IP Library › Granted Patent US 12,590,115
Granted Patent B2
US 12,590,115 · App. 17/439,755 · Granted Mar 31, 2026

Technologies useful for oligonucleotide preparation

Inventors: Pachamuthu Kandasamy (Lexington, MA); Mamoru Shimizu (Arlington, MA); David Charles Donnell Butler (Medford, MA); Jayakanthan Kumarasamy (Belmont, MA); Gopal Reddy Bommineni (Belmont, MA); Mohammed Rowshon Alam (Milford, MA); Sethumadhavan Divakaramenon (Lexington, MA); Bijay Tilak Bhattarai (Burlington, MA); Chandra Vargeese (Schwenksville, PA); Keith Andrew Bowman (Stow, MA); Stephany Michelle Standley (Wakefield, MA)
Assignee: WAVE LIFE SCIENCES LTD.
C07H1/02C07H19/04C07H21/00
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 12,590,115
App. No.
17/439,755
Granted
Mar 31, 2026
Kind
B2
Abstract

Among other things, the present disclosure provides technologies for oligonucleotide preparation, particularly chirally controlled oligonucleotide preparation, which technologies provide greatly improved crude purity and yield, and significantly reduce manufacturing costs.

Claims (106)

1 . A method for preparing an oligonucleotide, comprising one or more cycles, each of which independently comprises the following steps:

(1) a coupling step;

(2) optionally a pre-modification capping step;

(3) a modification step;

(4) optionally a post-modification capping step; and

(5) optionally a de-blocking step, and

wherein the oligonucleotide comprises a phosphorothioate internucleotidic linkage and an internucleotidic linkage having the structure of

and

wherein in at least one cycle, the coupling step independently comprises reacting a free hydroxyl group of an oligonucleotide or a nucleoside with a coupling partner compound comprising a chiral auxiliary group, and

wherein each partner compound comprising a chiral auxiliary group independently has the structure of

or a salt thereof, wherein:

BA is an optionally substituted group selected from C 3-30 cycloaliphatic, C 6-30 aryl, C 5-30 heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and C 3-30 heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or a nucleobase moiety;

each of R 2s and R 4s is independently R s ;

each R s is independently —H, halogen, —CN, —N 3 , —NO, —NO 2 , -L s -R′, -L s -Si(R) 3 , -L s -OR′, -L s -SR′, -L s —N(R′) 2 , —O-L s -R′, —O-L s -Si(R) 3 , —O-L s -OR′, —O-L s -SR′, or —O-L s -N(R′) 2 ;

R 2 is —CH 2 SO 2 R′, wherein R′ is 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, C 6-30 arylaliphatic, C 6-30 arylheteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

each L s is independently a covalent bond, or a bivalent, optionally substituted, linear or branched group selected from a C 1-30 aliphatic group and a C 1-30 heteroaliphatic group having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, wherein one or more methylene units are optionally and independently replaced by an optionally substituted group selected from C 1-6 alkylene, C 1-6 alkenylene, —C≡C—, a bivalent C 1 -C 6 heteroaliphatic group having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, —C(R′) 2 —, -Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′) C(O)N(R′)—, —N(R′) C(O)O—, —S(O)—, —S(O) 2 ″, —S(O) 2 N(R′)—, —C(O)S—, —C(O)O—, —P(O)(OR′)—, —P(O)(SR′)—, —P(O)(R′)—, —P(O)(NR′)—, —P(S)(OR′)—, —P(S)(SR′)—, —P(S)(R′)—, —P(S)(NR′)—, —P(R′)—, —P(OR′)—, —P(SR′)—, —P(NR′)—, —P(OR′)[B(R′) 3 ]—, —OP(O)(OR′)O—, —OP(O)(SR′)O—, —OP(O)(R′)O—, —OP(O)(NR′)O—, —OP(OR′)O—, —OP(SR′)O—, —OP(NR′)O—, —OP(R′)O—, or —OP(OR′)[B(R′) 3 ]O—, and one or more carbon atoms are optionally and independently replaced with Cy L ;

each -Cy- is independently an optionally substituted bivalent group selected from a C 3-20 cycloaliphatic ring, a C 6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

each Cy L is independently an optionally substituted tetravalent group selected from a C 3-20 cycloaliphatic ring, a C 6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

each R′ is independently —R, —C(O)R, —C(O)OR, or —S(O) 2 R; and

each R is independently —H, 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, C 6-30 arylaliphatic, C 6-30 arylheteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

two R groups are optionally and independently taken together to form a covalent bond, or:

two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or

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

2 . The method of claim 1 , wherein in a partner compound, R 4s is —H.

3 . The method of claim 1 , wherein in a partner compound, R 2s is —H, —F, or —OR, wherein R is optionally substituted C 1-6 aliphatic.

4 . The method of claim 1 , wherein in a partner compound, R 2s is —OCH 3 or —OCH 2 CH 2 OCH 3 .

5 . The method of claim 1 , wherein in a partner compound, R 2s is —OR, wherein R is optionally substituted C 1-6 aliphatic.

6 . The method of claim 1 , wherein in a partner compound, R 2s is —O—Si(R) 3 , wherein each R is independently not —H.

7 . The method of claim 1 , wherein R 2 is —CH 2 SO 2 R′, wherein R′ is optionally substituted phenyl.

8 . The method of claim 1 wherein R 2 is —CH 2 SO 2 R′, wherein R′ is phenyl.

9 . The method of claim 1 , wherein R 2 is —CH 2 SO 2 R′, wherein R′ is tert-butyl.

10 . The method of claim 1 , comprising removal of a chiral auxiliary group by contacting oligonucleotides comprising a chiral auxiliary group with a base under an anhydrous condition.

11 . The method of claim 10 , wherein the product oligonucleotide comprises a sugar comprising 2′-OH.

12 . The method of claim 10 , wherein the product oligonucleotide comprises a natural phosphate linkage.

13 . An oligonucleotide, wherein the oligonucleotide comprises:

an internucleotidic linkage of *P S or *P R; and

an internucleotidic linkage of *N S or *N R;

wherein:

*P S is of formula

or a salt form thereof;

*P R is of formula

or a salt form thereof;

*N S is of formula

or a salt form thereof;

*N R is of formula

or a salt form thereof;

—X-L s -R 5 is

R 4 and R 5 in —X—L S —R 5 are taken together with their intervening atoms to form an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

R 6 is —C(O)R′;

R 2 is —CH 2 SO 2 R′, wherein R′ is 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, C 6-30 arylaliphatic, C 6-30 arylheteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

P=W N is P N ;

P N is P(=N-L-R 5 ),

Q − is an anion;

Ring A L is an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

each of R 1 and R 5 in P N is independently —H, -L s -R′, halogen, —CN, —NO 2 , -L s -Si(R′) 3 , OR′, —SR′, or —N(R′) 2 ;

each R s is independently —H, halogen, CN, —N 3 , —NO, —NO 2 , -L s -R′, -L s -Si(R′) 3 , -L s -OR′, -L s -SR′, -L s —N(R′) 2 , —O-L s -R′, —O-L s -Si(R) 3 , —O-L s -OR′, —O-L s -SR′, or —O-L s —N(R′) 2 ;

g is 0-20;

each of L and L b is independently L S ;

each L s is independently a covalent bond, or a bivalent, optionally substituted, linear or branched group selected from a C 1-30 aliphatic group and a C 1-30 heteroaliphatic group having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, wherein one or more methylene units are optionally and independently replaced by an optionally substituted group selected from C 1-6 alkylene, C 1-6 alkenylene, —C≡C—, a bivalent C 1 -C 6 heteroaliphatic group having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, —C(R′) 2 —, -Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, C(NR′)—, —C(O)N(R′)—, —N(R′) C(O)N(R′)—, —N(R′) C(O)O—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R′)—, —C(O)S—, —C(O)O—, —P(O)(OR′)—, —P(O)(SR′)—, —P(O)(R′)—, —P(O)(NR′)—, —P(S)(OR′)—, —P(S)(SR′)—, —P(S)(R′)—, —P(S)(NR′)—, —P(R′)—, —P(OR′)—, —P(SR′)—, —P(NR′)—, —P(OR′)[B(R′) 3 ]—, —OP(O)(OR′)O—, —OP(O)(SR′)O—, —OP(O)(R′)O—, OP(O)(NR′)O—, —OP(OR′)O—, —OP(SR′)O—, —OP(NR′)O—, —OP(R′)O—, or OP(OR′)[B(R′) 3 ]O—, and one or more carbon atoms are optionally and independently replaced with Cy L ;

each -Cy- is independently an optionally substituted bivalent group selected from a C 3-20 cycloaliphatic ring, a C 6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

each Cy L is independently an optionally substituted tetravalent group selected from a C 3-20 cycloaliphatic ring, a C 6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

each R′ is independently —R, —C(O)R, —C(O)OR, or —S(O) 2 R; and

each R is independently —H, 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, C 6-30 arylaliphatic, C 6-30 arylheteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

two R groups are optionally and independently taken together to form a covalent bond, or:

two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or

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

14 . The oligonucleotide of claim 13 , wherein P=W N in *N S or *N R is

15 . The oligonucleotide of claim 13 , wherein R 2 is —CH 2 SO 2 R′, wherein R′ is optionally substituted phenyl.

16 . The oligonucleotide of claim 13 , wherein R 2 is —CH 2 SO 2 R′, wherein R′ is tert-butyl.

17 . The oligonucleotide of claim 13 , wherein R 2 is —CH 2 SO 2 R′, wherein R′ is phenyl.

18 . A method, comprising contacting an oligonucleotide with a base under an anhydrous condition, wherein the oligonucleotide comprises:

an internucleotidic linkage of *P S or *P R; and

an internucleotidic linkage of *N S or *N R;

wherein:

*P S is of formula

or a salt form thereof;

*P R is of formula

or a salt form thereof ;

*N S is of formula

or a salt form thereof;

*N R is of formula

or a salt form thereof;

—X-L s -R 5 is

R 4 and R 5 in —X—L S —R 5 are taken together with their intervening atoms to form an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

R 6 is —C(O)R′;

R 2 is —CH 2 SO 2 R′, wherein R′ is 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, C 6-30 arylaliphatic, C 6-30 arylheteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

P=W N is P N ;

P N is P(═N-L-R 5 ),

Q − is an anion;

Ring A L is an optionally substituted 3-20 membered monocyclic, bicyclic or polycyclic ring having 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

each of R 1 and R 5 in P N is independently —H, -L s -R′, halogen, —CN, —NO 2 , -L s -Si(R′) 3 , —OR′, —SR′, or —N(R′) 2 ;

each R s is independently —H, halogen, —CN, —N 3 , —NO, —NO 2 , -L s -R′, -L s -Si(R′) 3 , -L s -OR′, -L s -SR′, -L s —N(R′) 2 , —O-L s -R′, —O-L s -Si(R) 3 , —O-L s -OR′, —O-L s -SR′, or —O-L s —N(R′) 2 ;

g is 0-20;

each of L and L b is independently L S ;

each L s is independently a covalent bond, or a bivalent, optionally substituted, linear or branched group selected from a C 1-30 aliphatic group and a C 1-30 heteroaliphatic group having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, wherein one or more methylene units are optionally and independently replaced by an optionally substituted group selected from C 1-6 alkylene, C 1-6 alkenylene, —C≡C—, a bivalent C 1 -C 6 heteroaliphatic group having 1-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, —C(R′) 2 —, -Cy-, —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, C(NR′)—, —C(O)N(R′)—, —N(R′) C(O)N(R′)—, —N(R′) C(O)O—, —S(O)—, —S(0) 2 —, —S(O) 2 N(R′)—, —C(O)S—, —C(O)O—, —P(O)(OR′)—, —P(O)(SR′)—, —P(O)(R′)—, —P(O)(NR′)—, —P(S)(OR′)—, —P(S)(SR′)—, —P(S)(R′)—, —P(S)(NR′)—, —P(R′)—, —P(OR′)—, —P(SR′)—, —P(NR′)—, —P(OR′)[B(R′) 3 ]—, —OP(O)(OR′)O—, —OP(O)(SR′)O—, —OP(O)(R′)O—, OP(O)(NR′)O—, —OP(OR′)O—, —OP(SR′)O—, —OP(NR′)O—, —OP(R′)O—, or OP(OR′)[B(R′) 3 ]O—, and one or more carbon atoms are optionally and independently replaced with Cy L ;

each -Cy- is independently an optionally substituted bivalent group selected from a C 3-20 cycloaliphatic ring, a C 6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

each Cy L is independently an optionally substituted tetravalent group selected from a C 3-20 cycloaliphatic ring, a C 6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon;

each R′ is independently —R, —C(O)R, —C(O)OR, or —S(O) 2 R; and

each R is independently —H, 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, C 6-30 arylaliphatic, C 6-30 arylheteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or

two R groups are optionally and independently taken together to form a covalent bond, or:

two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or

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

19 . The method of claim 18 , wherein R 2 is —CH 2 SO 2 R′, wherein R′ is optionally substituted phenyl.

20 . The method of claim 18 , wherein R 2 is —CH 2 SO 2 R′, wherein R′ is phenyl.

21 . The method of claim 18 , wherein R 2 is —CH 2 SO 2 R′, wherein R′ is tert-butyl.

22 . The method of claim 18 , wherein the base is diethylamine.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 17, 2021
From: KANDASAMY, PACHAMUTHU; SHIMIZU, MAMORU; BUTLER, DAVID CHARLES DONNELL; KUMARASAMY, JAYAKANTHAN; BOMMINENI, GOPAL REDDY; ALAM, MOHAMMED ROWSHON; DIVAKARAMENON, SETHUMADHAVAN; BHATTARAI, BIJAY TILAK; VARGEESE, CHANDRA; BOWMAN, KEITH ANDREW; STANDLEY, STEPHANY MICHELLE
To: WAVE LIFE SCIENCES LTD.
Reel/Frame 058418/0970 →
Continuity (2)
Provisional Application 62821423 · Mar 20, 2019
Related Publication 20230089442A1 · Mar 23, 2023
References Cited (221)
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 12391942B2 · Zhang et al. · 2025 [cited by applicant]
US 12428442B2 · Butler et al. · 2025 [cited by applicant]
US 20060024330A1 · Wai et al. · 2006 [cited by applicant]
US 20150211006A1 · Butler · 2015 [cited by examiner]
US 20180216108A1 · Vargeese et al. · 2018 [cited by applicant]
US 20190077817A1 · Butler et al. · 2019 [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 20190375774A1 · Butler et al. · 2019 [cited by applicant]
US 20200157545A1 · Vargeese et al. · 2020 [cited by applicant]
US 20200190515A1 · Vargeese et al. · 2020 [cited by applicant]
US 20200231620A1 · Bowman et al. · 2020 [cited by applicant]
US 20200299692A1 · Frank-Kamenetsky et al. · 2020 [cited by applicant]
US 20200362337A1 · Dodart et al. · 2020 [cited by applicant]
US 20210032620A1 · Vargeese et al. · 2021 [cited by applicant]
US 20210115444A1 · Meena et al. · 2021 [cited by applicant]
US 20210130821A1 · Butler et al. · 2021 [cited by applicant]
US 20210198305A1 · Vargeese et al. · 2021 [cited by applicant]
US 20210228615A1 · Zhang 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 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 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 20240368207A1 · 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]
US 20250154190A1 · Kandasamy et al. · 2025 [cited by applicant]
US 20250262235A1 · Lu et al. · 2025 [cited by applicant]
US 20250270628A1 · Yang et al. · 2025 [cited by applicant]
US 20250302995A1 · Shivalila et al. · 2025 [cited by applicant]
JP 2003238586A · 2003 [cited by applicant]
WO WO2004007718A2 · 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 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 WO2016028187A1 · 2016 [cited by applicant]
WO WO2017015555A1 · 2017 [cited by applicant]
WO WO2017015575A1 · 2017 [cited by applicant]
WO WO2017062862A2 · 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 WO2018177825A1 · 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 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 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 WO2024035946A1 · 2024 [cited by applicant]
WO WO2025030155A1 · 2025 [cited by applicant]
WO WO2025160090A1 · 2025 [cited by applicant]
U.S. Appl. No. 16/624,896, filed Dec. 19, 2019, Butler et al. [cited by applicant]
U.S. Appl. No. 16/869,126, filed May 7, 2020, Vargeese et al. [cited by applicant]
U.S. Appl. No. 17/046,752, filed Oct. 9, 2020, Zhang et al. [cited by applicant]
U.S. Appl. No. 17/177,111, filed Feb. 16, 2021, Zhang et al. [cited by applicant]
U.S. Appl. No. 17/311,285, filed Jun. 4, 2021, Zhang et al. [cited by applicant]
U.S. Appl. No. 17/375,658, filed Jul. 14, 2021, Vargeese et al. [cited by applicant]
U.S. Appl. No. 17/439,755, filed Sep. 15, 2021, Kandasamy et al. [cited by applicant]
U.S. Appl. No. 17/442,663, filed Sep. 24, 2021, Yokota et al. [cited by applicant]
U.S. Appl. No. 17/605,997, filed Oct. 22, 2021, Byrne et al. [cited by applicant]
U.S. Appl. No. 17/605,998, filed Oct. 22, 2021, Byrne et al. [cited by applicant]
U.S. Appl. No. 17/766,677, filed Apr. 5, 2022, Monlan et al. [cited by applicant]
U.S. Appl. No. 17/766,680, filed Apr. 5, 2022, Liu et al. [cited by applicant]
International Search Report for PCT/US2020/023735, 5 pages (mailed Jul. 9, 2020). [cited by applicant]
Written Opinion for PCT/US2020/023735, 11 pages (mailed Jul. 9, 2020). [cited by applicant]
U.S. Appl. No. 18/204,895, filed Jun. 1, 2023, 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]
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]
Anderson, B. A. et al., Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides, Nucl. Acids. Res., 49… [cited by applicant]
Kupryushkin, M. S. Phosphoryl Guanidines: A New Type of Nucleic Acid Analogues, Acta Naturae, 6(4): 116-118 (2014). [cited by applicant]
Pavlova, A. S. et al., SDS-Page procedure: Application for characterization of new entirely uncharged nucleic acids analogs, Electrophor., 39:670-674 (2018). [cited by applicant]
Zhang, L. et al., The Combination of Mesyl-Phosphoramidate Inter-Nucleotide Linkages and 2′-O-Methyl in Selected Positions in the Antisense Oligonucleotide Enhances the Performance of RNaseH1 Active PS-ASOs, Nucleic Aci… [cited by applicant]
U.S. Appl. No. 19/271,472, filed Jul. 16, 2025, Zhang et al. [cited by applicant]
U.S. Appl. No. 19/276,854, filed Jul. 22, 2025, Zhang et al. [cited by applicant]
U.S. Appl. No. 19/281,441, filed Jul. 25, 2025, Butler et al. [cited by applicant]
U.S. Appl. No. 19/281,453, filed Jul. 25, 2025, Liu et al. [cited by applicant]
U.S. Appl. No. 19/284,561, filed Jul. 29, 2025, Butler et al. [cited by applicant]
U.S. Appl. No. 19/297,725, filed Aug. 12, 2025, Stetsenko et al. [cited by applicant]
Bazhenov, M. A. et al., Study of the Staudinger Reaction and Reveal of Key Factors Affecting the Efficacy of Automatic Synthesis of Phosphoryl Guanidinic Oligonucleotide Analogs, Russian J. Bioorganic Chem., 45(6):699-7… [cited by applicant]
Chubarov, A. S. et al., Allele-Specific PCR for KRAS Mutation Detection Using Phosphoryl Guanidine Modified Primers, Diagnostics, 10(872):1-14 (2020). [cited by applicant]
Dmitrienko, E. et al., Surface modification of SOI-FET sensors for label-free and specific detection of short RNA analyte, Nanomedicine (Lond), 11(16):2073-2082 (2016). [cited by applicant]
Dovydenko, I. S. et al., A convenient solid phase approach to obtain lipophilic 5′—phosphoramidate derivatives of DNA and RNA oligonucleotides, Nucleosides Nucleotides Nucleic Acids, 37(2):102-111 (2018). [cited by applicant]
Dyudeeva, E. S. et al., Physicochemical Properties of the Phosphoryl Guanidine Oligodeoxyribonucleotide Analogs, Russian J. Bioorganic Chem., 45(6):709-718 (2019). [cited by applicant]
Epanchintseva, A. et al., Non-covalent binding of nucleic acids with gold nanoparticles provides their stability and effective desorption in environment mimicking biological media, Nanotech., 29(355601):1-15 (2018). [cited by applicant]
Fokina, A. et al., Analysis of new charge-neutral DNA/RNA analogues phosphoryl guanidine oligonucleotides (PGO) by gel electrophoresis, Analytical Biochemistry, 555: 9-11 (2018). [cited by applicant]
Garafutdinov, R. R. et al., Data on multimerization efficiency for short linear DNA templates and phosphoryl guanidine primers during isothermal amplification with Bst exo-DNA polymerase, Data Brief, 2020 29(105188):1-1… [cited by applicant]
Garafutdinov, R. R. et al., Prevention of DNA multimerization using phosphoryl guanidine primers during isothermal amplification with Bst exo-DNA polymerase, Biochimie, 168:259-267 (2020). [cited by applicant]
Kupryushkin, M et al., ‘Dodecyl-modified oligodeoxyribonucleotides as platform for oligonucleotide delivery into eukaryotic cells,’ 13th Annual Meeting of the Oligonucleotide Therapeutics Society, (2017), abstract 057. [cited by applicant]
Kuznetsov, N. A. et al., New oligonucleotide derivatives as unreactive substrate analogues and potential inhibitors of human apurinic/apyrimidinic endonuclease APE1, Mol. Biosyst., 12(1):67-75 (2016). [cited by applicant]
Kuznetsov, N. A. et al., Pre-steady state kinetics of DNA binding and abasic site hydrolysis by tyrosyl-DNA phosphodiesterase 1, J. Biomol. Struct. Dyn., 35(11):2314-2327 (2017). [cited by applicant]
Lomzov, A. A. et al., Comparative physico chemical and biological studies of phosphorylguanidine oligonucleotide diasteriomers, Book of Abstracts, Albany 2019: The 20th Conversation, 76 (2019). [cited by applicant]
Lomzov, A. A. et al., Data for isolation and properties analysis of diastereomers of a mono-substituted phosphoryl guanidine trideoxyribonucleotide, Data Brief, 25(104148):1-25 (2019). [cited by applicant]
Lomzov, A. A. et al., Diastereomers of a mono-substituted phosphoryl guanidine trideoxyribonucleotide: Isolation and properties, Biochem. Biophys. Res. Commun., 513(4):807-811 (2019). [cited by applicant]
Lomzov, A. A. et al., Structure and hybridization properties of phosphorylguanidine oligonucleotides, Jrnl. Biomol. Struct. Dynamics, 37:83 (2019). [cited by applicant]
Markov, A. V. et al., Antiviral Activity of a New Class of Chemically Modified Antisense Oligonucleotides against Influenza A Virus, Russian J. Bioorganic Chem., 45(6):774-782 (2019). [cited by applicant]
Markov, O. V. et al., Transport Oligonucleotides-A Novel System for Intracellular Delivery of Antisense Therapeutics, Molecules, 25(3663):1-27 (2020). [cited by applicant]
Novopashina, D et al., Novel Peptide Conjugates of Modified Oligonucleotides for Inhibition of Bacterial RNase P, Front. Pharmacol., 10(813):1-21 (2019). [cited by applicant]
Pavlova A. S. et al., Amphiphilic “Like-a-Brush” Oligonucleotide Conjugates with Three Dodecyl Chains: Self-Assembly Features of Novel Scaffold Compounds for Nucleic Acids Delivery, Nanomaterials, 10(1948):1-19 (2020). [cited by applicant]
Su, Y. et al., Neutral and Negatively Charged Phosphate Modifications Altering Thermal Stability, Kinetics of Formation and Monovalent lon Dependence of DNA G-Quadruplexes, Chem. Asian J., 14(8):1212-1220 (2019). [cited by applicant]
Su, Y. et al., The Importance of Phosphates for DNA G-Quadruplex Formation: Evaluation of Zwitterionic G-Rich Oligodeoxynucleotides, ChemBioChem, 21(17):1-13 (2020). [cited by applicant]