IP Library › Granted Patent US 12,473,321
Granted Patent B2
US 12,473,321 · App. 18/522,146 · Granted Nov 18, 2025

Compositions and methods for phosphoramidite and oligonucleotide synthesis

Inventors: David Charles Donnell Butler (Medford, MA); Pachamuthu Kandasamy (Lexington, MA); Subramanian Marappan (Acton, MA); Ik-Hyeon Paik (Needham, MA); Jayakanthan Kumarasamy (Arlington, MA); Gopal Reddy Bommineni (Belmont, MA)
Assignee: WAVE LIFE SCIENCES LTD.
C07H1/06C07H19/10C07H19/207C07H21/00
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 12,473,321
App. No.
18/522,146
Granted
Nov 18, 2025
Kind
B2
Abstract

The present disclosure, among other things, provides technologies for oligonucleotide synthesis. In some embodiments, the present disclosure provides phosphoramidites and methods for synthesis thereof. In some embodiments, provided methods provides higher yields and/or purities. In some embodiments, provided methods remove byproducts without contact with an aqueous solution.

Claims (19)

1 . A composition comprising a compound having the structure of formula I:

or a salt thereof and a silylating reagent;

BA is

SU is

 wherein SU is connected to the phosphorus atom in formula I through the oxygen atom;

R 5s is R′ or —OR′;

R 2s is —H, —F, —CN, —N 3 , —NO, —NO 2 , —O—(C 1-10 alkyl), or —O-(optionally substituted C 1-6 alkylene)-OR′, or R 2s is L connecting C2 with C1, C2, C3, C4 or C5, wherein L is —O—CH 2 — wherein the —CH 2 — is optionally substituted;

 each R′ is independently —R, —C(O)R, —CO 2 R, or —SO 2 R, or:

two or more R′ are taken together with their intervening atoms to form an optionally substituted monocyclic, bicyclic or polycyclic, saturated, partially unsaturated, or aryl 3-30 membered ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; and

each R is independently hydrogen, or an optionally substituted group selected from C 1-30 aliphatic, C 1-30 heteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, C 6-30 aryl, a 5-30 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3-30 membered heterocyclic ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon.

2 . The compound of claim 1 , wherein the composition is selected from:

3 . The composition of claim 1 , wherein BA is

4 . The composition of claim 1 , wherein R 5s is DMTrO-.

5 . The composition of claim 3 , wherein R 5s is DMTrO-.

6 . The composition of claim 1 , wherein R 2s is —H, —F, —OMe, —OCH 2 CH 2 OMe, or R 2s is L connecting C2 with C4, wherein R 2s (C2)-O-(methylene)-(C4) or (C2)-O-(methylmethylene)-(C4).

7 . The composition of claim 1 , wherein R 2s is —H, —F, —OMe, —OCH 2 CH 2 OMe, or R 2s is L connecting C2 with C4, wherein R 2s (C2)-O-(methylene)-(C4) or (C2)-O-(methylmethylene)-(C4).

8 . The composition of claim 4 , wherein R 2s is —H, —F, —OMe, —OCH 2 CH 2 OMe, or R 2s is L connecting C2 with C4, wherein R 2s (C2)-O-(methylene)-(C4) or (C2)-O-(methylmethylene)-(C4).

9 . The composition of claim 5 , wherein R 2s is —H, —F, —OMe, —OCH 2 CH 2 OMe, or R 2s is L connecting C2 with C4, wherein R 2s (C2)-O-(methylene)-(C4) or (C2)-O-(methylmethylene)-(C4).

10 . The composition of claim 2 , wherein the compound is selected from:

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 6, 2025
From: BUTLER, DAVID CHARLES DONNELL; KANDASAMY, PACHAMUTHU; MARAPPAN, SUBRAMANIAN; PAIK, IK-HYEON; KUMARASAMY, JAYAKANTHAN; BOMMINENI, GOPAL REDDY
To: WAVE LIFE SCIENCES LTD.
Reel/Frame 071029/0779 →
Continuity (3)
Division 16463328
Provisional Application 62426079 · Nov 23, 2016
Related Publication 20240368207A1 · Nov 7, 2024
References Cited (273)
US 4725677A · Koster et al. · 1988 [cited by applicant]
US 5846466A · Abe et al. · 1998 [cited by applicant]
US 5869696A · Reddy et al. · 1999 [cited by applicant]
US 6133438A · Cook et al. · 2000 [cited by applicant]
US 6867294B1 · Sanghvi et al. · 2005 [cited by applicant]
US 7030230B2 · Ross et al. · 2006 [cited by applicant]
US 7057062B2 · Song et al. · 2006 [cited by applicant]
US 7101993B1 · Cook et al. · 2006 [cited by applicant]
US 7897758B2 · Wolter et al. · 2011 [cited by applicant]
US 8431693B2 · Manoharan et al. · 2013 [cited by applicant]
US 8470987B2 · Wada et al. · 2013 [cited by applicant]
US 8822671B2 · Shimizu et al. · 2014 [cited by applicant]
US 8859755B2 · Wada et al. · 2014 [cited by applicant]
US 9394333B2 · Wada et al. · 2016 [cited by applicant]
US 9598458B2 · Shimizu et al. · 2017 [cited by applicant]
US 9605019B2 · Verdine et al. · 2017 [cited by applicant]
US 9617547B2 · Gemba · 2017 [cited by applicant]
US 9695211B2 · Wada et al. · 2017 [cited by applicant]
US 9744183B2 · Verdine et al. · 2017 [cited by applicant]
US 9982257B2 · Butler et al. · 2018 [cited by applicant]
US 10144933B2 · Gemba et al. · 2018 [cited by applicant]
US 10149905B2 · Gemba et al. · 2018 [cited by applicant]
US 10160969B2 · Meena et al. · 2018 [cited by applicant]
US 10167309B2 · Shimizu et al. · 2019 [cited by applicant]
US 10280192B2 · Verdine et al. · 2019 [cited by applicant]
US 10307434B2 · Verdine et al. · 2019 [cited by applicant]
US 10322173B2 · Gemba et al. · 2019 [cited by applicant]
US 10329318B2 · Wada et al. · 2019 [cited by applicant]
US 10428019B2 · Wada et al. · 2019 [cited by applicant]
US 10450568B2 · Butler et al. · 2019 [cited by applicant]
US 10479995B2 · Vargeese et al. · 2019 [cited by applicant]
US 10590413B2 · Butler et al. · 2020 [cited by applicant]
US 10696711B2 · Shimizu et al. · 2020 [cited by applicant]
US 10724035B2 · Vargeese et al. · 2020 [cited by applicant]
US 10815482B2 · Meena et al. · 2020 [cited by applicant]
US 11013757B2 · Zhang et al. · 2021 [cited by applicant]
US 11136346B2 · Shimizu et al. · 2021 [cited by applicant]
US 11407775B2 · Butler et al. · 2022 [cited by applicant]
US 11596646B2 · Zhang et al. · 2023 [cited by applicant]
US 11597927B2 · Vargeese et al. · 2023 [cited by applicant]
US 11603532B2 · Vargeese et al. · 2023 [cited by applicant]
US 11608355B2 · Bowman et al. · 2023 [cited by applicant]
US 11634710B2 · Frank-Kamenetsky et al. · 2023 [cited by applicant]
US 11643657B2 · Butler et al. · 2023 [cited by applicant]
US 11718638B2 · Butler et al. · 2023 [cited by applicant]
US 11739325B2 · Vargeese et al. · 2023 [cited by applicant]
US 11873316B2 · Butler et al. · 2024 [cited by applicant]
US 20030017451A1 · Wang et al. · 2003 [cited by applicant]
US 20030032794A1 · Koch et al. · 2003 [cited by applicant]
US 20030232978A1 · Seeberger et al. · 2003 [cited by applicant]
US 20070196852A1 · Heindl et al. · 2007 [cited by applicant]
US 20110178284A1 · Wada et al. · 2011 [cited by applicant]
US 20110294124A1 · Wada et al. · 2011 [cited by applicant]
US 20130178612A1 · Wada et al. · 2013 [cited by applicant]
US 20130236536A1 · Phiasivongsa et al. · 2013 [cited by applicant]
US 20150166999A1 · Gemba · 2015 [cited by applicant]
US 20150179540A1 · Yasui · 2015 [cited by applicant]
US 20160331835A1 · Gemba et al. · 2016 [cited by applicant]
US 20160331836A1 · Gemba et al. · 2016 [cited by applicant]
US 20160333349A1 · Gemba et al. · 2016 [cited by applicant]
US 20160347784A1 · Verdine et al. · 2016 [cited by applicant]
US 20170029445A1 · Shimizu et al. · 2017 [cited by applicant]
US 20170029457A1 · Verdine et al. · 2017 [cited by applicant]
US 20170037399A1 · Meena et al. · 2017 [cited by applicant]
US 20170275621A1 · Butler et al. · 2017 [cited by applicant]
US 20180111958A1 · Wada et al. · 2018 [cited by applicant]
US 20180216107A1 · Frank-Kamenetsky et al. · 2018 [cited by applicant]
US 20180216108A1 · Vargeese et al. · 2018 [cited by applicant]
US 20180222936A1 · Verdine et al. · 2018 [cited by applicant]
US 20190127733A1 · Butler et al. · 2019 [cited by applicant]
US 20190249173A1 · Vargeese et al. · 2019 [cited by applicant]
US 20190264267A1 · Yang et al. · 2019 [cited by applicant]
US 20190390197A1 · Butler et al. · 2019 [cited by applicant]
US 20200080083A1 · Vargeese et al. · 2020 [cited by applicant]
US 20200362337A1 · Dodart et al. · 2020 [cited by applicant]
US 20210115444A1 · Meena et al. · 2021 [cited by applicant]
US 20210198305A1 · Vargeese et al. · 2021 [cited by applicant]
US 20210254062A1 · Zhang et al. · 2021 [cited by applicant]
US 20220098585A1 · Brown et al. · 2022 [cited by applicant]
US 20220127301A1 · Shimizu et al. · 2022 [cited by applicant]
US 20220145300A1 · Liu et al. · 2022 [cited by applicant]
US 20220162598A1 · Vargeese et al. · 2022 [cited by applicant]
US 20220186217A1 · Zhang et al. · 2022 [cited by applicant]
US 20220195429A1 · Vargeese et al. · 2022 [cited by applicant]
US 20220306573A1 · Zhang et al. · 2022 [cited by applicant]
US 20220307019A1 · Yokota et al. · 2022 [cited by applicant]
US 20220401467A1 · Zhang et al. · 2022 [cited by applicant]
US 20230089442A1 · Kandasamy et al. · 2023 [cited by applicant]
US 20230136645A1 · Butler et al. · 2023 [cited by applicant]
US 20230145795A1 · Byrne et al. · 2023 [cited by applicant]
US 20230203087A1 · Kandasamy et al. · 2023 [cited by applicant]
US 20230220384A1 · Monian et al. · 2023 [cited by applicant]
US 20230295617A1 · Vargeese et al. · 2023 [cited by applicant]
US 20230295619A1 · Maguire et al. · 2023 [cited by applicant]
US 20230329201A1 · Yang et al. · 2023 [cited by applicant]
US 20230348524A1 · Bowman et al. · 2023 [cited by applicant]
US 20230392137A1 · Monian et al. · 2023 [cited by applicant]
US 20240026358A1 · Monian et al. · 2024 [cited by applicant]
US 20240109931A1 · Vargeese et al. · 2024 [cited by applicant]
US 20240117347A1 · Butler et al. · 2024 [cited by applicant]
US 20240132894A1 · Vargeese et al. · 2024 [cited by applicant]
US 20240150756A1 · Frank-Kamenetsky et al. · 2024 [cited by applicant]
US 20240174710A1 · Butler et al. · 2024 [cited by applicant]
US 20240175016A1 · Liu et al. · 2024 [cited by applicant]
US 20240175018A1 · Vargeese et al. · 2024 [cited by applicant]
US 20240229026A1 · Butler et al. · 2024 [cited by applicant]
US 20250051778A1 · Byrne et al. · 2025 [cited by applicant]
US 20250066775A1 · Vargeese et al. · 2025 [cited by applicant]
CN 102675386A · 2012 [cited by applicant]
CN 102516337B · 2014 [cited by applicant]
CN 104684893A · 2015 [cited by applicant]
CN 103819501B · 2015 [cited by applicant]
CN 108779132A · 2018 [cited by applicant]
CN 108779139A · 2018 [cited by applicant]
JP 2003238586A · 2003 [cited by applicant]
JP 200589441A · 2005 [cited by applicant]
JP 2006292394A · 2006 [cited by applicant]
JP 2011121881A · 2011 [cited by applicant]
JP 2011184318A · 2011 [cited by applicant]
JP 2015523316A · 2015 [cited by applicant]
JP 2015528002A · 2015 [cited by applicant]
WO WO9709443A1 · 1987 [cited by applicant]
WO WO8909780A1 · 1989 [cited by applicant]
WO WO199515333A1 · 1995 [cited by applicant]
WO WO199531434A1 · 1995 [cited by applicant]
WO WO199740458A2 · 1997 [cited by applicant]
WO WO98016535A1 · 1998 [cited by applicant]
WO WO2004055037A2 · 2004 [cited by applicant]
WO WO2005014609A2 · 2005 [cited by applicant]
WO WO2005023828A1 · 2005 [cited by applicant]
WO WO2005028494A1 · 2005 [cited by applicant]
WO WO2005070859A1 · 2005 [cited by applicant]
WO WO2005085272A1 · 2005 [cited by applicant]
WO WO2005092909A1 · 2005 [cited by applicant]
WO WO2005097817A2 · 2005 [cited by applicant]
WO WO2009143369A2 · 2009 [cited by applicant]
WO WO2010064146A2 · 2010 [cited by applicant]
WO WO2011005761A1 · 2011 [cited by applicant]
WO WO2011034072A1 · 2011 [cited by applicant]
WO WO2011108682A1 · 2011 [cited by applicant]
WO WO2012039448A1 · 2012 [cited by applicant]
WO WO2012073857A1 · 2012 [cited by applicant]
WO WO2013012758A1 · 2013 [cited by applicant]
WO WO2014010250A1 · 2014 [cited by applicant]
WO WO2014010718A1 · 2014 [cited by applicant]
WO WO2014012081A2 · 2014 [cited by applicant]
WO WO2015107425A2 · 2015 [cited by applicant]
WO WO2015108046A1 · 2015 [cited by applicant]
WO WO2015108047A1 · 2015 [cited by applicant]
WO WO2015108048A1 · 2015 [cited by applicant]
WO WO2015168461A2 · 2015 [cited by applicant]
WO WO2016079181A1 · 2016 [cited by applicant]
WO WO2017015555A1 · 2017 [cited by applicant]
WO WO2017015575A1 · 2017 [cited by applicant]
WO WO2017062862A2 · 2017 [cited by applicant]
WO WO2017157672A1 · 2017 [cited by applicant]
WO WO2017160741A1 · 2017 [cited by applicant]
WO WO2017192664A1 · 2017 [cited by applicant]
WO WO2017192679A1 · 2017 [cited by applicant]
WO WO2017210647A1 · 2017 [cited by applicant]
WO WO2018022473A1 · 2018 [cited by applicant]
WO WO2018067973A1 · 2018 [cited by applicant]
WO WO2018098264A1 · 2018 [cited by applicant]
WO WO2018223056A1 · 2018 [cited by applicant]
WO WO2018223073A1 · 2018 [cited by applicant]
WO WO2018223081A1 · 2018 [cited by applicant]
WO WO2018237194A1 · 2018 [cited by applicant]
WO WO2019002237A1 · 2019 [cited by applicant]
WO WO2019032607A1 · 2019 [cited by applicant]
WO WO2019032612A1 · 2019 [cited by applicant]
WO WO2019055951A1 · 2019 [cited by applicant]
WO WO2019075357A1 · 2019 [cited by applicant]
WO WO2019200185A1 · 2019 [cited by applicant]
WO WO2019217784A1 · 2019 [cited by applicant]
WO WO2020118246A1 · 2020 [cited by applicant]
WO WO2020160336A1 · 2020 [cited by applicant]
WO WO2020191252A1 · 2020 [cited by applicant]
WO WO2020196662A1 · 2020 [cited by applicant]
WO WO2020219981A2 · 2020 [cited by applicant]
WO WO2020219983A2 · 2020 [cited by applicant]
WO WO2020227691A2 · 2020 [cited by applicant]
WO WO2021071788A2 · 2021 [cited by applicant]
WO WO2021071858A1 · 2021 [cited by applicant]
WO WO2021178237A2 · 2021 [cited by applicant]
WO WO2021234459A2 · 2021 [cited by applicant]
WO WO2021237223A1 · 2021 [cited by applicant]
WO WO2022046667A1 · 2022 [cited by applicant]
WO WO2022046723A1 · 2022 [cited by applicant]
WO WO2022099159A1 · 2022 [cited by applicant]
WO WO2024035946A1 · 2023 [cited by applicant]
WO WO2023049475A1 · 2023 [cited by applicant]
WO WO2023049477A2 · 2023 [cited by applicant]
WO WO2023075766A1 · 2023 [cited by applicant]
WO WO2023076352A2 · 2023 [cited by applicant]
WO WO2023154528A1 · 2023 [cited by applicant]
WO WO2023168014A2 · 2023 [cited by applicant]
WO WO2023201095A2 · 2023 [cited by applicant]
WO WO2023220440A1 · 2023 [cited by applicant]
WO WO2025030155A1 · 2025 [cited by applicant]
U.S. Appl. No. 18/316,932, filed May 12, 2023, Butler et al. [cited by applicant]
U.S. Appl. No. 18/613,034, filed Mar. 21, 2024, Vargeese et al. [cited by applicant]
U.S. Appl. No. 18/695,346, filed Mar. 25, 2024, Monian et al. [cited by applicant]
U.S. Appl. No. 18/695,348, filed Mar. 25, 2024, Acker et al. [cited by applicant]
U.S. Appl. No. 18/704,629, filed Apr. 25, 2024, Byrne et al. [cited by applicant]
Almer, et al. A New Approach to Stereospecific Synthesis of P-chiral Phosphorothioates. Preparation of Diastereomeric Dithymidyl-(3′-5′) Phosphorothioates, Chem. Commun., (3): 290-1 (2004). [cited by applicant]
Arai, K. et al., Synthesis and properties of novel 2′-O-alkoxymethyl-modified nucleic acids, Bioorganic & Medicinal Chemistry Letters, 21(21): 6285-6287 (2011). [cited by applicant]
Bobkov, G.V. et al., Phosphoramidite building blocks for efficient incorporation of 2′-O-aminoethoxy(and propoxy)methyl nucleosides into oligonucleotides, Tetrahedron, 64: 6238-6251 (2008). [cited by applicant]
Bradley, D. et al., Drying of Organic Solvents: Quantitative Evaluation of the Efficiency of Several Desiccants, J. Org. Chem., 75:8351-8354 (2010). [cited by applicant]
Chem Station, I tried collecting small silica gel material, blog, 15 pages, posted May 16, 2012, <https://www.chem-station.com/blog/2012/05/post-386.html>. [cited by applicant]
Cramer, H., Different Approaches to Oligonucleotide Synthesis, WAVE Life Sciences, Presented at the 7th Annual Oligo Networking Event, Roche Basel, Switzerland, 31 pages (Mar. 26, 2019). [cited by applicant]
Current Protocols in Nucleic Acid Chemistry, Edited by Beaucage, S.L. et al., Chapter 2: Protection of Nucleosides for Oligonucleotide Synthesis, 2.0.1.-2.16.31 (2012). [cited by applicant]
Deleavey, G.F. and Damha, M.J., Designing chemically modified oligonucleotides for targeted gene silencing. Chem. Biol., 19: 937-54 (2012). [cited by applicant]
Ellington, A. and Pollard, J.D., Introduction to the synthesis and purification of oligonucleotides, Curr. Protoc. Nucleic Acid Chem., Appendix 3:Appendix 3C, (2001). [cited by applicant]
Giebel FilTec, Fundamentals for the regeneration of silica gel, Giebel Adsorber, 5 pages (Jan. 1, 2009), <https://blog.giebel-adsorber.de/wp-content/uploads/2020/02/Silicagel_Fundamentals-Regeneration-Of-Silicagel_EN.pd… [cited by applicant]
Hargreaves, J.S. et al., The Degradation of dG Phosphoramidites in Solution, Nucleosides, Nucleotides and Nucleic Acids, 24(10): 691-707 (2015). [cited by applicant]
International Search Report for PCT/US2017/022135, 3 pages (Jun. 6, 2017). [cited by applicant]
International Search Report for PCT/US2017/062996, 4 pages (mailed Mar. 9, 2018). [cited by applicant]
Iwamoto et al., Stereocontrolled Synthesis of H-phosphonate DNA, Nucleic Acids Symposium Series, (50): 159-60 (2006). [cited by applicant]
Iwamoto, N. et al., Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides, Nature Biotechnology, 1-7 pages (2017). All Supplemental Data, 8-53 pages (2017). [cited by applicant]
Iwamoto, N. et al., Optimization of Therapeutic Phosphorothioate Oligonucleotides by P-Chirality Control, WAVE Life Sciences, PSJ Congress: The Pharmaceutical Society of Japan, (Mar. 25, 2015-Mar. 28, 2016). [cited by applicant]
Iwamoto, N. et al., Stereocontrolled solid-phase synthesis of oligonucleoside H-phosphonates by an oxazaphospholidine approach, Angewandte Chemie International Edition, 48(3):496-499 (2009). [cited by applicant]
Koshkin, A.A. 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… [cited by applicant]
Krotz, A.H. et al., Phosphorothioate Oligonucleotides with Low Phosphate Diester Content: Greater than 99.9% Sulfurization Efficiency with “Aged” Solutions of Phenylacetyl Disulfide (PADS), Organic Process Research & De… [cited by applicant]
Krotz, A.H. et al., Solution Stability and Degradation Pathway of Deoxyriboncleoside Phosphoramidites in Acetonitrile, Nucleosides, Nucleotides and Nucleic Acids, 23(5): 767-775 (2004). [cited by applicant]
Leviten, M., Wave's Purity Progress, Biocentury, 1-6 (Sep. 28, 2017). [cited by applicant]
Meena, Control of Human RNase H Mediated Cleavage by Stereopure Phosphorothioate Oligonucleotides, WAVE Life Sciences, TIDES Meeting, 23 pages (May 3-6, 2015). [cited by applicant]
Meena, Development of Allele Specific Antisense Oligonucleotides, WAVE Life Sciences, ACS Central Regional Meeting (CERM), Covington, KY (May 19, 2016). [cited by applicant]
Meena, Development of Allele Specific Antisense Oligonucleotides, WAVE Life Sciences, TIDES Meeting (May 11, 2016). [cited by applicant]
Meena, et al., Discovery and Early Clinical Development of the First Allele-Specific Stereopure ASO Drug Candidate with Disease—Modifying Potential for the Treatment of Huntington's Disease, WAVE Life Sciences, Poster, … [cited by applicant]
Meena, et al., Therapeutic Implications of Controlling P-Chirality in Phosphorothioate Oligonucleotides, TIDES Poster (May 12-15, 2014). [cited by applicant]
Nawrot et al., DNA Oligonucleotides Containing Stereodefined Phosphorothioate Linkages in Selected Positions, Current Protocols in Nucleic Acid Chemistry, UNIT 4.34: 4.34.1-4.34.15 (2009). [cited by applicant]
Nukaga, Y. et al., Stereocontrolled Solid-Phase Synthesis of Phosphate/Phosphorothioate (PO/PS) Chimeric Oligodeoxyribonucleotides on an Automated Synthesizer Using an Oxazaphospholidine-Phosphoramidite Method, J. Org. … [cited by applicant]
Nukaga, Y. et al., Stereocontrolled Solid-Phase Synthesis of Phosphorothioate Oligoribonucleotides Using 2′-O-(2-Cyanoethoxymethyl)-nucleoside 3′-O-Oxazaphospholiidine Monomers, Journal of Organic Chemistry, 77(18):7913… [cited by applicant]
Oka, N. and Wada, T., Stereocontrolled synthesis of oligonucleotide analogs containing chiral internucleotidic phosphorus atoms, Chemical Society Reviews, 40(12):5829-5843 (2011). [cited by applicant]
Oka, N. et al., Solid-Phase Synthesis of Stereoregular Oligodeoxyribonucleoside Phosphorothioates Using Bicyclic Oxazaphospholidine Derivatives as Monomer Units, Journal of the American Chemical Society, 130(47):16031-1… [cited by applicant]
Oka, N. et al., Solid-Phase Synthesis of Stereoregular Oligodeoxyribonucleoside Phosphorothioates Using Bicyclic Oxazaphospholidine Derivatives as Monomer Units, Journal of the American Chemical Society, 130(47):16031-1… [cited by applicant]
Pubchem, Substance Record for SID 174316404, Available Date: Mar. 31, 2014 (retrieved on Feb. 26, 2018). Retrieved from the Internet: <URL: https://pubchem.ncbi.nlm.nih.gov/substance/174316404>. [cited by applicant]
Pubchem, Substance Record for SID 174316700, Available Date: Mar. 31, 2014 (retrieved on Feb. 26, 2018). Retrieved from the Internet: <URL: https://pubchem.ncbi.nlm.nih.gov/substance/174316700>. [cited by applicant]
Pubchem, Substance Record for SID 174316999, Available Date: Mar. 31, 2014 {retrieved on Feb. 26, 2018). Retrieved from the Internet: <URL: https://pubchem.ncbi.nlm.nih.gov/substance/174316999>. [cited by applicant]
Schultz, R.G. and Gryaznov, S.M., Oligo-24-fluoro-24-deoxynucleotide N3′->P5′ phosphoramidates: synthesis and properties, Nucleic Acids Res., 24(15): 2966-2973 (1996). [cited by applicant]
Silicycle, How can the cols. be cleaned or regenerated, website, 2 pages (Jun. 14, 2021), <https://www.silicycle.com/faq/hplc/how-can-the-columns-be-cleaned-or-regenerated>. [cited by applicant]
Singh, S.K. et al., Synthesis of Novel Bicyclo[2.2.1] Ribonucleosides: 2′-Amino- and 2′-Thio-LNA Monomeric Nucleosides, J. Org. Chem., 63: 6078-6079 (1998). [cited by applicant]
Sorensen, M.D., Functionalized LNA (locked nucleic acid): high-affinity hybridization of oligonucleotides containing N-acylated and N-alkylated 2′-amino-LNA monomers, Chem. Comm., 2130-2131 (2003). [cited by applicant]
Stec, W.J. et al., Deoxyribonucleoside 3′-O-(2-Thio- and 2-Oxo-“spiro”-4,4-pentamethylene-1,3,2-oxathiaphospholane)s: Monomers for Stereocontrolled Synthesis of Oligo(deoxyribonucleoside phosphorothioate)s and Chimeric … [cited by applicant]
Stevens, W.C. et al., General methods for flash chromatography using disposable columns, Molecular Diversity, Kluwer Academic Publishers, DO, 13(2): 247-252 (2009). [cited by applicant]
Swayze, E.E. and Bhat, B., The medicinal chemistry of oligonucleotides, Crooke, S.T. (ed) Antisense Drug Technology: Principles, Strategies, and Applications, CRC Press, Boca Raton, FL: 143-82 (2007). [cited by applicant]
Tian, J. et al., Advancing high-throughput gene synthesis technology, Mol. BioSyst., 5: 714-722 (2009). [cited by applicant]
U.S. Food and Drug Administration, Development of New Stereoisomeric Drugs, 8 pages (May 1, 1992). URL: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122883.htm [Retrieved Jun. 15, 2016]. [cited by applicant]
Verhagen et al., A Conformationally locked Aminomethyl C-Glycoside and Studies on Its N-Pyren-1-ylcarbonyl Derivative Inserted into Oligodeoxynucleotides, European Journal of Organic Chemistry, 2538-2548 (2006). [cited by applicant]
Verma, S. and Eckstein, F., Modified oligonucleotides: synthesis and strategy for users, Annu. Rev. Biochem., 67:99-134 (1998). [cited by applicant]
Wan et al., Synthesis of Second Generation Antisense Oligonucleotides Containing Chiral Phosphorothioate Linkages and Evaluation of their Biophysical Properties and Biological Activity, 10th Annual Meeting of the Oligon… [cited by applicant]
Wan, Q. et al., Thermal pretreatment of silica composite filler materials, Journal of Thermal Analysis and Calorimetry, Kluwer Academic Publishers, Dordrecht, NL, 99(1): 237-243 (2009). [cited by applicant]
Wan, W. B. et al., Synthesis, biophysical properties and biological activity of second generation antisense oligonucleotides containing chiral phosphorothioate linkages, Nucleic Acids Research, 42(22):13456-13468 (2014). [cited by applicant]
Wan, W.B. and Seth, P.P., The Medicinal Chemistry of Therapeutic Oligonucleotides, J. Med. Chem., 59: 9645-9667 (2016). [cited by applicant]
Wan, W.B. et al., Synthesis, biophysical properties and biological activity of second generation antisense oligonucleotides containing chiral phosphorothioate linkages, Nucleic Acid Research, 42: 13456-13468 (2014). Sup… [cited by applicant]
Wilk, A. et al., Deoxyribonucleoside Cyclic N-Acylphosphoramidites as a New Class of Monomers for the Stereocontrolled Synthesis of Oligothymidylyl- and Oligodeoxycytidylyl-Phosphorothioates, Journal of the American Che… [cited by applicant]
Written Opinion for PCT/US2017/022135, 11 pages (Jun. 6, 2017). [cited by applicant]
Written Opinion for PCT/US2017/062996, 9 pages (mailed Mar. 9, 2018). [cited by applicant]
Yu, D. et al., Stereo-enriched phosphorothioate oligonucleotides: synthesis, biophysical and biological properties, Bioorg. Medic.Chem., 8(1):275-284 (2000). [cited by applicant]
Zhuravlev, L. T. et al., Structurally bound water and surface characterization of amorphous silica, Pure & Applied Chemistry, 61(11): 1969-1976 (1989). [cited by applicant]
U.S. Appl. No. 18/836,993, filed Aug. 8, 2024, Kandasamy et al. [cited by applicant]
U.S. Appl. No. 18/843,171, filed Aug. 30, 2024, Hu et al. [cited by applicant]
U.S. Appl. No. 18/856,553, filed Oct. 11, 2024, Lu et al. [cited by applicant]
U.S. Appl. No. 18/864,860, filed Nov. 11, 2024, Shivalila et al. [cited by applicant]
U.S. Appl. No. 18/864,863, filed Nov. 11, 2024, Liu et al. [cited by applicant]
U.S. Appl. No. 18/942,334, filed Nov. 8, 2024, Yang et al. [cited by applicant]
U.S. Appl. No. 18/953,020, filed Nov. 19, 2024, Meena et al. [cited by applicant]
U.S. Appl. No. 19/008,522, filed Jan. 2, 2025, Vargeese et al. [cited by applicant]
U.S. Appl. No. 19/085,460, filed Mar. 20, 2025, Bowman et al. [cited by applicant]
U.S. Appl. No. 19/102,669, filed Feb. 10, 2025, Lake et al. [cited by applicant]
Anonymous, Nucleoside phosphoramidite, Wikipedia, accessed Feb. 6, 2011. <https://en.wikipedia.org/wiki/Nucleoside_phosphoramidite>. [cited by applicant]
Li, N-S and Piccirilli, J. A., Synthesis of the Phosphoramidite Derivatives of 2′-Deoxy-2′-C-α-methylcytidine and 2′-Deoxy-2′-C-α-hydroxymethylcytidine: Analogues for Chemical Dissection of RNA's 2′-Hydroxyl Group, J. O… [cited by applicant]
Sandahl, A. F. et al., On-demand synthesis of phosphoramidites, Nat. Comm., 12(2760):1-7 (2021). [cited by applicant]
Cited By (1)
US 12,674,168