IP Library › Granted Patent US 12,344,648
Granted Patent B2
US 12,344,648 · App. 16/999,638 · Granted Jul 1, 2025

IL-15 conjugates and uses thereof

Inventors: Carolina E. Caffaro (La Jolla, CA); Jerod Ptacin (La Jolla, CA); Marcos Milla (La Jolla, CA)
Assignee: Synthrox, Inc.
C07K14/5443C07D487/12
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 12,344,648
App. No.
16/999,638
Granted
Jul 1, 2025
Kind
B2
Abstract

Disclosed herein are interleukin (IL)-15 conjugates and use in the treatment of one or more indications. Also described herein include pharmaceutical compositions and kits comprising one or more of IL-15 conjugates. In some embodiments, at least one amino acid residue in the IL-15 conjugate is replaced by the structure of Formula (I) described herein.

Claims (103)

1. An interleukin-15 (IL-15) conjugate comprising an IL-15 polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1 or 3 in which at least one amino acid residue in the IL-15 polypeptide is replaced by the structure of Formula (I):

wherein:

Z is CH 2 and Y is

Y is CH 2 and Z is

Z is CH 2 and Y is

 or

Y is CH 2 and Z is

W is a PEG group having a molecular weight selected from about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, about 30 kDa, about 35 kDa, about 40 kDa, about 45 kDa, about 50 kDa, and about 60 kDa;

X has the structure:

X−1 indicates the point of attachment to the preceding amino acid residue; and

X+1 indicates the point of attachment to the following amino acid residue;

wherein when the IL-15 conjugate comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1, the at least one amino acid residue replaced by the structure of Formula (I) is located in the IL-15 polypeptide at a position selected from S18, L25, E46, E53, N77, and S83, wherein the residue positions correspond to positions as set forth in SEQ ID NO: 1; and

wherein when the IL-15 conjugate comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3, the at least one amino acid residue replaced by the structure of Formula (I) is located in the IL-15 polypeptide at a position selected from S19, L26, E47, E54, N78, and S84, wherein the residue positions correspond to positions as set forth in SEQ ID NO: 3.

2. The IL-15 conjugate of claim 1 , wherein Z is CH 2 and Y is

3. The IL-15 conjugate of claim 1 , wherein Y is CH 2 and Z is

4. The IL-15 conjugate of claim 1 , wherein Z is CH 2 and Y is

5. The IL-15 conjugate of claim 1 , wherein Y is CH 2 and Z is

6. The IL-15 conjugate of claim 1 , wherein the PEG group has a molecular weight selected from about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, about 30 kDa, about 35 kDa, about 40 kDa, and about 45 kDa.

7. The IL-15 conjugate of claim 6 , wherein the PEG group has a molecular weight of about 30 kDa or about 40 kDa.

8. The IL-15 conjugate of claim 1 , wherein the IL-15 conjugate comprises the amino acid sequence of SEQ ID NO: 1 in which the at least one amino acid residue replaced by the structure of Formula (I) is located in the IL-15 polypeptide at a position selected from S18, L25, E46, E53, N77, and S83.

9. The IL-15 conjugate of claim 1 , wherein the IL-15 conjugate comprises the amino acid sequence of SEQ ID NO: 3 in which the at least one amino acid residue replaced by the structure of Formula (I) is located in the IL-15 polypeptide at a position selected from S19, L26, E47, E54, N78, and S84.

10. The IL-15 conjugate of claim 1 , wherein the structure of Formula (I) has the structure of Formula (II) or Formula (III):

wherein:

W is a PEG group having a molecular weight selected from about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, about 30 kDa, about 35 kDa, about 40 kDa, about 45 kDa, about 50 kDa, and about 60 kDa;

X has the structure:

X−1 indicates the point of attachment to the preceding amino acid residue; and

X+1 indicates the point of attachment to the following amino acid residue.

11. The IL-15 conjugate of claim 1 , wherein W is a linear PEG group.

12. The IL-15 conjugate of claim 11 , wherein W is a methoxy PEG group.

13. The IL-15 conjugate of claim 1 , wherein the structure of Formula (I) has the structure of Formula (IV) or Formula (V):

wherein:

W is a PEG group having a molecular weight selected from about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, about 30 kDa, about 35 kDa, about 40 kDa, about 45 kDa, about 50 kDa, and about 60 kDa;

X has the structure:

X−1 indicates the point of attachment to the preceding amino acid residue; and

X+1 indicates the point of attachment to the following amino acid residue.

14. The IL-15 conjugate of claim 10 , wherein the IL-15 conjugate comprises:

the amino acid sequence of SEQ ID NO: 1 in which the at least one amino acid residue replaced by the structure of Formula (II) or Formula (III) is located in the IL-15 polypeptide at a position selected from S18, L25, E46, E53, N77, and S83; or

the amino acid sequence of SEQ ID NO: 3 in which the at least one amino acid residue replaced by the structure of Formula (II) or Formula (III) is located in the IL-15 polypeptide at a position selected from S19, L26, E47, ,E54, N78, and S84.

15. The IL-15 conjugate of claim 13 , wherein the IL-15 conjugate comprises:

the amino acid sequence of SEQ ID NO: 1 in which the at least one amino acid residue replaced by the structure of Formula (IV) or Formula (V) is located in the IL-15 polypeptide at a position selected from S18, L25, E46, E53, N77, and S83; or

the amino acid sequence of SEQ ID NO: 3 in which the at least one amino acid residue replaced by the structure of Formula (IV) or Formula (V) is located in the IL-15 polypeptide at a position selected from S19, L26, E47, E54, N78, and S84.

16. The IL-15 conjugate of claim 1 , wherein the structure of Formula (I) has the structure of Formula (VI) or Formula (VII):

wherein:

n is an integer such that the PEG group having the structure of —(OCH 2 CH 2 ) n —OCH 3 has a molecular weight selected from about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, about 30 kDa, about 35 kDa, about 40 kDa, about 45 kDa, about 50 kDa, and about 60 kDa;

X has the structure:

X−1 indicates the point of attachment to the preceding amino acid residue; and

X+1 indicates the point of attachment to the following amino acid residue.

17. The IL-15 conjugate of claim 16 , wherein the IL-15 conjugate comprises:

the amino acid sequence of SEQ ID NO: 1 in which the at least one amino acid residue replaced by the structure of Formula (VI) or Formula (VII) is located in the IL-15 polypeptide at a position selected from S18, L25, E46, E53, N77, and S83; or

the amino acid sequence of SEQ ID NO: 3 in which the at least one amino acid residue replaced by the structure of Formula (VI) or Formula (VII) is located in the IL-15 polypeptide at a position selected from S19, L26, E47, E54, N78, and S84.

18. The IL-15 conjugate of claim 1 , wherein the structure of Formula (I) has the structure of Formula (VIII) or Formula (IX):

wherein:

n is an integer such that the PEG group having the structure of —(OCH 2 CH 2 ) n —OCH 3 has a molecular weight selected from about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, about 30 kDa, about 35 kDa, about 40 kDa, about 45 kDa, about 50 kDa, and about 60 kDa;

X has the structure:

X−1 indicates the point of attachment to the preceding amino acid residue; and

X+1 indicates the point of attachment to the following amino acid residue.

19. The IL-15 conjugate of claim 1 , which is a pharmaceutically acceptable salt, solvate, or hydrate.

20. The IL-15 conjugate of claim 18 , wherein the IL-15 conjugate comprises:

the amino acid sequence of SEQ ID NO: 1 in which the at least one amino acid residue replaced by the structure of Formula (VIII) or Formula (IX) is located in the IL-15 polypeptide at a position selected from S18, L25, E46, E53, N77, and S83; or

the amino acid sequence of SEQ ID NO: 3 in which the at least one amino acid residue replaced by the structure of Formula (VI) or Formula (VII) is located in the IL-15 polypeptide at a position selected from S19, L26, E47, E54, N78, and S84.

21. A pharmaceutical composition comprising an effective amount of the IL-15 conjugate of claim 1 .

22. The pharmaceutical composition of claim 21 , wherein the pharmaceutical composition comprises a mixture of IL-15 conjugates, wherein the mixture comprises (i) IL-15 conjugates in which the structure of Formula (I) has the structure of Formula (II) and (ii) IL-15 conjugates in which the structure of Formula (I) has the structure of Formula (III):

wherein:

W is a PEG group having a molecular weight selected from about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, about 30 kDa, about 35 kDa, about 40 kDa, about 45 kDa, about 50 kDa, and about 60 kDa;

X has the structure:

X−1 indicates the point of attachment to the preceding amino acid residue; and

X+1 indicates the point of attachment to the following amino acid residue.

23. The pharmaceutical composition of claim 21 , wherein the pharmaceutical composition comprises a mixture of IL-15 conjugates, wherein the mixture comprises (i) IL-15 conjugates in which the structure of Formula (I) has the structure of Formula (IV) and (ii) IL-15 conjugates in which the structure of Formula (I) has the structure of Formula (V):

wherein:

W is a PEG group having a molecular weight selected from about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, about 30 kDa, about 35 kDa, about 40 kDa, about 45 kDa, about 50 kDa, and about 60 kDa;

X has the structure:

X−1 indicates the point of attachment to the preceding amino acid residue; and

X+1 indicates the point of attachment to the following amino acid residue.

24. The pharmaceutical composition of claim 21 , wherein the pharmaceutical composition comprises a mixture of IL-15 conjugates, wherein the mixture comprises (i) IL-15 conjugates in which the structure of Formula (I) has the structure of Formula (VI) and (ii) IL-15 conjugates in which the structure of Formula (I) has the structure of Formula (VII):

wherein:

n is an integer such that the PEG group having the structure of —(OCH 2 CH 2 ) n —OCH 3 has a molecular weight selected from about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, about 30 kDa, about 35 kDa, about 40 kDa, about 45 kDa, about 50 kDa, and about 60 kDa;

X has the structure:

X−1 indicates the point of attachment to the preceding amino acid residue; and

X+1 indicates the point of attachment to the following amino acid residue.

25. The pharmaceutical composition of claim 21 , wherein the pharmaceutical composition comprises a mixture of IL-15 conjugates, wherein the mixture comprises (i) IL-15 conjugates in which the structure of Formula (I) has the structure of Formula (VIII) and (ii) IL-15 conjugates in which the structure of Formula (I) has the structure of Formula (IX):

wherein:

n is an integer such that the PEG group having the structure of —(OCH 2 CH 2 ) n —OCH 3 has a molecular weight selected from about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, about 30 kDa, about 35 kDa, about 40 kDa, about 45 kDa, about 50 kDa, and about 60 kDa;

X has the structure:

X−1 indicates the point of attachment to the preceding amino acid residue; and

X+1 indicates the point of attachment to the following amino acid residue.

26. The IL-15 conjugate of claim 1 , wherein the IL-15 polypeptide comprises:

an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 1 in which the at least one amino acid residue replaced by the structure of Formula (I) is located in the IL-15 polypeptide at a position selected from S18, L25, E46, E53, N77, and S83; or

an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 3 in which the at least one amino acid residue replaced by the structure of Formula (I) is located in the IL-15 polypeptide at a position selected from S19, L26, E47, E54, N78, and S84.

27. The IL-15 conjugate of claim 10 , wherein the IL-15 polypeptide comprises:

an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 1 in which the at least one amino acid residue replaced by the structure of Formula (II) or Formula (III) is located in the IL-15 polypeptide at a position selected from S18, L25, E46, E53, N77, and S83; or

an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 3 in which the at least one amino acid residue replaced by the structure of Formula (II) or Formula (III) is located in the IL-15 polypeptide at a position selected from S19, L26, E47, E54, N78, and S84.

28. The IL-15 conjugate of claim 13 , wherein the IL-15 polypeptide comprises:

an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 1 in which the at least one amino acid residue replaced by the structure of Formula (IV) or Formula (V) is located in the IL-15 polypeptide at a position selected from S18, L25, E46, E53, N77, and S83; or

an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 3 in which the at least one amino acid residue replaced by the structure of Formula (IV) or Formula (V) is located in the IL-15 polypeptide at a position selected from S19, L26, E47, E54, N78, and S84.

29. The IL-15 conjugate of claim 16 , wherein the IL-15 polypeptide comprises:

an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 1 in which the at least one amino acid residue replaced by the structure of Formula (VI) or Formula (VII) is located in the IL-15 polypeptide at a position selected from S18, L25, E46, E53, N77, and S83; or

an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 3 in which the at least one amino acid residue replaced by the structure of Formula (VI) or Formula (VII) is located in the IL-15 polypeptide at a position selected from S19, L26, E47, E54, N78, and S84.

30. The IL-15 conjugate of claim 18 , wherein the IL-15 polypeptide comprises:

an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 1 in which the at least one amino acid residue replaced by the structure of Formula (VIII) or Formula (IX) is located in the IL-15 polypeptide at a position selected from S18, L25, E46, E53, N77, and S83; or

an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 3 in which the at least one amino acid residue replaced by the structure of Formula (VIII) or Formula (IX) is located in the IL-15 polypeptide at a position selected from S19, L26, E47, E54, N78, and S84.

31. The IL-15 conjugate of claim 17 , wherein n in Formula (VI) or Formula (VII) is an integer such that the PEG group having the structure of —(OCH 2 CH 2 ) n —OCH 3 has a molecular weight of about 30 kDa or about 40 kDa.

32. The IL-15 conjugate of claim 20 , wherein n in Formula (VIII) or Formula (IX) is an integer such that the PEG group having the structure of —(OCH 2 CH 2 ) n —OCH 3 has a molecular weight of about 30 kDa or about 40 kDa.

33. An IL-15 conjugate comprising the amino acid sequence of any one of SEQ ID NOs: 4-9 and 52-57, wherein X is N6-((2-azidoethoxy)-carbonyl)-L-lysine (AzK) covalently attached via a conjugating moiety comprising a dibenzocyclooctyne group to a PEG group having a molecular weight of about 30 kDa or about 40 kDa.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 12, 2025
From: SYNTHORX, INC.
To: SANOFI
Reel/Frame 073718/0079 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 16, 2020
From: PTACIN, JEROD; CAFFARO, CAROLINA E.; MILLA, MARCOS
To: SYNTHORX, INC.
Reel/Frame 054073/0109 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 16, 2020
From: PTACIN, JEROD; CAFFARO, CAROLINA E.; MILLA, MARCOS
To: SYNTHORX, INC.
Reel/Frame 054073/0161 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 16, 2020
From: PTACIN, JEROD; CAFFARO, CAROLINA E.; MILLA, MARCOS
To: SYNTHORX, INC.
Reel/Frame 054383/0138 →
Continuity (4)
Provisional Application 62958177 · Jan 7, 2020
Provisional Application 62931663 · Nov 6, 2019
Provisional Application 62890741 · Aug 23, 2019
Related Publication 20210054040A1 · Feb 25, 2021
References Cited (383)
US 3687808A · Merigan, Jr. et al. · 1972 [cited by applicant]
US 4469863A · Ts'o et al. · 1984 [cited by applicant]
US 4476301A · Imbach et al. · 1984 [cited by applicant]
US 4587044A · Miller et al. · 1986 [cited by applicant]
US 4605735A · Miyoshi et al. · 1986 [cited by applicant]
US 4667025A · Miyoshi et al. · 1987 [cited by applicant]
US 4762779A · Snitman · 1988 [cited by applicant]
US 4789737A · Miyoshi et al. · 1988 [cited by applicant]
US 4824941A · Gordon et al. · 1989 [cited by applicant]
US 4828979A · Klevan et al. · 1989 [cited by applicant]
US 4835263A · Nguyen et al. · 1989 [cited by applicant]
US 4845205A · Dinh et al. · 1989 [cited by applicant]
US 4849513A · Smith et al. · 1989 [cited by applicant]
US 4876335A · Yamane et al. · 1989 [cited by applicant]
US 4904582A · Tullis · 1990 [cited by applicant]
US 4910300A · Urdea et al. · 1990 [cited by applicant]
US 4948882A · Ruth · 1990 [cited by applicant]
US 4958013A · Letsinger · 1990 [cited by applicant]
US 4981957A · Lebleu et al. · 1991 [cited by applicant]
US 5015733A · Smith et al. · 1991 [cited by applicant]
US 5023243A · Tullis · 1991 [cited by applicant]
US 5034506A · Summerton et al. · 1991 [cited by applicant]
US 5082830A · Brakel et al. · 1992 [cited by applicant]
US 5093232A · Urdea et al. · 1992 [cited by applicant]
US 5109124A · Ramachandran et al. · 1992 [cited by applicant]
US 5112963A · Pieles et al. · 1992 [cited by applicant]
US 5118800A · Smith et al. · 1992 [cited by applicant]
US 5118802A · Smith et al. · 1992 [cited by applicant]
US 5130302A · Spielvogel et al. · 1992 [cited by applicant]
US 5134066A · Rogers et al. · 1992 [cited by applicant]
US 5138045A · Cook 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 5177196A · Meyer, Jr. et al. · 1993 [cited by applicant]
US 5185444A · Summerton et al. · 1993 [cited by applicant]
US 5188897A · Suhadolnik et al. · 1993 [cited by applicant]
US 5214134A · Weis et al. · 1993 [cited by applicant]
US 5214136A · Lin et al. · 1993 [cited by applicant]
US 5216141A · Benner · 1993 [cited by applicant]
US 5218105A · Cook et al. · 1993 [cited by applicant]
US 5235033A · Summerton et al. · 1993 [cited by applicant]
US 5245022A · Weis et al. · 1993 [cited by applicant]
US 5254469A · Warren, III et al. · 1993 [cited by applicant]
US 5258506A · Urdea et al. · 1993 [cited by applicant]
US 5262536A · Hobbs, Jr. · 1993 [cited by applicant]
US 5264423A · Cohen et al. · 1993 [cited by applicant]
US 5264562A · Matteucci · 1993 [cited by applicant]
US 5264564A · Matteucci · 1993 [cited by applicant]
US 5272250A · Spielvogel et al. · 1993 [cited by applicant]
US 5276019A · Cohen et al. · 1994 [cited by applicant]
US 5278302A · Caruthers et al. · 1994 [cited by applicant]
US 5286717A · Cohen et al. · 1994 [cited by applicant]
US 5292873A · Rokita et al. · 1994 [cited by applicant]
US 5317098A · Shizuya et al. · 1994 [cited by applicant]
US 5319080A · Leumann · 1994 [cited by applicant]
US 5321131A · Agrawal et al. · 1994 [cited by applicant]
US 5359044A · Cook et al. · 1994 [cited by applicant]
US 5367066A · Urdea et al. · 1994 [cited by applicant]
US 5371241A · Brush · 1994 [cited by applicant]
US 5391723A · Priest · 1995 [cited by applicant]
US 5393878A · Leumann · 1995 [cited by applicant]
US 5399676A · Froehler · 1995 [cited by applicant]
US 5405938A · Summerton et al. · 1995 [cited by applicant]
US 5405939A · Suhadolnik et al. · 1995 [cited by applicant]
US 5414077A · Lin et al. · 1995 [cited by applicant]
US 5416203A · Letsinger · 1995 [cited by applicant]
US 5432272A · Benner · 1995 [cited by applicant]
US 5434257A · Matteucci et al. · 1995 [cited by applicant]
US 5451463A · Nelson et al. · 1995 [cited by applicant]
US 5453496A · Caruthers et al. · 1995 [cited by applicant]
US 5455233A · Spielvogel et al. · 1995 [cited by applicant]
US 5457187A · Gmeiner et al. · 1995 [cited by applicant]
US 5459255A · Cook et al. · 1995 [cited by applicant]
US 5466677A · Baxter et al. · 1995 [cited by applicant]
US 5466786A · Buhr et al. · 1995 [cited by applicant]
US 5470967A · Huie et al. · 1995 [cited by applicant]
US 5476925A · Letsinger et al. · 1995 [cited by applicant]
US 5484908A · Froehler et al. · 1996 [cited by applicant]
US 5486603A · Buhr · 1996 [cited by applicant]
US 5489677A · Sanghvi et al. · 1996 [cited by applicant]
US 5502177A · Matteucci et al. · 1996 [cited by applicant]
US 5510475A · Agrawal et al. · 1996 [cited by applicant]
US 5512439A · Hornes et al. · 1996 [cited by applicant]
US 5512667A · Reed et al. · 1996 [cited by applicant]
US 5514785A · Ness et al. · 1996 [cited by applicant]
US 5519126A · Hecht · 1996 [cited by applicant]
US 5519134A · Acevedo et al. · 1996 [cited by applicant]
US 5525465A · Haralambidis et al. · 1996 [cited by applicant]
US 5525711A · Hawkins et al. · 1996 [cited by applicant]
US 5536821A · Agrawal et al. · 1996 [cited by applicant]
US 5539082A · Nielsen et al. · 1996 [cited by applicant]
US 5541306A · Agrawal et al. · 1996 [cited by applicant]
US 5541307A · Cook et al. · 1996 [cited by applicant]
US 5541313A · Ruth · 1996 [cited by applicant]
US 5545730A · Urdea et al. · 1996 [cited by applicant]
US 5550111A · Suhadolnik et al. · 1996 [cited by applicant]
US 5552538A · Urdea et al. · 1996 [cited by applicant]
US 5552540A · Haralambidis · 1996 [cited by applicant]
US 5561225A · Maddry et al. · 1996 [cited by applicant]
US 5563253A · Agrawal et al. · 1996 [cited by applicant]
US 5565552A · Magda et al. · 1996 [cited by applicant]
US 5567810A · Weis et al. · 1996 [cited by applicant]
US 5567811A · Misiura et al. · 1996 [cited by applicant]
US 5571799A · Tkachuk et al. · 1996 [cited by applicant]
US 5574142A · Meyer, Jr. et al. · 1996 [cited by applicant]
US 5576427A · Cook et al. · 1996 [cited by applicant]
US 5578717A · Urdea et al. · 1996 [cited by applicant]
US 5578718A · Cook et al. · 1996 [cited by applicant]
US 5580731A · Chang et al. · 1996 [cited by applicant]
US 5585481A · Arnold, Jr. et al. · 1996 [cited by applicant]
US 5587361A · Cook et al. · 1996 [cited by applicant]
US 5587371A · Sessler et al. · 1996 [cited by applicant]
US 5587469A · Cook et al. · 1996 [cited by applicant]
US 5591584A · Chang et al. · 1997 [cited by applicant]
US 5591722A · Montgomery et al. · 1997 [cited by applicant]
US 5594121A · Froehler et al. · 1997 [cited by applicant]
US 5595726A · Magda et al. · 1997 [cited by applicant]
US 5596086A · Matteucci et al. · 1997 [cited by applicant]
US 5596091A · Switzer · 1997 [cited by applicant]
US 5597696A · Linn et al. · 1997 [cited by applicant]
US 5597909A · Urdea et al. · 1997 [cited by applicant]
US 5599923A · Sessler et al. · 1997 [cited by applicant]
US 5599928A · Hemmi et al. · 1997 [cited by applicant]
US 5602240A · Mesmaeker et al. · 1997 [cited by applicant]
US 5608046A · Cook et al. · 1997 [cited by applicant]
US 5610289A · Cook et al. · 1997 [cited by applicant]
US 5610300A · Altmann et al. · 1997 [cited by applicant]
US 5614617A · Cook et al. · 1997 [cited by applicant]
US 5618704A · Sanghvi et al. · 1997 [cited by applicant]
US 5623070A · Cook et al. · 1997 [cited by applicant]
US 5625050A · Beaton et al. · 1997 [cited by applicant]
US 5627053A · Usman et al. · 1997 [cited by applicant]
US 5633360A · Bischofberger et al. · 1997 [cited by applicant]
US 5639873A · Barascut et al. · 1997 [cited by applicant]
US 5645985A · Froehler et al. · 1997 [cited by applicant]
US 5646265A · McGee · 1997 [cited by applicant]
US 5658873A · Bertsch-Frank et al. · 1997 [cited by applicant]
US 5663312A · Chaturvedula · 1997 [cited by applicant]
US 5670633A · Cook et al. · 1997 [cited by applicant]
US 5677437A · Teng et al. · 1997 [cited by applicant]
US 5677439A · Weis et al. · 1997 [cited by applicant]
US 5681941A · Cook et al. · 1997 [cited by applicant]
US 5688941A · Cook et al. · 1997 [cited by applicant]
US 5700920A · Altmann et al. · 1997 [cited by applicant]
US 5714331A · Ole Buchardt et al. · 1998 [cited by applicant]
US 5719262A · Ole Buchardt et al. · 1998 [cited by applicant]
US 5750692A · Cook et al. · 1998 [cited by applicant]
US 5763588A · Matteucci et al. · 1998 [cited by applicant]
US 5830653A · Froehler et al. · 1998 [cited by applicant]
US 6005096A · Matteucci et al. · 1999 [cited by applicant]
US 6268490B1 · Imanishi et al. · 2001 [cited by applicant]
US 6525191B1 · Ramasamy · 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 6955807B1 · Shanafelt et al. · 2005 [cited by applicant]
US 7034133B2 · Wengel et al. · 2006 [cited by applicant]
US 7053207B2 · Wengel · 2006 [cited by applicant]
US 7399845B2 · Seth et al. · 2008 [cited by applicant]
US 7427672B2 · Imanishi et al. · 2008 [cited by applicant]
US 8012465B2 · Elias et al. · 2011 [cited by applicant]
US 8501805B2 · Seth et al. · 2013 [cited by applicant]
US 8546556B2 · Seth et al. · 2013 [cited by applicant]
US 9682934B2 · Stafford et al. · 2017 [cited by applicant]
US 9732134B2 · Gavin et al. · 2017 [cited by applicant]
US 9840493B2 · Yang et al. · 2017 [cited by applicant]
US 9861705B2 · Bossard et al. · 2018 [cited by applicant]
US 9938516B2 · Zimmerman et al. · 2018 [cited by applicant]
US 9988619B2 · Zimmerman et al. · 2018 [cited by applicant]
US 10610571B2 · Ptacin et al. · 2020 [cited by applicant]
US 10851144B2 · Butz et al. · 2020 [cited by applicant]
US 10960079B2 · Bossard et al. · 2021 [cited by applicant]
US 11077195B2 · Ptacin et al. · 2021 [cited by applicant]
US 11622993B2 · Ptacin et al. · 2023 [cited by applicant]
US 11701407B2 · Ptacin et al. · 2023 [cited by applicant]
US 20040171570A1 · Allerson et al. · 2004 [cited by applicant]
US 20050130923A1 · Bhat et al. · 2005 [cited by applicant]
US 20060074035A1 · Hong et al. · 2006 [cited by applicant]
US 20070287831A1 · Seth et al. · 2007 [cited by applicant]
US 20080039618A1 · Allerson et al. · 2008 [cited by applicant]
US 20100316595A1 · Elias et al. · 2010 [cited by applicant]
US 20170260137A1 · Stafford et al. · 2017 [cited by applicant]
US 20170313753A1 · Gavin et al. · 2017 [cited by applicant]
US 20180086734A1 · Yang et al. · 2018 [cited by applicant]
US 20200181220A1 · Ptacin et al. · 2020 [cited by applicant]
US 20200188484A1 · Ptacin et al. · 2020 [cited by applicant]
US 20200231644A1 · Ptacin et al. · 2020 [cited by applicant]
US 20200246467A1 · Ptacin et al. · 2020 [cited by applicant]
US 20200299349A1 · Garcia et al. · 2020 [cited by applicant]
US 20200330601A1 · Ptacin et al. · 2020 [cited by applicant]
US 20200399338A1 · Caffaro et al. · 2020 [cited by applicant]
US 20210023230A1 · Bossard et al. · 2021 [cited by applicant]
US 20210024602A1 · Sprogøe et al. · 2021 [cited by applicant]
US 20210046160A1 · Ptacin et al. · 2021 [cited by applicant]
US 20210054040A1 · Caffaro et al. · 2021 [cited by applicant]
US 20210060169A1 · Ikeda et al. · 2021 [cited by applicant]
US 20210070827A1 · Ptacin et al. · 2021 [cited by applicant]
US 20210139554A1 · Butz et al. · 2021 [cited by applicant]
US 20210196796A1 · Penaflor-Aspuria et al. · 2021 [cited by applicant]
US 20210221863A1 · Kang et al. · 2021 [cited by applicant]
US 20210338829A1 · Caffaro et al. · 2021 [cited by applicant]
US 20220016249A1 · Ptacin et al. · 2022 [cited by applicant]
US 20220016252A1 · Abbadessa et al. · 2022 [cited by applicant]
US 20220273767A1 · Caffaro et al. · 2022 [cited by applicant]
US 20220324792A1 · Aerni et al. · 2022 [cited by applicant]
US 20230277627A1 · Caffaro et al. · 2023 [cited by applicant]
US 20230302089A1 · Caffaro et al. · 2023 [cited by applicant]
US 20230416327A1 · Caffaro et al. · 2023 [cited by applicant]
US 20240082359A1 · Ptacin et al. · 2024 [cited by applicant]
US 20240226309A1 · Abbadessa et al. · 2024 [cited by applicant]
US 20240287151A1 · Caffaro et al. · 2024 [cited by applicant]
EP 0614907A1 · 1994 [cited by applicant]
EP 0629633A2 · 1994 [cited by applicant]
EP 2382228B1 · 2020 [cited by applicant]
EP 3280725B1 · 2020 [cited by applicant]
JP 2019503348A1 · 2019 [cited by applicant]
JP 2021514974A1 · 2021 [cited by applicant]
RU 2644671C2 · 2018 [cited by applicant]
WO 9213869A1 · 1992 [cited by applicant]
WO 9414226A1 · 1994 [cited by applicant]
WO 9422890A1 · 1994 [cited by applicant]
WO 9735869A1 · 1997 [cited by applicant]
WO 1999014226A3 · 1999 [cited by applicant]
WO 9962923A2 · 1999 [cited by applicant]
WO 0105801A1 · 2001 [cited by applicant]
WO 02070533A2 · 2002 [cited by applicant]
WO 2004007713A1 · 2004 [cited by applicant]
WO 2004106356A1 · 2004 [cited by applicant]
WO 2005021570A1 · 2005 [cited by applicant]
WO 2005026187A1 · 2005 [cited by applicant]
WO 2006049297A1 · 2006 [cited by applicant]
WO 2007015557A1 · 2007 [cited by applicant]
WO 2007066737A1 · 2007 [cited by applicant]
WO 2007090071A2 · 2007 [cited by applicant]
WO 2007134181A3 · 2008 [cited by applicant]
WO 2008101157A1 · 2008 [cited by applicant]
WO 2009006478A2 · 2009 [cited by applicant]
WO 2008150729A3 · 2009 [cited by applicant]
WO 2008154401A3 · 2009 [cited by applicant]
WO 2009123216A1 · 2009 [cited by applicant]
WO 2011043385A1 · 2011 [cited by applicant]
WO 2011139699A3 · 2013 [cited by applicant]
WO 2015021432A1 · 2015 [cited by applicant]
WO WO2015153753A2 · 2015 [cited by examiner]
WO 2015157555 · 2016 [cited by applicant]
WO 2016115168A1 · 2016 [cited by applicant]
WO 2017106767A1 · 2017 [cited by applicant]
WO WO2017112528A2 · 2017 [cited by examiner]
WO 2017223528A1 · 2017 [cited by applicant]
WO 2019014262A1 · 2019 [cited by applicant]
WO 2019014267A1 · 2019 [cited by applicant]
WO 2019028419A1 · 2019 [cited by applicant]
WO WO2019028425A1 · 2019 [cited by examiner]
WO 2019165453A1 · 2019 [cited by applicant]
WO 2020020783A1 · 2020 [cited by applicant]
WO 2020056066A1 · 2020 [cited by applicant]
WO 2020097325A1 · 2020 [cited by applicant]
WO 2020146221A1 · 2020 [cited by applicant]
WO 2020163532A1 · 2020 [cited by applicant]
WO 2020201095A1 · 2020 [cited by applicant]
WO 2020219943A1 · 2020 [cited by applicant]
WO 2020252418A2 · 2020 [cited by applicant]
WO 2021030374A1 · 2021 [cited by applicant]
WO 2021030483A1 · 2021 [cited by applicant]
WO 2021030602A1 · 2021 [cited by applicant]
WO 2021030706A1 · 2021 [cited by applicant]
WO 2021041206A1 · 2021 [cited by applicant]
WO 2021050554A1 · 2021 [cited by applicant]
WO 2021091986A1 · 2021 [cited by applicant]
WO 2021093633A1 · 2021 [cited by applicant]
WO 2021133839A1 · 2021 [cited by applicant]
WO 2021140416A2 · 2021 [cited by applicant]
WO 2021263026A1 · 2021 [cited by applicant]
WO 2022076853A1 · 2022 [cited by applicant]
WO 2022076859A1 · 2022 [cited by applicant]
WO 2022174101A1 · 2022 [cited by applicant]
WO 202256538A1 · 2022 [cited by applicant]
WO 2023127750A1 · 2023 [cited by applicant]
WO 2023137401A1 · 2023 [cited by applicant]
Bohringer et al. Synthesis of 5′-deoxy-5′-methylphosphonate linked thymidine oligonucleotides. Tet Lett 34:2723-2726 (1993). [cited by applicant]
Braasch et al. Locked nucleic acid (LNA): fine-tuning the recognition of DNA and RNA. Chem Bio 8:1-7 (2001). [cited by applicant]
Chaturvedi et al. Stabilization of triple-stranded oligonucleotide complexes: use of probes containing alternating phosphodiester and stereo-uniform cationic phosphoramidate linkages. Nucleic Acids Res. 24:2318-2323 (19… [cited by applicant]
Chen et al. Phosphonate Analogues of Cytosine Arabinoside Monophosphate. Phosphorus, Sulfur and Silicon 177:1783-1786 (2002). [cited by applicant]
Chen et al. Selective chemical labeling of proteins. Org. Biomol. Chem. 14:5417 (2016). [cited by applicant]
Collingwood et al. The Synthesis and Incorporation in Oligonucleotides of a Thymidine Dimer Containing an Internucleoside Phosphinate Linkage. Synlett 7:703-705 (1995). [cited by applicant]
Crooke et al. Pharmacokinetic properties of several novel oligonucleotide analogs in mice. J Pharmacol Exp Ther 277:923-937 (1996). [cited by applicant]
De Mesmaeker et al. Amide-Modified Oligonucleotides with Preorganized Backbone and Furanose Rings: Highly Increased Thermodynamic Stability of the Duplexes Formed with their RNA and DNA Complements. Synlett 1997(11) 128… [cited by applicant]
Dhami et al. Systematic exploration of a class of hydrophobic unnatural base pairs yields multiple new candidates for the expansion of the genetic alphabet. Nucleic Acids Res 42:10235-10244 (2014). [cited by applicant]
Dien et al. Progress Toward a Semi-Synthetic Organism with an Unrestricted Expanded Genetic Alphabet. J Am Chem Soc. 140:16115-16123 (2018). [cited by applicant]
Dumas et al. Designing logical codon reassignment—Expanding the chemistry in biology. Chem Sci 6:50-69 (2015). [cited by applicant]
Elayadi et al. Application of PNA and LNA oligomers to chemotherapy. Curr Opinion Invens Drugs 2:558-561 (2001). [cited by applicant]
Englisch et al. Chemically Modified Oligonucleotides as Probes and Inhibitors. Angew. Chem. Int. Ed. Eng. 30:613-629 (1991). [cited by applicant]
Eppacher et al. Synthesis and Incorporation of C(5 ′)-Ethynylated Uracil-Derived Phosphoramidites into RNA. Helvetica Chimica Acta 87:3004-3020 (2004). [cited by applicant]
Fairhurst et al. Synthesis and Hybridisation Properties of Phosphonamidate Ester Modified Nucleic Acid. Synlett 4:467-472 (2001). [cited by applicant]
Feldman et al. A Tool for the Import of Natural and Unnatural Nucleoside Triphosphates into Bacteria. J Am Chem Soc 140(4):1447-1454 (2018). [cited by applicant]
Feldman et al. In Vivo Structure-Activity Relationships and Optimization of an Unnatural Base Pair for Replication in a Semi-Synthetic Organism. J Am Chem Soc 139:11427-11433 (2017). [cited by applicant]
Feldman. Expansion of the Genetic Alphabet: A Chemist's Approach to Synthetic Biology. Ace Chem Res 51 (2):394-403 (2018). [cited by applicant]
Gallier et al. Ex-Chiral-Pool Synthesis of 13-Hydroxyphosphonate Nucleoside Analogues. Eur J Org Chem 6:925-933 (2007). [cited by applicant]
Gong et al. Recent advances in bioorthogonal reactions for site-specific protein labeling and engineering. Tetrahedron Letters 56:2123-2131 (2015). [cited by applicant]
Hampton et al. Design of substrate-site-directed inhibitors of adenylate kinase and hexokinase. Effect of substrate substituents on affinity on affinity for the adenine nucleotide sites. J Med Chem 19:1371-1377 (1976). [cited by applicant]
Hampton et al. Design of substrate-site-directed irreversible inhibitors of adenosine 5′-phosphate aminohydrolase. Effect of substrate substituents on affinity for the substrate site. J Med Chem 19(8):1029-1033 (1976). [cited by applicant]
Hampton et al. Synthesis of 6′-cyano-6′-deoxyhomoadenosine-6′-phosphonic acid and its phosphoryl and pyrophosphoryl an hydrides and studies of their interactions with adenine nucleotide utilizing enzymes. J Am Chem Soc … [cited by applicant]
Hutter et al. From Phosphate to Bis(methylene) Sulfone: Non-Ionic Backbone Linkers in DNA. Helvetica Chimica Acta 85:2777-2806 (2002). [cited by applicant]
Jager et al. Oligonucleotide N-alkylphosphoramidates: synthesis and binding to polyn ucleotides. Biochemistry 27 :724 7-7246 (1988). [cited by applicant]
Jung et al. Synthesis of phosphonate derivatives of uridine, cytidine, and cytosine arabinoside. Bioorg Med Chem 8:2501-2509 (2000). [cited by applicant]
Kandimalla et al. Effect of chemical modifications of cytosine and guanine in a CpG-motif of oligonucleotides: structure-immunostimulatory activity relationships. Bioorg. Med. Chem. 9:807-813 (2001). [cited by applicant]
Kappler et al. Isozyme-specific enzyme inhibitors. 11. L-homocysteine-ATP S-C5′ covalent adducts as inhibitors of rat methionine adenosyltransferases. J Med Chem 29:1030-1038 (1986). [cited by applicant]
Kappler et al. Species—or isozyme-specific enzyme inhibitors. 8. Synthesis of disubstituted two-substrate condensation products as inhibitors of rat adenylate kinases. J Med Chem 25:1179-1184 (1982). [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. Tetrah… [cited by applicant]
Kroschwitz, J.I., The Concise Encyclopedia of Polymer Science and Engineering, Ed., John Wiley & Sons pp. 858-859 (1990). [cited by applicant]
Kumar et al. The First Analogues of LNA (Locked Nucleic Acids): Phosphorothioate LNA and 2′-Thio-LNA. Bioorg Med Chem Lett 8:2219-2222 (1998). [cited by applicant]
Lavergne et al. Expanding the scope of replicable unnatural DNA: Stepwise optimization of a predominantly hydrophobic base pair. JACS 135:5408-5419 (2013). [cited by applicant]
Ledbetter et al. Reprograming the Replisome of a Semisynthetic Organism for the Expansion of the Genetic Alphabet. J Am Chem Soc. 140:758-765 (2018). [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 86:6553-6556 (1989). [cited by applicant]
Malyshev et al. A semi-synthetic organism with an expanded genetic alphabet. Nature 509(7500):385-388 (2014). [cited by applicant]
Malyshev et al. Efficient and sequence-independent replication of DNA containing a third base pair establishes a functional six-letter genetic alphabet. PNAS USA 109: 12005-12010 (2012). [cited by applicant]
Manoharan et al. Chemical Modifications to Improve Uptake and Bioavailability of Antisense Oligonucleotides. Ann. N.Y. Acad. Scie 660:306-309 (1992). [cited by applicant]
Manoharan et al. Cholic Acid-Oligonucleotide Conjugates for Antisense Applications. Bioorg. Med. Chem. Let 4:1053-1060 (1994). [cited by applicant]
Manoharan et al. Introduction of a Lipophilic Thioether in the Minor Groove of Nucleic Acids for Antisense Applications. Bioorg. Med. Chem. Let 3:2765-2770 (1993). [cited by applicant]
Manoharan et al. Lipidic Nucleic Acids. Tetrahedron Lett 36:3651-3654 (1995). [cited by applicant]
Manoharan et al. Oligonucleotide Conjugates: Alteration of the Pharmacokinetic Properties of Antisense Agents. Nucleosides & Nucleotides 14:969-973 (1995). [cited by applicant]
Matteucci. Oligonucleotide Analogs: an Overview in Oligonucleotides as Therapeutic Agents, (Chadwick and Cardew, ed.) John Wiley and Sons, New York, NY; Zon, 1993, Oligonucleoside Phosphorothioates in Protocols for Olig… [cited by applicant]
Abbadessa et al, Co-pending U.S. Appl. No. 17/357,615, filed Jun. 24, 2021; also cited herein as US 2022/0016252. [cited by applicant]
Aerni et al, Co-pending U.S. Appl. No. 17/845,495, filed Jun. 21, 2022; also cited herein as US 2022/0324792. [cited by applicant]
Caffaro et al, Co-pending U.S. Appl. No. 17/313,579, filed May 6, 2021; also cited herein as US 2021/0338829. [cited by applicant]
Caffaro et al, Co-pending U.S. Appl. No. 17/735,564, filed May 3, 2022; also cited herein as US 2022/0273767. [cited by applicant]
Ptacin et al, Co-pending U.S. Appl. No. 17/350,672, filed Jun. 17, 2021; also cited herein as US 2022/0016249. [cited by applicant]
Gupta et al., “Protein PEGylation for cancer therapy: bench to bedside”, Journal of Cell Communication and Signaling, vol. 13, No. 3, Nov. 29, 2018, pp. 319-330. [cited by applicant]
International Search Report and Written Opinion, International Application No. PCT/US2020/047389, dated Nov. 20, 2020, 12 pages. [cited by applicant]
Micklefield. Backbone Modification of Nucleic Acids: Synthesis, Structure and Therapeutic Applications. Current Medicinal Chemistry 8:1157-1179 (2001). [cited by applicant]
Mikhailov et al. Substrate Properties of C′-Methylnucleoside and C′-Methyl-2′-deoxynucleoside 5′-Triphosphates in RNA and DNA Synthesis Reactions Catalysed by RNA and DNA Polymerases Nucleosides & Nucleotides 10 (1-3):3… [cited by applicant]
Miller et al. Conformation and interaction of dinucleoside mono- and diphosphates. V. Syntheses and properties of adenine and thymine nucleoside alkyl phosphotriesters, the neutral analogs of dinucleoside monophosphates… [cited by applicant]
Mishra et al. Improved leishmanicidal effect of phosphorotioate antisense oligonucleotides by LDL-mediated delivery. Biochem Biophys Acta 1264:229-237 (1995). [cited by applicant]
Napolitano et al. Emergent rules for codon choice elucidated by editing rare argine codons in [cited by applicant]
Nawrot et al. A novel class of DNA analogs bearing 5′-C-phosphonothymidine units: synthesis and physicochemical and biochemical properties. Oligonucleotides16(1):68-82 (2006). [cited by applicant]
Nelson et al. N3′- > PS′ Oligodeoxyribonucleotide Phosphoramidates: A New Method of Synthesis Based on a Phosphoramidite Amine-Exchange Reaction. J Org Chem 62:7278-7287 (1997). [cited by applicant]
Neumann et al. Encoding multiple unnatural amino acids via evolution of a quadruplet-decoding ribosome Nature 464 (7287):441-444 (2010). [cited by applicant]
Nielsen et al. Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide. Science 254:1497-1500 (1991). [cited by applicant]
Oberhauser et al. Effective incorporation of 2′-O-methyl-oligoribonucleotides into liposomes and enhanced cell association through modification with thiocholesterol. Nucl. Acids Res. 20:533-538 (1992). [cited by applicant]
Orum et al. Locked nucleic acids: a promising molecular family for gene-function analysis and antisense drug development. Curr Opinion Mol Ther 3:239-243 (2001). [cited by applicant]
Ostrov et al. Design, synthesis, and testing toward a 57-codon genome. Science 353(6301): 819-822 (2016). [cited by applicant]
Peyrottes et al. Oligodeoxynucleoside phosphoramidates (P-NH2): synthesis and thermal stability of duplexes with DNA and RNA targets. Nucleic Acids Res 24:1841-1848 (1996). [cited by applicant]
Ring et al., “Mechanistic and structural insight into the functional dichotomy between interleukin-2 and interleukin-15”, Nat Immunol. Dec. 2012, 13(12): 1187-1195. [cited by applicant]
Saha et al. 5′-Methyl-DNA—A New Oligonucleotide Analog: Synthesis and Biochemical Properties J Org Chem 60:788-789 (1995). [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. 10:1111-1118 (1991). [cited by applicant]
Sanghvi, Chapter 15, Antisense Research and Applications, Crookeand Lebleu Eds., CRC Press, 1993, 273-288. [cited by applicant]
Schultz et al. Oligo-2′-fluoro-2′-deoxynucleotide N3′- > PS′ phosphoramidates: synthesis and properties. Nucleic Acids Res 24:2966-2973 (1996). [cited by applicant]
Singh et al. LNA (locked nucleic acids): synthesis and high-affinity nucleic acid recognition. Chem Commun 4:455-456 (1998). [cited by applicant]
Singh et al. Synthesis of 2′-amino-LNA: A novel conformationally restricted high-affinity oligonucleotide analogues with a handle. J Bio Chem 63:10035-10039 (1998). [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 129(26):8362-8379 (2007). [cited by applicant]
Svinarchuk et al. Inhibition of HIV proliferation in MT-4 cells by antisense oligonucleotide conjugated to lipophilic groups. Biochimie 75:49-54 (1993). [cited by applicant]
Vrudhula et al. Isozyme-specific enzyme inhibitors. 13. S-[5′(R)-[(N-triphosphoamino)methyl]adenosyl]-L-homocysteine, a potent inhibitor of rat methionine adenosyltransferases. J Med Chem 30:888-894 (1987). [cited by applicant]
Wahlestedt et al. Potent and nontoxic antisense oligonucleotides containing locked nucleic acids. PNAS USA 97:5633-5638 (2000). [cited by applicant]
Wang et al. Biophysical and biochemical properties of oligodeoxy-nucleotides containing 4′-C-and 5′-C-substituted thymidines. Bioorg Med Chem Lett 9:885-890 (1999). [cited by applicant]
Wang et al. Synthesis of Azole Nucleoside 5 ′-Monophosphate Mimics (P1 Ms) and Their Inhibitory Properties of IMP Dehydrogenases. Nucleosides Nucleotides & Nucleic Acids 23(1 & 2):317-337 (2004). [cited by applicant]
Wu et al. Functionalization of the sugar moiety of oligoribonucleotides on solid support. Bioconjugate Chem 10:921-924 (1999). [cited by applicant]
Zhang et al. A semisynthetic organism engineered for the stable expansion of the genetic alphabet. PNAS USA 114 (6):1317-1322 (2017). [cited by applicant]
Zhang et al. A Semi-Synthetic Organism that Stores and Retrieves Increased Genetic Information. Nature 551 (7682):644-647 (2017). [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 74:11… [cited by applicant]
Zon. Chapter 8: Oligonucleotide Phosphorothioates in Protocols for Oligonucleotides and Analogs, Synthesis and Properties. Humana Press (pp. 165-190) (1993). [cited by applicant]
Ptacin, J., et al., Co-pending U.S. Appl. No. 16/634,487, filed Jan. 27, 2020; also cited previously as US 2020/0231644. [cited by applicant]
Ptacin, J., et al., Co-pending U.S. Appl. No. 16/803,816, filed Feb. 27, 2020; also cited previously as US 2020/0188484. [cited by applicant]
Ptacin, J., et al., Co-pending U.S. Appl. No. 16/918,930, filed Jul. 1, 2020; also cited previously as US 2020/0330601. [cited by applicant]
Ptacin, J., et al., Co-pending U.S. Appl. No. 16/993,967, filed Aug. 14, 2020. [cited by applicant]
Caffaro, C., et al., Co-pending U.S. Appl. No. 17/001,965, filed Aug. 25, 2020. [cited by applicant]
Ptacin, J., et al., Co-pending U.S. Appl. No. 17/016,003, filed Sep. 9, 2020. [cited by applicant]
Wu et al., Synthesis of 5′-C- and 2′-O-(Bromoalkyl)-Substituted Ribonucleoside Phosphoramidites for the Post-synthetic Functionalization of Oligonucleotides on Solid Support, Helvetica Chimica Acta, vol. 83, pp. 1127-11… [cited by applicant]
Chen X. et al., Fusion protein linkers: property, design and functionality, Advanced drug delivery reviews, 2013, v. 65, n. 10, pp. 1357-1369. [cited by applicant]
Maeda Y. et al., Engineering of Functional chimeric protein G-Vargula Luciferase, Analytical biochemistry, 1997, v. 249, n. 2, p. 147-152. [cited by applicant]
Orlando M., Modification of proteins and low molecular weight subtances with hydroxyethyl starch (HES), Inauguraldissertation, Giesen, 2003, p. 14. [cited by applicant]
Rowley J. et al., Inhibition of tumor growth by NK1. 1+ cells and CD8+ T cells activated by IL-15 through receptor β/common γ signalingin trans, The Journal of Immunology, 2008, v. 181, n. 12, p. 8237-8247. [cited by applicant]
Treetharmathurot B. et al, Effect of PEG molecular weigh and linking chemistry on the biological activity and thermal stability of PEGylated trypsin, International Journal of Pharmaceutics, 2008, v. 357, pp. 252-259. [cited by applicant]
Zhou J. et al. Preparation and PEGylation of exendin-4 peptide secreted from yeast Pichia pastoris, European journal of pharmaceutics and biopahrmaceutics, 2009, V. 72, N. 2, p. 412-417. [cited by applicant]
Abbadessa, et al., Co-pending U.S. Appl. No. 18/524,157, filed Nov. 30, 2023. [cited by applicant]
Caffaro, et al., Co-pending U.S. Appl. No. 18/179,198, filed Mar. 6, 2023; also cited as US 2023/0302089 A1. [cited by applicant]
Caffaro, et al., Co-pending U.S. Appl. No. 18/296,710, filed Apr. 6, 2023; also cited as US 2023/0277627 A1. [cited by applicant]
Caffaro, et al., Co-pending U.S. Appl. No. 18/296,711, filed Apr. 6, 2023; also cited as US 2023/0416327 A1. [cited by applicant]
Caffaro, et al., Co-pending U.S. Appl. No. 18/415,445, filed Jan. 17, 2024. [cited by applicant]
Caffaro, et al., Co-pending U.S. Appl. No. 18/424,573, filed Jan. 26, 2024. [cited by applicant]
Ptacin et al, Co-pending U.S. Appl. No. 18/886,814, filed on Sep. 16, 2024. [cited by applicant]
Ptacin, et al., Co-pending U.S. Appl. No. 18/327,535, filed Jun. 1, 2023; also cited as US 2024/0082359 A1. [cited by applicant]
Vanbrunt, M.P. et al., Genetically Encoded Azide Containing Amino Acid in Mammalian Cells Enables Site-Specific Antibody-Drug Conjugates Using Click Cycloaddition Chemistry, Bioconjug. Chem., 2015, vol. 26, pp. 2249-226… [cited by applicant]
Colman P.M. et al.: “Effects of amino acid sequence changes on antibody-antigen interations”, Research in Immunology, 1994, vol. 145, Issue 1, pp. 33-36. [cited by applicant]