IP Library › Granted Patent US 12,747,260
Granted Patent B2
US 12,747,260 · App. 17/611,765 · Granted Sep 29, 2026

Synthesis of oligomeric compounds comprising phosphorothioate diester and phosphodiester linkages

Inventors: Andrew K. McPherson (San Diego, CA); Andrew A. Rodriguez (San Diego, CA); Daniel C. Capaldi (Carlsbad, CA)
Assignee: Ionis Pharmaceuticals, Inc.
C07H1/00C07H21/02C07H21/04
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,747,260
App. No.
17/611,765
Granted
Sep 29, 2026
Kind
B2
Abstract

The present disclosure provides methods for synthesizing oligomeric compounds having at least one phosphorothioate diester linkage and at least one phosphate diester internucleoside linkage. In certain embodiments, the present disclosure provides oxidation reagents that produce low amounts of unwanted phosphate diester impurities in oligomeric compounds having at least one phosphorothioate diester linkage and at least one phosphate diester internucleoside linkage.

Claims (13)

1 . A process for synthesizing an oligomeric compound comprising an oligonucleotide, comprising contacting a first oligonucleotide intermediate having a phosphite triester linkage with an oxidizing agent to form a second oligonucleotide intermediate having a phosphate triester linkage; wherein the oxidizing agent consists of a mixture of 12 , a halide salt, pyridine, and water, and wherein the concentration of I 2 is 0.05 M and the concentration of the halide salt is 0.05 M; wherein the halide salt is selected from NaI, KI, or LiI.

2 . The process of claim 1 , wherein the oxidizing agent consists of a mixture of I 2 , a halide salt, and a 9:1 volumetric ratio of pyridine and water.

3 . The process of claim 1 , wherein the oligonucleotide intermediates are attached to a solid support.

4 . The process of claim 1 , wherein at least 4 internucleoside linkages of the oligonucleotide are phosphorothioate diester internucleoside linkages.

5 . The process of claim 1 , wherein each internucleoside linkage of the oligonucleotide is either a phosphorothioate diester internucleoside linkage or a phosphate diester internucleoside linkage.

6 . The process of claim 1 , wherein the oligomeric compound further comprises a conjugate group.

7 . The process of claim 6 , wherein the conjugate group comprises one or more N-acetyl galactosamine moieties.

8 . The process of claim 7 , wherein the conjugate group comprises Formula (V):

9 . The process of claim 1 , wherein the oligonucleotide consists of 5-40 linked nucleosides.

10 . The process of claim 1 , wherein the oligonucleotide consists of at least 13 linked nucleosides.

11 . The process of claim 1 , wherein the second oligonucleotide intermediate undergoes one or more further reactions.

12 . The process of claim 11 , wherein the second oligonucleotide intermediate undergoes multiple further reactions to yield an oligomeric compound comprising an oligonucleotide.

13 . The process of claim 1 , wherein the process results in an oligonucleotide product having less than 2%, 3%, 4%, or 5% of the (P═O) 1 impurity.

Continuity (3)
Provisional Application 62953087 · Dec 23, 2019
Provisional Application 62849799 · May 17, 2019
Related Publication 20220251128A1 · Aug 11, 2022
References Cited (263)
US 3687808A · Merigan et al. · 1972 [cited by applicant]
US 4751219A · Kempen et al. · 1988 [cited by applicant]
US 4845205A · Huynh Dinh et al. · 1989 [cited by applicant]
US 5034506A · Summerton et al. · 1991 [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 5185444A · Summerton et al. · 1993 [cited by applicant]
US 5367066A · Urdea et al. · 1994 [cited by applicant]
US 5432272A · Benner · 1995 [cited by applicant]
US 5434257A · Matteucci 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 5484908A · Froehler et al. · 1996 [cited by applicant]
US 5502177A · Matteucci et al. · 1996 [cited by applicant]
US 5525711A · Hawkins et al. · 1996 [cited by applicant]
US 5552540A · Haralambidis · 1996 [cited by applicant]
US 5587469A · Cook et al. · 1996 [cited by applicant]
US 5587470A · Cook et al. · 1996 [cited by applicant]
US 5594121A · Froehler et al. · 1997 [cited by applicant]
US 5596091A · Switzer · 1997 [cited by applicant]
US 5614617A · Cook et al. · 1997 [cited by applicant]
US 5645985A · Froehler 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 5703218A · Urdea 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 5783684A · Reddy et al. · 1998 [cited by applicant]
US 5808027A · Cook et al. · 1998 [cited by applicant]
US 5811534A · 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 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 6525031B2 · Manoharan · 2003 [cited by applicant]
US 6525191B1 · Ramasamy · 2003 [cited by applicant]
US 6531584B1 · Cook 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 7135565B2 · Dellinger et al. · 2006 [cited by applicant]
US 7262177B2 · Ts'o 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 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 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 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 RE44779E · Imanishi et al. · 2014 [cited by applicant]
US 8796437B2 · Swayze et al. · 2014 [cited by applicant]
US 9005906B2 · Swayze et al. · 2015 [cited by applicant]
US 9012421B2 · Migawa et al. · 2015 [cited by applicant]
US 20030077829A1 · MacLachlan · 2003 [cited by applicant]
US 20030119724A1 · Ts'o et al. · 2003 [cited by applicant]
US 20030158403A1 · Manoharan et al. · 2003 [cited by applicant]
US 20030175906A1 · Manoharan et al. · 2003 [cited by applicant]
US 20040024194A1 · Ravikumar · 2004 [cited by applicant]
US 20050026192A1 · Moore et al. · 2005 [cited by applicant]
US 20050164235A1 · Manoharan et al. · 2005 [cited by applicant]
US 20060148740A1 · Platenburg · 2006 [cited by applicant]
US 20060183886A1 · Tso et al. · 2006 [cited by applicant]
US 20080039618A1 · Allerson 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 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 20100240730A1 · Beigelman et al. · 2010 [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 20110207799A1 · Rozema 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 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 20120230938A1 · Rozema et al. · 2012 [cited by applicant]
US 20130004427A1 · El-Sayed 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 20130203836A1 · Rajeev et al. · 2013 [cited by applicant]
US 20130236968A1 · Manoharan et al. · 2013 [cited by applicant]
US 20150191727A1 · Migawa et al. · 2015 [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 WO0047593A1 · 2000 [cited by examiner]
WO 2000055179A1 · 2000 [cited by applicant]
WO WO2002043771 · 2002 [cited by applicant]
WO WO2004024757 · 2004 [cited by applicant]
WO WO2004101619 · 2004 [cited by applicant]
WO WO2004106356 · 2004 [cited by applicant]
WO WO2007134181 · 2007 [cited by applicant]
WO WO2008098788 · 2008 [cited by applicant]
WO WO2008101157 · 2008 [cited by applicant]
WO WO2009082607 · 2009 [cited by applicant]
WO WO2009126933 · 2009 [cited by applicant]
WO WO2009134487 · 2009 [cited by applicant]
WO WO2010054406 · 2010 [cited by applicant]
WO WO2010088537 · 2010 [cited by applicant]
WO WO2010129709 · 2010 [cited by applicant]
WO WO2010144740 · 2010 [cited by applicant]
WO WO2010148013 · 2010 [cited by applicant]
WO WO2011038356 · 2011 [cited by applicant]
WO WO2011100131 · 2011 [cited by applicant]
WO WO2011120053 · 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 WO2012177947 · 2012 [cited by applicant]
WO WO2013033230 · 2013 [cited by applicant]
WO WO2013075035 · 2013 [cited by applicant]
WO WO2013165816 · 2013 [cited by applicant]
WO WO2013166121 · 2013 [cited by applicant]
WO 2014012081A2 · 2014 [cited by applicant]
WO WO2014179620 · 2014 [cited by applicant]
WO WO2014179620A1 · 2014 [cited by examiner]
WO WO2015106128 · 2015 [cited by applicant]
WO WO2017015555 · 2017 [cited by applicant]
WO WO2020236618 · 2020 [cited by applicant]
WO 2020249571A1 · 2020 [cited by applicant]
Bergstrom, D., & Schmaltz, T. Organoiron-mediated alkylation of phosphite esters: synthesis of (dicarbonyl)(.eta.5-cyclopentadienyl)iron-derived nucleoside phosphonate esters. The Journal of Organic Chemistry, 57(3), 87… [cited by examiner]
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]
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., “Novel Antisense and Peptide Nucleic Acid Strategies for Controlling Gene Expression” Biochemistry (2002) 41(14): 4503-4510. [cited by applicant]
Cedillo et al., “Synthesis of 5′-GalNAc-Conjugated Oligonucleotides: A Comparison of Solid and Solution-Phase Conjugation Strategies” Molecules (2017) 22(8): 1-12. [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, St., et al., “Antisense Drug Technology” Second Edition, CRC Press (2008) Chapters 1-28. [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]
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]
International Search Report for PCT/US20/033196 dated Oct. 1, 2020. [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]
Kabanov et al., “A new class of antivirals: antisense oligonucleotides combined with a hydrophobic substituent effectively inhibit influenza virus reproduction and synthesis of virus-specific proteins in MDCK cells” FEB… [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]
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]
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]
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., “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., “Synthesis of Peptide-Based Trivalent Scaffold for Preparation of Cluster Glycosides” Methods in Enzymology (2003) 362: 38-43. [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., “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]
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]
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., “Cholic Acid-Oligonucleotide Conjugates for Antisense Applications” Bioorg. Med. Chem. Lett. (1994) 4:1053-1060. [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., “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., “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]
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]
Nishina et al., “Chimeric Antisense Oligonucleotide Conjugated to α-Tocopherol” [cited by applicant]
Nishina et al., “Efficient In Vivo Delivery of siRNA to the Liver by Conjugation of α-Tocopherol” Molecular Therapy (2008) 16: 734-740. [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]
Oka et al., “An Oxazaphospholidine Approach for the Stereocontrolled Synthesis of Oligonucleoside and Phosphorothioates” JACS (2003) 125: 8307-8317. [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]
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]
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]
Rodriguez “Improved Oxidizer Formulations for the Synthesis of PO/PS Mixed Backbone Oligonucleotides” Presentation for TIDES (Boston) Sep. 23, 2021. [cited by applicant]
Saison-Behmoaras et al., “Short modified antisense oligonucleotides directed against Ha-ras point mutation induce selective cleavage of the mRNA and inhibit T24 cells proliferation” EMBO J. (1991) 10(5):1111-1118. [cited by applicant]
Sakaki et al., “Human Transthyretin (Prealbumin) Gene and Molecular Genetics of Familial Amyloidotic Polyneruopathy” Mol Biol Med. (1989) 6: 161-168. [cited by applicant]
Sanghvi, Chapter 15, Antisense Research and Applications, Crooke and Lebleu ed., CRC Press (1993) 273-288. [cited by applicant]
Maddry et al., “Synthesis of Nonionic Oligonucleotide Analogues” Carbohydrate Modifications in Antisense Research, ACS Symposium: (1994) Chapters 3 & 4. [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]
Shea et al., “Synthesis, hybridization properties and antiviral activity of lipid-oligodeoxynucleotide conjugates” Nucl. Acids Res. (1990) 18(13):3777-3783. [cited by applicant]
Singh et al., “LNA (locked nucleic acids): synthesis and high-affinity nucleic acid recognition” Chem. Commun. (1998) 455-456. [cited by applicant]
Singh et al., “Synthesis of 2′-amino-LNA: A novel conformationally restricted high-affinity oligonucleotide analogue with a handle” J. Org. Chem. (1998) 63: 10035-10039. [cited by applicant]
Sliedregt et al., “Design and Synthesis of Novel Amphiphilic Dendritic Galactosides for Selective Targeting of Liposomes to the Hepatic Asialoglycoprotein Receptor” J. Med. Chem. (1999) 42:609-618. [cited by applicant]
Srivastava et al., “Five- and Six-Membered Conformationally Locked 2′,4′-Carbocyclic ribo-Thymidines: Synthesis, Structure, and Biochemical Studies” J. Am. Chem. Soc. (2007) 129(26):8362-8379. [cited by applicant]
Svinarchuk et al., “Inhibition of HIV proliferation in MT-4 cells by antisense oligonucleotide conjugated to lipophilic groups” Biochimie (1993) 75:49-54. [cited by applicant]
Tomiya et al., “Liver-targeting of primaquine-(poly-c-glutamic acid) and its degradation in rat hepatocytes” Bioorganic & Medicinal Chemistry (2013) 21: 5275-5281. [cited by applicant]
Toyokuni et al., “Synthetic vaccines: I. Synthesis of multivalent Tn antigen cluster-lysyllysine conjugates” Tetrahedron Lett (1990) 31(19): 2673-2676. [cited by applicant]
Valentijn et al., “Solid-phase Synthesis of Lysine-based Cluster Galactosides with High Affinity for the Asialoglycoprotein Receptor” Tetrahedron (1997) 53(2): 759-770. [cited by applicant]
Van Rossenberg et al., “Stable polyplexes based on arginine-containing oligopeptides for in vivo gene delivery” Gene Ther (2004) 11: 457-464. [cited by applicant]
Vester et al., “Chemically modified oligonucleotides with efficient RNase H response” Bioorg. Med. Chem. Letters (2008) 18: 2296-2300. [cited by applicant]
Wan et al. “Synthesis, biophysical properties and biological activity of second generation antisense oligonucleotides containing chiral phosphorothioate linkages” Nuc. Acid. Res. (2014) 42: 13456-13468. [cited by applicant]
Westerlind et al., “Ligands of the asialoglycoprotein receptor for targeted gene delivery, part 1: Synthesis of and binding studies with biotinylated cluster glycosides containing N-acetylgalactosamine” Glycoconjugate J… [cited by applicant]
Zhou et al., “Fine Tuning of Electrostatics around the Internucleotidic Phosphate through Incorporation of Modified 2′,4′-Carbocyclic-LNAs and -ENAs Leads to Significant Modulation of Antisense Properties” J. Org. Chem.… [cited by applicant]
Beaucage et al., “Advances in the Synthesis of Oligonucleotides by the Phosphoramidite Approach” Tetrahedron (1992) 48: 2223-2311. [cited by applicant]
Extended EP Search Report for 20810107.1 dated Apr. 21, 2023, 8 pages. [cited by applicant]
Farrance et al., “Improved chemistry for oligodeoxyribonucleotide synthesis substantially improves restriction enzyme cleavage of a synthetic 35mer” Nucleic Acids Res (1989) 17: 1231-1245. [cited by applicant]
Pon et al., “An improved iodine/water oxidation reagent for automated oligonucleotide synthesis” Nucleic Acids Res (1987) 15: 7203, 1 page. [cited by applicant]