IP Library › Granted Patent US 11,618,746
Granted Patent B2
US 11,618,746 · App. 16/717,099 · Granted Apr 4, 2023

Inhibitors of APOL1 and methods of using same

Inventors: Jingrong Cao (Newton, MA); Jon H. Come (Cambridge, MA); Leslie A. Dakin (Framingham, MA); Francois Denis (Boston, MA); Warren A. Dorsch (Waltham, MA); Anne Fortier (Jamaica Plain, MA); Martine Hamel (Boston, MA); Elaine B. Krueger (Milton, MA); Brian Ledford (Norton, MA); Suganthini S. Nanthakumar (Newton, MA); Olivier Nicolas (Montreal, CA); Camil Sayegh (Boston, MA); Timothy J. Senter (Arlington, MA); Tiansheng Wang (Concord, MA); Michael Brodney (Newton, MA); Kan-Nian Hu (Brighton, MA); Peter Rose (Littleton, MA); Kevin Gagnon (Burlington, MA); Yi Shi (Natick, MA); Muna Shrestha (Belmont, MA); Ales Medek (Winchester, MA); Faith Witkos (Attleboro, MA)
Assignee: Vertex Pharmaceuticals Incorporated
C07D403/12C07D405/14C07B2200/05C07B2200/13
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Quick Facts
Patent No.
US 11,618,746
App. No.
16/717,099
Granted
Apr 4, 2023
Kind
B2
Abstract

The disclosure provides a compound of Formula (I), including deuterated derivatives, pharmaceutically acceptable salts, and solvates thereof, solid state forms of those compounds, compositions comprising those compounds and solid forms, and methods of using the same, including use in treating focal segmental glomerulosclerosis (FSGS) and/or non-diabetic kidney disease (NDKD).

Claims (299)

1. A compound chosen from compounds of Formula (I)

deuterated derivatives thereof, pharmaceutically acceptable salts of those compounds and deuterated derivatives, and solvates of any of the foregoing, wherein:

(i) each R 1 is independently chosen from

halogen groups,

hydroxy,

thiol,

amino,

cyano,

—OC(O)C 1 -C 6 linear, —OC(O)C 3 -C 6 branched, and —OC(O)C 3 -C 6 cyclic alkyl groups,

—C(O)OC 1 -C 6 linear, —C(O)OC 3 -C 6 branched, and —C(O)OC 3 -C 6 cyclic alkyl groups,

—NHC(O)C 1 -C 6 linear, —NHC(O)C 3 -C 6 branched, and —NHC(O)C 3 -C 6 cyclic alkyl groups,

—C(O)NHC 1 -C 6 linear, —C(O)NHC 3 -C 6 branched, and —C(O)NHC 3 -C 6 cyclic alkyl groups,

—NHC(O)C 5 -C 6 aryl groups,

—C(O)NHC 5 -C 6 aryl groups,

—NHC(O) 5- to 6-membered heteroaryl groups,

—C(O)NH 5- to 6-membered heteroaryl groups,

—NHS(O) 2 C 1 -C 6 linear, —NHS(O) 2 C 3 -C 6 branched, and —NHS(O) 2 C 3 -C 6 cyclic alkyl groups,

—S(O) 2 NHC 1 -C 6 linear, —S(O) 2 NHC 3 -C 6 branched, and —S(O) 2 NHC 3 -C 6 cyclic alkyl groups,

—NHS(O) 2 C 5 -C 6 aryl groups,

—S(O) 2 NHC 5 -C 6 aryl groups,

—NHS(O) 2 5- to 6-membered heteroaryl groups,

—S(O) 2 NH 5- to 6-membered heteroaryl groups,

—NHC(O)NHC 1 -C 6 linear, —NHC(O)NHC 3 -C 6 branched, and —NHC(O)NHC 3 -C 6 cyclic alkyl groups,

—NHC(O)NHC 5 -C 6 aryl groups,

—NHC(O)NH 5- to 6-membered heteroaryl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkyl groups,

C 2 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkenyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic hydroxyalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkoxy groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic thioalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic haloalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic haloaminoalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic halothioalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic haloalkoxy groups,

benzyloxy, benzylamino, or benzylthio groups,

3 to 6-membered heterocycloalkenyl groups,

3 to 6-membered heterocycloalkyl groups, and

5 and 6-membered heteroaryl groups;

(ii) each R 2 is independently chosen from

halogen groups,

hydroxy,

thiol,

amino,

cyano,

—NHC(O)C 1 -C 6 linear, —NHC(O)C 3 -C 6 branched, and —NHC(O)C 3 -C 6 cyclic alkyl groups,

—C(O)NHC 1 -C 6 linear, —C(O)NHC 3 -C 6 branched, and —C(O)NHC 3 -C 6 cyclic alkyl groups,

—NHC(O)C 5 -C 6 aryl groups,

—C(O)NHC 5 -C 6 aryl groups,

—NHC(O) 5- to 6-membered heteroaryl groups,

—C(O)NH 5- to 6-membered heteroaryl groups,

—NHS(O) 2 C 1 -C 6 linear, —NHS(O) 2 C 3 -C 6 branched, and —NHS(O) 2 C 3 -C 6 cyclic alkyl groups,

—S(O) 2 NHC 1 -C 6 linear, —S(O) 2 NHC 3 -C 6 branched, and —S(O) 2 NHC 3 -C 6 cyclic alkyl groups,

—NHS(O) 2 C 5 -C 6 aryl groups,

—S(O) 2 NHC 5 -C 6 aryl groups,

—NHS(O) 2 5- to 6-membered heteroaryl groups,

—S(O) 2 NH 5- to 6-membered heteroaryl groups,

—NHC(O)NHC 1 -C 4 linear, —NHC(O)NHC 3 -C 4 branched, and —NHC(O)NHC 3 -C 4 cyclic alkyl groups,

—NHC(O)NHC 5 -C 6 aryl groups,

—NHC(O)NH 5- to 6-membered heteroaryl groups,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic alkyl groups,

C 2 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic alkenyl groups,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic hydroxyalkyl groups,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic alkoxy groups,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic thioalkyl groups,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic haloalkyl groups,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic haloaminoalkyl groups,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic halothioalkyl groups, and

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic haloalkoxy groups;

(iii) m is chosen from 0, 1, 2, 3, and 4;

(iv) n is chosen from 0, 1, 2, 3, 4, and 5;

(v) Y is chosen from divalent C 1 -C 8 linear and C 3 -C 8 branched alkyl groups, divalent C 1 -C 8 linear and branched alkoxy groups, divalent C 1 -C 8 linear and C 3 -C 8 branched aminoalkyl groups, and divalent C 1 -C 8 linear and C 3 -C 8 branched thioalkyl groups, wherein the divalent alkyl groups, divalent alkoxy groups, divalent aminoalkyl groups, and divalent thioalkyl groups are optionally substituted with at least one group chosen from

C 1 -C 6 alkyl groups,

C 5 -C 6 aryl groups,

5 to 6-membered heteroaryl groups,

halogen groups,

hydroxy, and

amino;

(vi) each of R 3 and R 1 is independently chosen from

hydrogen,

hydroxy,

thiol,

amino,

halogen groups,

C 1 -C 3 linear, C 3 branched, and C 3 cyclic alkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic hydroxyalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkoxy groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic thioalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic haloalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic haloaminoalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic halothioalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic haloalkoxy groups, or

R 3 and R 4 , together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl group or carbonyl group;

(vii) each of R 5 and R 6 is independently chosen from

hydrogen,

thiol,

amino,

halogen groups,

hydroxy,

C 1 -C 3 linear, C 3 branched, and C 3 cyclic alkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic hydroxyalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and cyclic alkoxy groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic thioalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic haloalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic haloaminoalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic halothioalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic haloalkoxy groups,

—OC(O)C 1 -C 6 linear, —OC(O)C 3 -C 6 branched, and —OC(O)C 3 -C 6 cyclic alkyl groups,

—C(O)OC 1 -C 6 linear, —C(O)OC 3 -C 6 branched, and —C(O)OC 3 -C 6 cyclic alkyl groups,

—NHC(O)C 1 -C 6 linear, —NHC(O)C 3 -C 6 branched, and —NHC(O)C 3 -C 6 cyclic alkyl groups,

—C(O)NHC 1 -C 6 linear, —C(O)NHC 3 -C 6 branched, and —C(O)NHC 3 -C 6 cyclic alkyl groups,

—NHC(O)C 5 -C 6 aryl groups,

—C(O)NHC 5 -C 6 aryl groups,

—NHC(O) 5- to 6-membered heteroaryl groups,

—C(O)NH 5- to 6-membered heteroaryl groups,

—NHS(O) 2 C 1 -C 6 linear, —NHS(O) 2 C 3 -C 6 branched, and —NHS(O) 2 C 3 -C 6 cyclic alkyl groups,

—S(O) 2 NHC 1 -C 6 linear, —S(O) 2 NHC 3 -C 6 branched, and —S(O) 2 NHC 3 -C 6 cyclic alkyl groups,

—NHS(O) 2 C 5 -C 6 aryl groups,

—S(O) 2 NHC 5 -C 6 aryl groups,

—NHS(O) 2 5- to 6-membered heteroaryl groups,

—S(O) 2 NH 5- to 6-membered heteroaryl groups,

—NHC(O)NHC 1 -C 6 linear, —NHC(O)NHC 3 -C 6 branched, and —NHC(O)NHC 3 -C 6 cyclic alkyl groups,

—NHC(O)NHC 5 -C 6 aryl groups, and

—NHC(O)NH 5- to 6-membered heteroaryl groups; and

(viii) each of R 7 , R 8 , and R 9 is independently chosen from

hydrogen,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic hydroxyalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic alkoxy groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic thioalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic haloalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic haloaminoalkyl groups,

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic halothioalkyl groups, and

C 1 -C 6 linear, C 3 -C 6 branched, and C 3 -C 6 cyclic haloalkoxy groups.

2. A compound chosen from compounds of Formula II:

deuterated derivatives thereof, pharmaceutically acceptable salts of those compounds and deuterated derivatives, and solvates of any of the foregoing, wherein:

(i) each R 1 is independently chosen from

halogen groups,

cyano,

methyl,

cyclopropyl,

isopropyl,

C 2 -C 3 linear and C 3 branched alkenyl groups,

hydroxypropyl groups,

methoxy,

dihydrofuran groups, and

furan groups;

(ii) each R 2 is independently chosen from

fluoro,

cyano, and

methyl;

(iii) m is chosen from 0, 1, 2, and 3;

(iv) n is chosen from 0, 1, and 2; and

(v) Y is divalent ethyl or divalent thiomethyl optionally substituted with at least one group chosen from

fluoro,

methyl, and

hydroxy.

3. A compound chosen from compounds of Formula IIIa:

deuterated derivatives thereof, pharmaceutically acceptable salts of those compounds and deuterated derivatives, and solvates of any of the foregoing, wherein:

(i) each R 1 is independently chosen from

fluoro,

chloro,

bromo,

cyano,

methyl,

cyclopropyl,

ethyl,

hydroxypropyl,

isopropyl,

propen-2-yl,

dihydrofuran,

furan, and

methoxy;

(ii) each R 2 is independently chosen from

fluoro,

bromo,

cyano, and

methyl; and

(iii) Y is divalent ethyl or divalent thiomethyl optionally substituted with at least one group chosen from

fluoro,

methyl, and

hydroxy.

4. A compound chosen from

deuterated derivatives thereof, pharmaceutically acceptable salts of those compounds and deuterated derivatives, and solvates of any of the foregoing.

5. Compound 2:

in a form selected from Form A of Compound 2, Hydrate Form B of Compound 2, Hydrate Form C of Compound 2, Hydrate Form D of Compound 2, Hydrate Form E of Compound 2, Hydrate Form F of Compound 2, MTBE Solvate Form of Compound 2, DMF Solvate Form, and Amorphous Form of Compound 2.

6. A composition comprising the Form A of Compound 2, the Hydrate Form B of Compound 2, the Hydrate Form C of Compound 2, the Hydrate Form D of Compound 2, the Hydrate Form E of Compound 2, the Hydrate Form F of Compound 2, the MTBE Solvate Form of Compound 2, or the DMF Solvate Form of Compound 2 according to claim 5 .

7. Compound 87:

in a form selected from Form A of Compound 87, Hydrate Form of Compound 87, IPAc Solvate Form of Compound 87, and Amorphous Form of Compound 87.

8. A composition comprising the Form A of Compound 87, the Hydrate Form of Compound 87, or the IPAc Solvate Form of Compound 87 according to claim 7 .

9. A pharmaceutical composition comprising the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 1 and a pharmaceutically acceptable carrier.

10. A method of treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof the compound deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 1 .

11. A method of inhibiting APOL1 activity comprising contacting said APOL1 with the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 1 .

12. A pharmaceutical composition comprising the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 2 and a pharmaceutically acceptable carrier.

13. A method of treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 2 .

14. A method of inhibiting APOL1 activity comprising contacting said APOL1 with the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 2 .

15. A pharmaceutical composition comprising the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 3 and a pharmaceutically acceptable carrier.

16. A method of treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 3 .

17. A method of inhibiting APOL1 activity comprising contacting said APOL1 with the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 3 .

18. A pharmaceutical composition comprising the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 4 and a pharmaceutically acceptable carrier.

19. A method of treating focal segmental glomerulosclerosis and/or non-diabetic kidney disease comprising administering to a patient in need thereof the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 4 .

20. A method of inhibiting APOL1 activity comprising contacting said APOL1 with the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 4 .

21. The compound, deuterated derivative, pharmaceutically acceptable salt, or solvate of claim 1 , wherein:

each R 1 is independently chosen from

halogen groups,

hydroxy,

cyano,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic alkyl groups,

C 2 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic alkenyl groups,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic hydroxyalkyl groups,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic alkoxy groups,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic haloalkyl groups,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic haloalkoxy groups,

benzyloxy groups,

3 to 6-membered heterocycloalkenyl groups,

3 to 6-membered heterocycloalkyl groups, and

5 and 6-membered heteroaryl groups;

(ii) each R 2 is independently chosen from

halogen groups,

cyano,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic alkoxy groups,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic haloalkoxy groups,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic alkyl groups, and

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic haloalkyl groups;

(iii) m is chosen from 0, 1, 2, 3, and 4;

(iv) n is chosen from 0, 1, 2, 3, 4, and 5;

(v) Y is chosen from divalent C 1 -C 8 linear and C 3 -C 8 branched alkyl groups and divalent C 1 -C 8 linear and C 3 -C 8 branched thioalkyl groups, wherein the divalent alkyl groups and divalent thioalkyl groups are optionally substituted with at least one group chosen from

C 1 -C 4 alkyl groups,

halogen groups, and

hydroxy;

(vi) each of R 3 and R 1 is independently chosen from

hydrogen,

C 1 -C 3 linear, C 3 branched, and C 3 cyclic alkyl groups,

C 1 -C 3 linear, C 3 branched, and C 3 cyclic hydroxyalkyl groups, and

C 1 -C 3 linear, C 3 branched, and C 3 cyclic haloalkyl groups, or

R 3 and R 4 , together with the carbon atom to which they are attached, form a C 3 -C 6 cycloalkyl group or carbonyl group;

(vii) each of R 5 and R 6 is independently chosen from

hydrogen,

hydroxy,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic alkyl groups,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic haloalkyl groups, and

—OC(O)C 1 -C 4 linear, —OC(O)C 3 -C 4 branched, and —OC(O)C 3 -C 4 cyclic alkyl groups; and

(viii) each of R 7 , R 8 , and R 9 is independently chosen from hydrogen,

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic alkyl groups, and

C 1 -C 4 linear, C 3 -C 4 branched, and C 3 -C 4 cyclic haloalkyl groups.

22. A compound chosen from compounds of Formula IIIb:

deuterated derivatives thereof, pharmaceutically acceptable salts of those compounds and deuterated derivatives, and solvates of any of the foregoing, wherein:

(i) each R 1 is independently chosen from

fluoro,

chloro,

bromo,

cyano,

methyl,

cyclopropyl,

ethyl,

hydroxypropyl,

isopropyl,

propen-2-yl,

dihydrofuran,

furan, and

methoxy;

(ii) each R 2 is independently chosen from

fluoro,

bromo,

cyano, and

methyl; and

(iii) Y is divalent ethyl or divalent thiomethyl optionally substituted with at least one group chosen from

fluoro,

methyl, and

hydroxy.

23. A compound chosen from compounds of Formula IIIc:

deuterated derivatives thereof, pharmaceutically acceptable salts of those compounds and deuterated derivatives, and solvates of any of the foregoing, wherein:

(i) each R 1 is independently chosen from

fluoro,

chloro,

bromo,

cyano,

methyl,

cyclopropyl,

ethyl,

hydroxypropyl,

isopropyl,

propen-2-yl,

dihydrofuran,

furan, and

methoxy;

(ii) each R 2 is independently chosen from

fluoro,

bromo,

cyano, and

methyl; and

(iii) Y is divalent ethyl or divalent thiomethyl optionally substituted with at least one group chosen from

fluoro,

methyl, and

hydroxy.

24. A method of treating APOL1 mediated kidney disease comprising administering to a patient in need thereof the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 1 .

25. A method of treating APOL1 mediated kidney disease comprising administering to a patient in need thereof the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 2 .

26. A method of treating APOL1 mediated kidney disease comprising administering to a patient in need thereof the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 3 .

27. A method of treating APOL1 mediated kidney disease comprising administering to a patient in need thereof the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 4 .

28. A method of treating APOL1 mediated kidney disease comprising administering to a patient in need thereof the compound, deuterated derivative, pharmaceutically acceptable salt, or solvate according to claim 21 .

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 9, 2020
From: CAO, JINGRONG; COME, JON H.; DAKIN, LESLIE A.; DENIS, FRANCOIS; DORSCH, WARREN A.; FORTIER, ANNE; HAMEL, MARTINE; KRUEGER, ELAINE B.; LEDFORD, BRIAN; NANTHAKUMAR, SUGANTHINI S.; NICOLAS, OLIVIER; SAYEGH, CAMIL; SENTER, TIMOTHY J.; WANG, TIANSHENG; BRODNEY, MICHAEL; GAGNON, KEVIN; HU, KAN-NIAN; ROSE, PETER; SHI, YI; SHRESTHA, MUNA; MEDEK, ALES; WITKOS, FAITH
To: VERTEX PHARMACEUTICALS INCORPORATED
Reel/Frame 052123/0629 →
Continuity (2)
Provisional Application 62780667 · Dec 17, 2018
Related Publication 20200377479A1 · Dec 3, 2020
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