IP Library › Granted Patent US 12,343,378
Granted Patent B2
US 12,343,378 · App. 17/960,911 · Granted Jul 1, 2025

Compositions and methods for treating pulmonary hypertension

Inventors: Ravindra Kumar (Cambridge, MA); John Knopf (Cambridge, MA)
Assignee: ACCELERON PHARMA INC.
A61K38/1875A61K38/179A61K38/1796A61K38/45A61K45/06A61P7/00A61P11/00C07K14/71C07K2319/30
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 12,343,378
App. No.
17/960,911
Granted
Jul 1, 2025
Kind
B2
Abstract

In some aspects, the disclosure relates to GDF/BMP antagonists and methods of using GDF3/BMP antagonists to treat, prevent, or reduce the progression rate and/or severity of pulmonary hypertension (PH), particularly treating, preventing or reducing the progression rate and/or severity of one or more PH-associated complications. The disclosure also provides methods of using a GDF/BMP antagonist to treat, prevent, or reduce the progression rate and/or severity of a variety of conditions including, but not limited to, pulmonary vascular remodeling, pulmonary fibrosis, and right ventricular hypertrophy. The disclosure further provides methods of using a GDF/BMP antagonist to reduce right ventricular systolic pressure in a subject in need thereof.

Claims (73)

1. A method of treating pulmonary arterial hypertension, comprising administering to a patient in need thereof a fusion protein comprising:

a) an ActRIIA polypeptide comprising the amino acid sequence of SEQ ID NO: 10;

b) an Fc domain of an IgG1 immunoglobulin; and

c) a linker domain,

wherein the linker domain is positioned between the ActRIIA polypeptide and the Fc domain of the IgG1 immunoglobulin.

2. The method of claim 1 , wherein proliferation of smooth muscle and endothelial cells in the pulmonary artery is inhibited.

3. The method of claim 1 , wherein the method increases the exercise capacity of the patient.

4. The method of claim 3 , wherein the method increases the patient's 6-minute walk distance (6MWD).

5. The method of claim 4 , wherein the patient's 6MWD is increased by at least 10 meters.

6. The method of claim 4 , wherein the patient's 6MWD is increased by at least 50 meters.

7. The method of claim 1 , wherein the method reduces the patient's Borg dyspnea index (BDI).

8. The method of claim 7 , wherein the method reduces the patient's BDI by at least 0.5 index points.

9. The method of claim 7 , wherein the method reduces the patient's BDI by at least 5 index points.

10. The method of claim 1 , wherein the method reduces pulmonary vascular resistance in the patient.

11. The method of claim 1 , wherein the method increases pulmonary capillary wedge pressure.

12. The method of claim 1 , wherein the method increases left ventricular end-diastolic pressure.

13. The method of claim 1 , wherein the method decreases pulmonary arterial pressure in the patient.

14. The method of claim 13 , wherein the method decreases pulmonary arterial pressure in the patient by at least 10%.

15. The method of claim 1 , wherein the method decreases ventricle hypertrophy in the patient.

16. The method of claim 15 , wherein the method decreases ventricle hypertrophy in the patient by at least 10%.

17. The method of claim 2 , wherein the method decreases smooth muscle hypertrophy in the patient.

18. The method of claim 17 , wherein the method decreases smooth muscle hypertrophy in the patient by at least 10%.

19. The method of claim 1 , wherein the method decreases pulmonary arteriole muscularity in the patient.

20. The method of claim 19 , wherein the method decreases pulmonary arteriole muscularity in the patient by at least 10%.

21. The method of claim 1 , wherein the method decreases pulmonary vascular resistance in the patient.

22. The method of claim 21 , wherein the method decreases pulmonary vascular resistance in the patient by at least 10%.

23. The method of claim 1 , wherein the patient has a hemoglobin level from greater than 8 and less than 15 g/dl.

24. The method of claim 1 , wherein the method delays clinical worsening of pulmonary arterial hypertension.

25. The method of claim 1 , wherein the method reduces the risk of hospitalization for one or more complications associated with pulmonary arterial hypertension.

26. A method of treating pulmonary arterial hypertension, comprising administering to a patient in need thereof a fusion protein comprising:

a) an ActRIIA polypeptide comprising the amino acid sequence of SEQ ID NO: 10;

b) an Fc domain of an IgG1 immunoglobulin; and

c) a linker domain,

wherein the linker domain is positioned between the ActRIIA polypeptide and the Fc domain of the IgG1 immunoglobulin, and wherein the method increases exercise capacity of the patient.

27. The method of claim 1 , wherein the linker domain comprises an amino acid sequence of SEQ ID NO: 23.

28. The method of claim 26 , wherein the linker domain comprises an amino acid sequence of SEQ ID NO: 23.

29. The method of claim 1 , wherein the Fc domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 14.

30. The method of claim 26 , wherein the Fc domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 14.

31. The method of claim 1 , wherein the Fc domain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 14.

32. The method of claim 26 , wherein the Fc domain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 14.

33. The method of claim 1 , wherein the Fc domain comprises an amino acid sequence of SEQ ID NO: 14.

34. The method of claim 26 , wherein the Fc domain comprises an amino acid sequence of SEQ ID NO: 14.

35. A method of treating pulmonary arterial hypertension in a human patient in need thereof, comprising administering to the human patient an effective amount of a fusion protein comprising:

a) an ActRIIA polypeptide domain comprising the amino acid sequence of SEQ ID NO: 10;

b) an Fc domain of an IgG1 immunoglobulin; and

c) a linker domain comprising the amino acid sequence of SEQ ID NO: 23;

wherein the linker domain is positioned between the ActRIIA polypeptide domain and the Fc domain.

36. The method of claim 35 , wherein the Fc domain comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 14.

37. The method of claim 35 , wherein the Fc domain comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 14.

38. The method of claim 35 , wherein the Fc domain comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 14.

39. The method of claim 35 , wherein the Fc domain comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 14.

40. The method of claim 35 , wherein the Fc domain comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 14.

41. The method of claim 35 , wherein the Fc domain comprises the amino acid sequence of SEQ ID NO: 14.

42. The method of claim 35 , wherein the fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 32.

43. The method of claim 35 , wherein the fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 32.

44. The method of claim 35 , wherein the fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 32.

45. The method of claim 35 , wherein the fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 32.

46. The method of claim 35 , wherein the fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 32.

47. The method of claim 35 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 32.

48. The method of claim 35 , wherein the fusion protein is a homodimer.

49. The method of claim 46 , wherein the fusion protein is a homodimer.

50. The method of claim 35 , wherein the human patient has Functional Class II or Class III pulmonary hypertension in accordance with the World Health Organization's functional classification system for pulmonary hypertension.

51. The method of claim 49 , wherein the human patient has Functional Class II pulmonary hypertension in accordance with the World Health Organization's functional classification system for pulmonary hypertension.

52. The method of claim 50 , wherein the human patient has Functional Class III pulmonary hypertension in accordance with the World Health Organization's functional classification system for pulmonary hypertension.

53. The method of claim 35 , wherein the human patient has one or more subtypes of pulmonary arterial hypertension selected from the group consisting of: idiopathic pulmonary arterial hypertension, heritable pulmonary arterial hypertension, drug- and/or toxin-induced pulmonary hypertension, pulmonary hypertension associated with connective tissue disease, and pulmonary hypertension associated with congenital systemic-to-pulmonary shunts at least 1 year following shunt repair.

54. The method of claim 53 , wherein the human patient has idiopathic pulmonary arterial hypertension.

55. The method of claim 35 , wherein the treatment increases an exercise capacity of the human patient.

56. The method of claim 38 , wherein the method promotes the regression from Functional Class II or Class III to Functional Class I or Class II pulmonary hypertension in accordance with the World Health Organization's functional classification system for pulmonary hypertension.

57. The method of claim 35 , wherein the method delays clinical worsening of pulmonary arterial hypertension.

58. The method of claim 35 , wherein the treatment reduces pulmonary vascular resistance of the human patient.

59. The method of claim 35 , wherein the treatment reduces pulmonary arterial pressure of the human patient.

60. The method of claim 35 , wherein the fusion protein is administered subcutaneously.

61. The method of claim 35 , wherein the fusion protein is administered as a pharmaceutical composition comprising the fusion protein and one or more physiologically acceptable carriers or excipients.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 5, 2024
From: KUMAR, RAVINDRA; KNOPF, JOHN
To: ACCELERON PHARMA INC.
Reel/Frame 068499/0148 →
Continuity (9)
Continuation 17339606 · Jun 4, 2021
Continuation 17002542 · Aug 25, 2020
Continuation 16829642 · Mar 25, 2020
Continuation 15945565 · Apr 4, 2018
Continuation 15650420 · Jul 14, 2017
Provisional Application 62510403 · May 24, 2017
Provisional Application 62453888 · Feb 2, 2017
Provisional Application 62362955 · Jul 15, 2016
Related Publication 20230233648A1 · Jul 27, 2023
References Cited (153)
US 5288931A · Chang et al. · 1994 [cited by applicant]
US 7112660B1 · Domingues et al. · 2006 [cited by applicant]
US 8895016B2 · Sherman et al. · 2014 [cited by applicant]
US 9145433B2 · Bhamidipati et al. · 2015 [cited by applicant]
US 10695405B2 · Kumar et al. · 2020 [cited by applicant]
US 10722558B2 · Kumar et al. · 2020 [cited by applicant]
US 10946067B2 · Kumar et al. · 2021 [cited by applicant]
US 10973880B2 · Kumar et al. · 2021 [cited by applicant]
US 11065303B2 · Kumar et al. · 2021 [cited by applicant]
US 11219666B2 · Kumar et al. · 2022 [cited by applicant]
US 11622992B2 · Kumar · 2023 [cited by examiner]
US 20030045474A1 · Sailer et al. · 2003 [cited by applicant]
US 20030144203A1 · Bowen · 2003 [cited by applicant]
US 20050239719A1 · Zeldis · 2005 [cited by applicant]
US 20070056050A1 · Clokie et al. · 2007 [cited by applicant]
US 20070248609A1 · De Kretser et al. · 2007 [cited by applicant]
US 20090017019A1 · Shields et al. · 2009 [cited by applicant]
US 20090142333A1 · Knopf et al. · 2009 [cited by applicant]
US 20100015144A1 · Sherman et al. · 2010 [cited by applicant]
US 20100056505A1 · Lee et al. · 2010 [cited by applicant]
US 20110224236A1 · Rothblatt · 2011 [cited by applicant]
US 20140045844A1 · Schafer et al. · 2014 [cited by applicant]
US 20140154743A1 · Levy et al. · 2014 [cited by applicant]
US 20140271459A1 · Dutzar et al. · 2014 [cited by applicant]
US 20140303068A1 · O'Hehir et al. · 2014 [cited by applicant]
US 20150266950A1 · Sung et al. · 2015 [cited by applicant]
US 20150283209A1 · Sung et al. · 2015 [cited by applicant]
US 20150306150A1 · Zhang et al. · 2015 [cited by applicant]
US 20150361163A1 · Kumar et al. · 2015 [cited by applicant]
US 20160039922A1 · Attie · 2016 [cited by applicant]
US 20160287664A1 · Yu et al. · 2016 [cited by applicant]
US 20160347814A1 · Levine et al. · 2016 [cited by applicant]
US 20170202918A1 · Yung et al. · 2017 [cited by applicant]
US 20180008672A1 · Chalothorn et al. · 2018 [cited by applicant]
US 20180125928A1 · Attie · 2018 [cited by applicant]
US 20180327477A1 · Kumar et al. · 2018 [cited by applicant]
AU 2012244215A1 · 2012 [cited by applicant]
CN 103920139A · 2014 [cited by applicant]
CN 107709357A · 2018 [cited by applicant]
EP 2594280A1 · 2013 [cited by applicant]
KR 20150115961A · 2015 [cited by applicant]
WO WO9411502A2 · 1994 [cited by applicant]
WO WO2005084699A1 · 2005 [cited by applicant]
WO WO2006012627A2 · 2006 [cited by applicant]
WO WO2007062188A2 · 2007 [cited by applicant]
WO WO2008073351A2 · 2008 [cited by applicant]
WO WO2008073928A1 · 2008 [cited by applicant]
WO WO2008076437A2 · 2008 [cited by applicant]
WO WO2008094708A2 · 2008 [cited by applicant]
WO WO2008097541A2 · 2008 [cited by applicant]
WO WO2009134428A2 · 2009 [cited by applicant]
WO WO2010019261A1 · 2010 [cited by applicant]
WO WO2010062640A1 · 2010 [cited by applicant]
WO WO2010083034A1 · 2010 [cited by applicant]
WO WO2010114860A1 · 2010 [cited by applicant]
WO WO2011056497A1 · 2011 [cited by applicant]
WO WO2011115922A1 · 2011 [cited by applicant]
WO WO2012051559A2 · 2012 [cited by applicant]
WO WO2014071158A1 · 2014 [cited by applicant]
WO WO2014160336A1 · 2014 [cited by applicant]
WO WO2015017576A1 · 2015 [cited by applicant]
WO WO2015161220A1 · 2015 [cited by applicant]
WO WO2015192111A1 · 2015 [cited by applicant]
WO WO2016164089A2 · 2016 [cited by applicant]
WO WO2016164497A1 · 2016 [cited by applicant]
WO WO2016164501A1 · 2016 [cited by applicant]
WO WO2016171948A1 · 2016 [cited by applicant]
WO WO2016183280A1 · 2016 [cited by applicant]
WO WO2017015622A2 · 2017 [cited by applicant]
Alaoui-Ismaili, M. and Falb, D., “Design of second generation therapeutic recombinant bone morphogenetic proteins,” Cytokine & Growth Factor Reviews, vol. 20(5-6): 501-507 (2009). [cited by applicant]
Attie et al., “A phase I study of ACE-536, a regulator of erythroid differentiation, in healthy volunteers,” American Journal of Hematology, vol. 89(7): 766-770 (2014). [cited by applicant]
Bernier et al., “Pharmacological chaperone action on G-protein-coupled receptors,” Current Opinions in Pharmacology, vol. 4(5): 528-533 (2004). [cited by applicant]
Bhattacharya et al., “Impact of genetic variation on three dimensional structure and function of proteins,” PLoS One, vol. 12(3): e0171355. [cited by applicant]
BIOSIS Accession No. 2015:276893 & Piga, A. et al., ‘ACE-536 Increases Hemoglobin and Decreases Transfusion Burden and Serum Ferritin in Adults with Beta-Thalassemia: Preliminary Results from a Phase 2 Study’, Blood, vo… [cited by applicant]
Cappellini et al., “A Phase 2a, Open-Label, Dose-Finding Study to Determine the Safety and Tolerability of Sotatercept (ACE-011) in Adults with Beta (β)-Thalassemia: Interim Results,” Blood, vol. 122(21): 3448 (2013). [cited by applicant]
Carrancio et al., “An activin receptor IIA ligand trap promotes erythropoiesis resulting in a rapid induction of red blood cells and haemoglobin,” British Journal of Haematology, vol. 165:870-882 (2014). [cited by applicant]
Castonguay et al., “Soluble endoglin specifically binds bone morphongenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppress tumor growth,” The Journal of Biological Chemistry, vol.… [cited by applicant]
“Efficacy versus Potency”, https://step1.medbullets.com/pharmacology/; 107007/efficacy-vs-patency, accessed Jan. 2, 2019. [cited by applicant]
Fenton, et al., “Rheostat positions: A new classification of protein positions relevant to pharmacogenomics”, Medicinal Chemistry Research 29: 1133-1146 (2020). [cited by applicant]
Fox et al., “Pulmonary arterial hypertension: classification, diagnosis and contemporary management,” Postgrad Medicine J, vol. 82:717-722 (2006). [cited by applicant]
Guazzi et al., “Pulmonary Hypertension Due to Left Heart Disease,” Circulation, vol. 126(8):975-990 (2012). [cited by applicant]
Guo et al., “Protein tolerance to random amino acid change,” Proceedings of the National Academy of Sciences, vol. 101(25): 9205-9210 (2004). [cited by applicant]
Hill et al., “Postoperative Pulmonary Hypertension: Etiology and Treatment of a Dangerous Complication,” Respiratory Care, vol. 54(7): 958-968 (2009). [cited by applicant]
Humbert, M., “Update in Pulmonary Hypertension 2008,” American Journal of Respiratory Critical Care Medicine, vol. 179: 650-656 (2009). [cited by applicant]
Kohno et al., “Binding Characteristics of Tumor Necrosis Factor Receptor-FC Fusion Proteins vs Anti-Tumor Necrosis Factor mAbs,” J. Investigative Dermatology, vol. 12(1): 5-8 (2007). [cited by applicant]
Lis et al., “Tumor necrosis factor inhibitors—state of knowledge,” Arch Med Sci. vol. 10(6): 1175-1185 (2014). [cited by applicant]
Long et al., “Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension,” Nature Medicine, vol. 21(7): 777-785 (2015). [cited by applicant]
Montani et al., “Pulmonary arterial hypertension,” Orphanet Journal of Rare Diseases, vol. 8(1): p. 97: 1-28 (2013). [cited by applicant]
Pietra, et al., “Pathologic Assessment of Vasculopathies in Pulmonary Hypertension,” Journal of the American College of Cardiology, vol. 43(12) Suppl S: 25S-32S (2004). [cited by applicant]
Project Information No. 5R01HL074352-07 “BMPR2 and the Pathogenesis of Pulmonary Hypertension”, NIH RePorter—NIH Research Portfolio Online Reporting Tool Expenditures and Results (Feb. 20, 2020) 2 pages. [cited by applicant]
National Organization for Rare Disorders, “Pulmonary Arterial Hypertension”, The website downloaded Nov. 2, 2020 from https://rarediseases.org/rare-disease/pulmonary-arterial-hypertensin/; 13 pages (2020). [cited by applicant]
Rose-Jones et al., “Pulmonary Hypertension: Types and Treatments,” Current Cardiology Reviews, vol. 11:73-79 (2015). [cited by applicant]
Rubin, L.J., “Diagnosis and Management of Pulmonary Arterial Hypertension: ACCP Evidence-Based Clinical Practice Guidelines,” Chest, vol. 126(1): 7S-10S (2004). [cited by applicant]
Simonneau et al., “Updated Clinical Classification of Pulmonary Hypertension,” Journal of the American College of Cardiology, vol. 54(1) Suppl S: S43-S54 (2009). [cited by applicant]
Sotatercept (https://www.genome.jp/dbget-bin/www_bget?dr:D09670; accessed Feb. 1, 2022). [cited by applicant]
Spiess et al., “Alternative molecular formats and therapeutic applications for bispecific antibodies,” Molecular Immunology, vol. 67: 95-106 (2015). [cited by applicant]
Tokuriki et al., “Stability effects of mutations and protein evolvability,” Current Opinions in Structural Biology, vol. 19(5): 596-604 (2009). [cited by applicant]
Ulloa-Aguirre et al., “Pharmacologic rescue of conformationally-defective proteins: implications for the treatment of human disease,” Traffic, vol. 5(11): 821-837 (2004). [cited by applicant]
Yndestad et al., Elevated levels of activin A in clinical and experimental pulmonary hypertension, J. Applied Physiology, vol. 106(4): 1356-1364 (2009). [cited by applicant]
Yung et al., “ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension,” Science Translational Medicine, vol. 12(543): 5660 (2020). [cited by applicant]
Issued U.S. Pat. No. 10,722,558 (U.S. Appl. No. 15/650,420). [cited by applicant]
Issued U.S. Pat. No. 10,695,405 (U.S. Appl. No. 15/945,565). [cited by applicant]
Issued U.S. Pat. No. 11,622,992 U.S. Appl. No. 16/829,642. [cited by applicant]
Issued U.S. Pat. No. 10,973,880 (U.S. Appl. No. 17/002,288. [cited by applicant]
Issued U.S. Pat. No. 11,219,666 (U.S. Appl. No. 17/002,292). [cited by applicant]
Issued U.S. Pat. No. 11,065,303 (U.S. Appl. No. 17/002,542). [cited by applicant]
Issued U.S. Pat. No. 10,946,067 (U.S. Appl. No. 17/002,553). [cited by applicant]
Abandoned U.S. Appl. No. 17/155,559. [cited by applicant]
Issued U.S. Patent No. 11,318, 188 (U.S. Appl. No. 17/339,593). [cited by applicant]
Issued U.S. Pat. No. 11,497,794, (U.S. Appl. No. 17/339,606). [cited by applicant]
Issued U.S. Pat. No. 7,709,605 (U.S. Appl. No. 11/190,202). [cited by applicant]
Issued U.S. Pat. No. 8,252,900 (U.S. Appl. No. 12/751,868). [cited by applicant]
Issued U.S. Pat. No. 9,138,459 (U.S. Appl. No. 13/588,468). [cited by applicant]
Abandoned U.S. Appl. No. 14/836,684. [cited by applicant]
Abandoned U.S. Appl. No. 16/222,562. [cited by applicant]
Issued U.S. Pat. No. 7,612,041 (U.S. Appl. No. 11/603,485). [cited by applicant]
Issued U.S. Pat. No. 7,951,771 (U.S. Appl. No. 12/284,864). [cited by applicant]
Issued U.S. Pat. No. 8,067,360 (U.S. Appl. No. 12/284,862). [cited by applicant]
Issued U.S. Pat. No. 8,629,109 (U.S. Appl. No. 13/176,718). [cited by applicant]
Issued U.S. Pat. No. 9,163,075 (U.S. Appl. No. 14/027,542). [cited by applicant]
Issued U.S. Pat. No. 10,071,135 (U.S. Appl. No. 14/849,313). [cited by applicant]
Issued U.S. Pat. No. 11,129,873 (U.S. Appl. No. 16/054,107). [cited by applicant]
Pending U.S. Appl. No. 17/410,175. [cited by applicant]
Pending U.S. Appl. No. 18/443,985. [cited by applicant]
Abandoned U.S. Appl. No. 12/459,202. [cited by applicant]
Abandoned U.S. Appl. No. 15/005,762. [cited by applicant]
Abandoned U.S. Appl. No. 16/821,593 (Pub No. 2021/0038689). [cited by applicant]
Issued U.S. Pat. No. 8,895,016 (U.S. Appl. No. 12/459,188). [cited by applicant]
Issued U.S. Pat. No. 10,093,707 (U.S. Appl. No. 14/549,263). [cited by applicant]
Abandoned U.S. Appl. No. 16/121,338. [cited by applicant]
Abandoned U.S. Appl. No. 17/132,155. [cited by applicant]
Abandoned U.S. Appl. No. 17/395,372. [cited by applicant]
Issued U.S. Pat. No. 7,988,973 (U.S. Appl. No. 12/002,872). [cited by applicant]
Abandoned U.S. Appl. No. 12/286,381. [cited by applicant]
Issued U.S. Pat. No. 8,007,809 (U.S. Appl. No. 12/286,333). [cited by applicant]
Abandoned U.S. Appl. No. 13/189,353. [cited by applicant]
Abandoned U.S. Appl. No. 16/240,276. [cited by applicant]
Abandoned U.S. Appl. No. 17/132,024. [cited by applicant]
Abandoned U.S. Appl. No. 17/395,365. [cited by applicant]
Issued U.S. Pat. No. 10,227,393 (U.S. Appl. No. 15/092,609). [cited by applicant]
Issued U.S. Pat. No. 10,906,958 (U.S. Appl. No. 16/251,325). [cited by applicant]
Abandoned U.S. Appl. No. 16/951,192. [cited by applicant]
Pending U.S. Appl. No. 18/236,082. [cited by applicant]
Pending U.S. Appl. No. 17/666,705. [cited by applicant]
Issued U.S. Pat. No. 10,934,532 (U.S. Appl. No. 15/726,255). [cited by applicant]
Allowed U.S. Appl. No. 17/134,703. [cited by applicant]
Myllarniemi et al., “Upregulation of activin-B and follistatin in pulmonary fibrosis—a translational study using human biopsies and a specific inhibior in mouse fibrosis models,” BMC Pulmonary Medicine, vol. 14(170): (1… [cited by applicant]
Montani, David et al., “Pulmonary arterial hypertension”, Orphanet Journal of Rare Diseases, vol. 8:97, 1-58 (2013). [cited by applicant]
Kenny, Jane R. et al., “Therapeutic Protein Drug-Drug Interactions: Navigating the Knowledge Gaps-Highlights from the 2012 AAPS NBC Roundtable and IQ Consortium/FDA Workshop”, The AAPS Journal, vol. 15(4): 933-940 (2013… [cited by applicant]
Oba et al., “Pulmonary hypertension associated with left ventricular disease,” Medical Progress, vol. 255(1):89-93 (2015). [cited by applicant]
Rath et al., “Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics,” Critical Reviews in Biotechnology, vol. 35(2): 235-254 (2015). [cited by applicant]
Sugimura et al., “Pulmonary hypertension associated with left ventricular disease,” Angiology Frontier, vol. 14(2): 117-122 (2015). [cited by applicant]
Tyagi et al., “Chemical modification and chemical cross-linking for protein/enzyme stabilization”, Biochemistry (Mosc)P. vol. 63(3): 334-344 (1998). [cited by applicant]