited by applicant]
US 20240067967A1 · Khvorova et al. · 2024 [cited by applicant]
US 20240084297A1 · Khvorova et al. · 2024 [cited by applicant]
US 20240132888A1 · Khvorova et al. · 2024 [cited by applicant]
US 20240132892A1 · Khvorova et al. · 2024 [cited by applicant]
CN 101199858A · 2008 [cited by applicant]
CN 101365801A · 2009 [cited by applicant]
CN 104884618A · 2015 [cited by applicant]
CN 105194689A · 2015 [cited by applicant]
EP 1752536A1 · 2007 [cited by applicant]
EP 2407539A1 · 2012 [cited by applicant]
EP 2601204A2 · 2013 [cited by applicant]
EP 2853597A1 · 2015 [cited by applicant]
EP 3277811A1 · 2018 [cited by applicant]
EP 3277814A1 · 2018 [cited by applicant]
EP 3277815A1 · 2018 [cited by applicant]
EP 3408391A1 · 2018 [cited by applicant]
EP 3550021A1 · 2019 [cited by applicant]
EP 3642341A1 · 2020 [cited by applicant]
EP 3929293A2 · 2021 [cited by applicant]
EP 3946369A2 · 2022 [cited by applicant]
EP 4126040A2 · 2023 [cited by applicant]
JP H0641183A · 1994 [cited by applicant]
JP H6504680A · 1994 [cited by applicant]
JP 2001501614A · 2001 [cited by applicant]
JP 2009504782A · 2009 [cited by applicant]
JP 2010506598A · 2010 [cited by applicant]
JP 2012502657A · 2012 [cited by applicant]
JP 2013049714A · 2013 [cited by applicant]
JP 2015061534A · 2015 [cited by applicant]
JP 2016171815A · 2016 [cited by applicant]
JP 2016526529A · 2016 [cited by applicant]
JP 2018516091A · 2018 [cited by applicant]
WO WO1992013869A1 · 1992 [cited by applicant]
WO WO1993009239A1 · 1993 [cited by applicant]
WO WO1993024641A2 · 1993 [cited by applicant]
WO WO1994022890A1 · 1994 [cited by applicant]
WO WO1996003500A1 · 1996 [cited by applicant]
WO WO1998013526A1 · 1998 [cited by applicant]
WO WO2003029459A2 · 2003 [cited by applicant]
WO WO2004008946A2 · 2004 [cited by applicant]
WO WO2004013280A2 · 2004 [cited by applicant]
WO WO2004044136A2 · 2004 [cited by applicant]
WO WO2004061081A2 · 2004 [cited by applicant]
WO WO2004108956A1 · 2004 [cited by applicant]
WO WO2005078095A1 · 2005 [cited by applicant]
WO WO2006019430A2 · 2006 [cited by applicant]
WO WO2007022470A2 · 2007 [cited by applicant]
WO WO2007022506A2 · 2007 [cited by applicant]
WO WO2007051045A2 · 2007 [cited by applicant]
WO WO2007056153A2 · 2007 [cited by applicant]
WO WO2007091269A2 · 2007 [cited by applicant]
WO WO2007094218A1 · 2007 [cited by applicant]
WO WO2007112414A2 · 2007 [cited by applicant]
WO WO2008005562A2 · 2008 [cited by applicant]
WO WO2008049078A1 · 2008 [cited by applicant]
WO WO2008070477A2 · 2008 [cited by applicant]
WO WO2008154482A2 · 2008 [cited by applicant]
WO WO2008154482A3 · 2008 [cited by applicant]
WO WO2009002944A1 · 2008 [cited by applicant]
WO WO2009054551A2 · 2009 [cited by applicant]
WO WO2009099991A2 · 2009 [cited by applicant]
WO WO2009102427A2 · 2009 [cited by applicant]
WO WO2010008582A2 · 2010 [cited by applicant]
WO WO2010011346A1 · 2010 [cited by applicant]
WO WO2010033246A1 · 2010 [cited by applicant]
WO WO2010033247A2 · 2010 [cited by applicant]
WO WO2010033248A2 · 2010 [cited by applicant]
WO WO2010048352A2 · 2010 [cited by applicant]
WO WO2010048585A2 · 2010 [cited by applicant]
WO WO2010059226A2 · 2010 [cited by applicant]
WO WO2010078536A1 · 2010 [cited by applicant]
WO WO2010090762A1 · 2010 [cited by applicant]
WO WO2010111503A2 · 2010 [cited by applicant]
WO WO2010118263A1 · 2010 [cited by applicant]
WO WO2011097643A1 · 2011 [cited by applicant]
WO WO2011109698A1 · 2011 [cited by applicant]
WO WO2011119852A1 · 2011 [cited by applicant]
WO WO2011119871A1 · 2011 [cited by applicant]
WO WO2011119887A1 · 2011 [cited by applicant]
WO WO2011125943A1 · 2011 [cited by applicant]
WO WO2011139702A2 · 2011 [cited by applicant]
WO WO2011158924A1 · 2011 [cited by applicant]
WO WO2012005898A2 · 2012 [cited by applicant]
WO WO2012037254A1 · 2012 [cited by applicant]
WO WO2012058210A1 · 2012 [cited by applicant]
WO WO2012078637A2 · 2012 [cited by applicant]
WO WO2012118911A1 · 2012 [cited by applicant]
WO WO2012131365A1 · 2012 [cited by applicant]
WO WO2012177906A1 · 2012 [cited by applicant]
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Khorev et al. 2008. Trivalent, Gal/GalNAc-containing ligands designed for the asialoglycoprotein receptor. Bioorgan. & Medicin. Chem. 16:5216-5231 (Year: 2008). [cited by examiner]
Miller and Gardiner. 2010. Adaptable Synthesis of C-Glycosidic Multivalent Carbohydrates and Succinamide-Linked Derivatization. Org. Lett 12(22):5262-5265 (Year: 2010). [cited by examiner]
Osborn et al. 2018. Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways. BioRxiv posted Mar. 23, 2018 (Year: 2018). [cited by examiner]
U.S. Appl. No. 18/375,206, filed Sep. 2023. [cited by examiner]
U.S. Appl. No. 18/446,929, filed Aug. 2023. [cited by examiner]
Akinc et al., A Combinatorial Library of Lipid-like Materials for Delivery of RNAi Therapeutics, Nature Biotechnology, vol. 26, No. 5, 20 Pages, May 2008. [cited by applicant]
Allerson et al., Fully 2′-Modified Oligonucleotide Duplexes with Improved in Vitro Potency and Stability Compared to Unmodified Small Interfering RNA, Journal of Medicinal Chemistry, vol. 48, No. 4, pp. 901-904, Jan. 20… [cited by applicant]
Alterman et al., Hydrophobically Modified siRNAs Silence Huntingtin mRNA in Primary Neurons and Mouse Brain, Molecular Therapy-Nucleic Acids, vol. 4, pp. e266, Dec. 1, 2015. [cited by applicant]
Alvarez-Erviti et al., Delivery of siRNA to the Mouse Brain by Systemic Injection of Targeted Exosomes, Nature Biotechnology, vol. 29, No. 4, pp. 341-345, Apr. 2011. [cited by applicant]
Atwell et al., Stable Heterodimers From Remodeling the Domain Interface of a Homodimer Using a Phage Display Library, Journal of Molecular Biology, vol. 270, Issue 1, pp. 26-35, Jul. 4, 1997. [cited by applicant]
Biscans et al., Diverse Lipid Conjugates for Functional Extra-Hepatic siRNA Delivery in Vivo, Nucleic Acids Research, vol. 47, No. 3, pp. 1082-1096, Dec. 14, 2018. [cited by applicant]
Braasch et al., RNA Interference in Mammalian Cells by Chemically-Modified RNA, Biochemistry, vol. 42, No. 26, pp. 7967-7975, Jun. 11, 2003. [cited by applicant]
Chen et al., Influence of Particle Size on the in Vivo Potency of Lipid Nanoparticle Formulations of siRNA, Journal of Controlled Release, vol. 235, pp. 236-244, Aug. 10, 2016. [cited by applicant]
Coles et al., A High-Throughput Method for Direct Detection of Therapeutic Oligonucleotide-Induced Gene Silencing In Vivo, Nucleic Acid Therapeutics, vol. 26, Issue 2, pp. 86-92, Apr. 11, 2016. [cited by applicant]
Dahlman et al., In Vivo Endothelial siRNA Delivery using Polymeric Nanoparticles with Low Molecular Weight, Nature Nanotechnology, vol. 9, No. 8, 17 Pages, Aug. 2014. [cited by applicant]
Egusquiaguirre et al., Nanoparticle Delivery Systems for Cancer Therapy: Advances in Clinical and Preclinical Research, Clinical and Translational Oncology, vol. 14, Issue 2, pp. 83-93, Feb. 2012. [cited by applicant]
El Andaloussi et al., Exosome-Mediated Delivery of siRNA In Vitro and In Vivo, Nature Protocols, vol. 7, No. 12, pp. 2112-2126, Nov. 15, 2012. [cited by applicant]
El Andaloussi et al., Exosomes for Targeted siRNA Delivery Across Biological Barriers, Advanced Drug Delivery Reviews, vol. 65, Issue 3, pp. 391-397, Mar. 2013. [cited by applicant]
El Andaloussi et al., Extracellular Vesicles: Biology and Emerging Therapeutic Opportunities, Nature Reviews Drug Discovery, vol. 12, No. 5, pp. 347-357, Apr. 15, 2013. [cited by applicant]
Elmen et al., Locked Nucleic Acid (LNA) Mediated Improvements in siRNA Stability and Functionality, Nucleic Acids Research, vol. 33, Issue 1, pp. 439-447, Jan. 14, 2005. [cited by applicant]
Frank et al., Structural Basis for 5′-Nucleotide Base-specific Recognition of Guide RNA by Human AGO2, Nature, vol. 465, pp. 818-822, Jun. 2010. [cited by applicant]
Geary et al., Pharmacokinetics, Biodistribution and Cell Uptake of Antisense Oligonucleotides, Advanced Drug Delivery Reviews, vol. 87, pp. 46-51, Jun. 29, 2015. [cited by applicant]
Geary, Antisense Oligonucleotide Pharmacokinetics and Metabolism, Expert Opinion on Drug Metabolism & Toxicology, vol. 5, pp. 381-391, Apr. 1, 2009. [cited by applicant]
Godinho et al., Pharmacokinetic Profiling of Conjugated Therapeutic Oligonucleotides: A High-Throughput Method based upon Serial Blood Microsampling Coupled to Peptide Nucleic Acid Hybridization Assay, Nucleic Acid Ther… [cited by applicant]
Goodson et al., Dental Applications, Medical Applications of Controlled Release, vol. 2, pp. 115-138, 1984. [cited by applicant]
Hammerling et al., Monoclonal Antibodies and T-Cell Hybridomas, Research Monographs in Immunology, vol. 3, pp. 563-681, 1981. [cited by applicant]
Haraszti et al., 5′-Vinylphosphonate improves tissue accumulation and efficacy of conjugated siRNAs in vivo, Nucleic Acids Research, vol. 45, No. 13, pp. 7581-7592, Jul. 27, 2017. [cited by applicant]
Harborth et al., Sequence, Chemical, and Structural Variation of Small Interfering RNAs and Short Hairpin RNAs and the Effect on Mammalian Gene Silencing, Antisense and Nucleic Acid Drug Development, vol. 13, pp. 83-105… [cited by applicant]
Hassler et al., Comparison of Partially and Fully Chemically-Modified siRNA in Conjugate-Mediated Delivery in Vivo, Nucleic Acids Research, vol. 46, No. 5, pp. 2185-2196, Mar. 16, 2018. [cited by applicant]
Herdewijn, Heterocyclic Modifications of Oligonucleotides and Antisense Technology, Antisense and Nucleic Acid Drug Development, vol. 10, Issue 4, pp. 297-310, Jul. 8, 2004. [cited by applicant]
Huang, Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics, Molecular Therapy—Nucleic Acids, vol. 6,, pp. 116-132, Mar. 17, 2017. [cited by applicant]
Jackson et al., Position-Specific Chemical Modification of siRNAs Reduces “Off-Target” Transcript Silencing, RNA, vol. 12, No. 7, pp. 1197-1205, May 8, 2006. [cited by applicant]
Karaki et al., Lipid-Oligonucleotide Conjugates Improve Cellular Uptake and Efficiency of TCTP-Antisense in Castration-Resistant Prostate Cancer, Journal of Controlled Release, vol. 258, pp. 1-9, Jul. 28, 2017. [cited by applicant]
Karlin et al., Applications and Statistics for Multiple High-Scoring Segments in Molecular Sequences, Proceedings of the National Academy of Sciences of the USA, vol. 90, pp. 5873-5877, Jun. 1993. [cited by applicant]
Karlin et al., Methods for Assessing the Statistical Significance of Molecular Sequence Features by Using General Scoring Schemes, Proceedings of the National Academy of science of the USA, vol. 87, No. 6, pp. 2264-2268… [cited by applicant]
Khan et al., Silencing Myostatin using Cholesterol-Conjugated siRNAs Induces Muscle Growth, Molecular Therapy, Nucleic Acids, vol. 5, 9 Pages, Jan. 1, 2016. [cited by applicant]
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