IP Library › Granted Patent US 12,403,183
Granted Patent B2
US 12,403,183 · App. 16/993,979 · Granted Sep 2, 2025

Factor VIII polypeptide formulations

Inventors: Kevin Maloney (Waltham, MA); Daniel Gage (Waltham, MA); Ahmad Abdul-Fattah (Waltham, MA)
Assignee: BIOVERATIV THERAPEUTICS INC.
A61K38/37C07K14/755C07K16/2833C07K2319/30
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Quick Facts
Patent No.
US 12,403,183
App. No.
16/993,979
Granted
Sep 2, 2025
Kind
B2
Abstract

The present invention provides a formulation of a Factor VIII polypeptide, e.g., FVIII-Fc, and methods of using the same. The FVIII polypeptide can be a recombinant FVIII protein, a short-acting FVIII protein, or a long-acting FVIII protein. The pharmaceutical formulation comprising a FVIII polypeptide can be used for individual prophylaxis, weekly prophylaxis, episodic (on-demand) treatment, or perioperative management of hemophilia.

Claims (79)

1. A pharmaceutical composition comprising:

a. a chimeric polypeptide comprising a FVIII portion and an Fc region;

b. about 10 mg/mL to about 25 mg/mL sucrose;

c. about 10 mg/mL to about 13 mg/mL sodium chloride (NaCl);

d. about 0.75 mg/mL to about 2.25 mg/mL L-histidine;

e. about 5 mM to about 10 mM calcium chloride; and

f. about 0.08 mg/mL to about 0.25 mg/mL polysorbate 20 or polysorbate 80.

2. The pharmaceutical composition of claim 1 , wherein the chimeric polypeptide comprises a processed FVIII portion.

3. The pharmaceutical composition of claim 1 , wherein the chimeric polypeptide comprises a single chain FVIII portion.

4. A pharmaceutical kit comprising:

(a) a first container comprising a lyophilizate, where the lyophilizate comprises

(i) a chimeric polypeptide comprising a FVIII portion and an Fc region,

(ii) about 40 mg of sucrose;

(iii) about 36 mg of sodium chloride (NaCl);

(iv) about 3.1 mg of L-histidine;

(v) about 2.40 mg calcium chloride dihydrate; and

(vi) about 0.40 mg polysorbate 20 or polysorbate 80; and

(b) a second container comprising sterile water for injections at a volume sufficient to produce, when combined with the lyophilizate of the first container, a solution comprising:

(i) the chimeric polypeptide;

(ii) about 13.3 mg/ml of sucrose;

(iii) about 12.0 mg/ml of NaCl;

(iv) about 1.03 mg/ml of L-histidine;

(v) about 5.4 mM of calcium chloride; and

(vi) about 0.13 mg/ml of polysorbate 20 or polysorbate 80.

5. The pharmaceutical kit of claim 4 , wherein mannitol, glycine, alanine, or hydroxyethyl starch is not included.

6. The pharmaceutical kit of claim 4 , wherein NaCl is the only bulking agent.

7. The pharmaceutical kit of claim 4 , wherein the first container is a glass vial comprising a rubber stopper.

8. The pharmaceutical kit of claim 4 , wherein the second container is a syringe body.

9. The pharmaceutical kit of claim 4 , and wherein the syringe body is associated with a plunger.

10. The pharmaceutical composition of claim 1 , wherein the Fc region comprises an amino acid sequence that is at least 95% identical to amino acids 21 to 247 of SEQ ID NO: 4.

11. The pharmaceutical composition of claim 10 , wherein the Fc region comprises an amino acid sequence that is identical to amino acids 21 to 246 of SEQ ID NO: 4.

12. The pharmaceutical composition of claim 10 , wherein the chimeric polypeptide is an rFVIIIFc monomer-dimer hybrid.

13. The pharmaceutical composition of claim 12 , wherein the Fc region is a first Fc region, and the rFVIIIFc monomer-dimer hybrid comprises a second Fc region that comprises an amino acid sequence that is at least 95% identical to amino acids 21 to 247 of SEQ ID NO: 4.

14. The pharmaceutical composition of claim 13 , wherein the first Fc region comprises an Fc domain with a hinge region, wherein the second Fc region comprises an Fc domain with a hinge region, and wherein the first Fc region is covalently bound to the second Fc region via a disulfide bond.

15. The pharmaceutical composition of claim 14 , wherein the first Fc region comprises an amino acid sequence at least 99% identical to amino acids 21 to 247 of SEQ ID NO: 4, and wherein the second Fc region comprises an amino acid sequence at least 99% identical to amino acids 21 to 247 of SEQ ID NO: 4.

16. The pharmaceutical composition of claim 1 , which comprises about 50 IU/mL to about 2500 IU/mL of a combination of rFVIIIFc monomer-dimer hybrids comprising (i) a first rFVIIIFc monomer-dimer hybrid in which the FVIII portion is a single chain FVIII; and (ii) a second rFVIIIFc monomer-dimer hybrid in which the FVIII portion is a processed Factor VIII.

17. The pharmaceutical composition of claim 16 , wherein the single chain FVIII comprises an amino acid sequence that is at least 95% identical to amino acids 20 to 1457 of SEQ ID NO: 2.

18. The pharmaceutical composition of claim 17 , wherein the single chain FVIII comprises an amino acid sequence identical to amino acids 20 to 1457 of SEQ ID NO: 2.

19. The pharmaceutical kit of claim 4 , wherein the Fc region comprises an amino acid sequence that is at least 95% identical to amino acids 21 to 247 of SEQ ID NO: 4.

20. The pharmaceutical kit of claim 19 , wherein the Fc region comprises an amino acid sequence that is identical to amino acids 21 to 246 of SEQ ID NO: 4.

21. The pharmaceutical kit of claim 19 , wherein the chimeric polypeptide is an rFVIIIFc monomer-dimer hybrid.

22. The pharmaceutical kit of claim 21 , wherein the Fc region is a first Fc region, and the rFVIIIFc monomer-dimer hybrid comprises a second Fc region that comprises an amino acid sequence that is at least 95% identical to amino acids 21 to 247 of SEQ ID NO: 4.

23. The pharmaceutical kit of claim 21 , wherein the first Fc region comprises an Fc domain with a hinge region, wherein the second Fc region comprises an Fc domain with a hinge region, and wherein the first Fc region is covalently bound to the second Fc region via a disulfide bond.

24. The pharmaceutical kit of claim 23 , wherein the first Fc region comprises an amino acid sequence at least 99% identical to amino acids 21 to 247 of SEQ ID NO: 4, and wherein the second Fc region comprises an amino acid sequence at least 99% identical to amino acids 21 to 247 of SEQ ID NO: 4.

25. The pharmaceutical kit of claim 4 , wherein the lyophilizate comprises about 50 IU/mL to about 2500 IU/mL of a combination of rFVIIIFc monomer-dimer hybrids comprising (i) a first rFVIIIFc monomer-dimer hybrid in which the FVIII portion is a single chain FVIII; and (ii) a second rFVIIIFc monomer-dimer hybrid in which the FVIII portion is a processed Factor VIII.

26. The pharmaceutical kit of claim 25 , wherein the single chain FVIII comprises an amino acid sequence that is at least 95% identical to amino acids 20 to 1457 of SEQ ID NO: 2.

27. The pharmaceutical kit of claim 26 , wherein the single chain FVIII comprises an amino acid sequence identical to amino acids 20 to 1457 of SEQ ID NO: 2.

28. A pharmaceutical kit comprising:

(a) a first container comprising a lyophilizate, where the lyophilizate comprises

(i) a chimeric polypeptide comprising a FVIII portion and an Fc region;

(ii) sucrose;

(iii) sodium chloride (NaCl);

(iv) L-histidine;

(v) calcium chloride; and

(vi) polysorbate 20; and

(b) a second container comprising sterilized water,

wherein, when the lyophilizate of the first container is combined with the sterilized water of the second container, a solution comprising the following is produced:

(i) the chimeric polypeptide;

(ii) about 10 mg/mL to about 25 mg/mL sucrose;

(iii) about 10 mg/mL to about 13 mg/mL sodium chloride (NaCl);

(iv) about 0.75 mg/mL to about 2.25 mg/mL L-histidine;

(v) about 5 mM to about 10 mM calcium chloride; and

(vi) about 0.08 mg/mL to about 0.25 mg/mL polysorbate 20.

29. The pharmaceutical kit of claim 28 , wherein the Fc region comprises an amino acid sequence that is at least 95% identical to amino acids 21 to 247 of SEQ ID NO: 4.

30. The pharmaceutical kit of claim 29 , wherein the Fc region comprises an amino acid sequence that is identical to amino acids 21 to 246 of SEQ ID NO: 4.

31. The pharmaceutical kit of claim 29 , wherein the chimeric polypeptide is an rFVIIIFc monomer-dimer hybrid.

32. The pharmaceutical kit of claim 29 , wherein the Fc region is a first Fc region, and the rFVIIIFc monomer-dimer hybrid comprises a second Fc region that comprises an amino acid sequence that is at least 95% identical to amino acids 21 to 247 of SEQ ID NO: 4.

33. The pharmaceutical kit of claim 31 , wherein the first Fc region comprises an Fc domain with a hinge region, wherein the second Fc region comprises an Fc domain with a hinge region, and wherein the first Fc region is covalently bound to the second Fc region via a disulfide bond.

34. The pharmaceutical kit of claim 33 , wherein the first Fc region comprises an amino acid sequence at least 99% identical to amino acids 21 to 247 of SEQ ID NO: 4, and wherein the second Fc region comprises an amino acid sequence at least 99% identical to amino acids 21 to 247 of SEQ ID NO: 4.

35. The pharmaceutical kit of claim 31 , wherein the lyophilizate comprises about 50 IU/mL to about 2500 IU/mL of a combination of rFVIIIFc monomer-dimer hybrids comprising (i) a first rFVIIIFc monomer-dimer hybrid in which the FVIII portion is a single chain FVIII; and (ii) a second rFVIIIFc monomer-dimer hybrid in which the FVIII portion is a processed Factor VIII.

36. The pharmaceutical kit of claim 35 , wherein the single chain FVIII comprises an amino acid sequence that is at least 95% identical to amino acids 20 to 1457 of SEQ ID NO: 2.

37. The pharmaceutical kit of claim 36 , wherein the single chain FVIII comprises an amino acid sequence identical to amino acids 20 to 1457 of SEQ ID NO: 2.

38. The pharmaceutical kit of claim 28 , wherein mannitol, glycine, alanine, or hydroxyethyl starch is not included.

39. The pharmaceutical kit of claim 28 , wherein NaCl is the only bulking agent.

40. The pharmaceutical kit of claim 28 , wherein the first container is a glass vial comprising a rubber stopper.

41. The pharmaceutical kit of claim 28 , wherein the second container is a syringe body.

42. The pharmaceutical kit of claim 41 , and wherein the syringe body is associated with a plunger.

43. The pharmaceutical composition of claim 1 , wherein the polysorbate 20 or polysorbate 80 is polysorbate 20.

44. The pharmaceutical kit of claim 4 , wherein the polysorbate 20 or polysorbate 80 is polysorbate 20.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2025
From: MALONEY, KEVIN; GAGE, DANIEL
To: BIOGEN IDEC MA INC.
Reel/Frame 071865/0870 →
EMPLOYMENT AGREEMENT Recorded Jul 29, 2025
From: ABDUL-FATTAH, AHMAD M.
To: BIOGEN IDEC MA INC.
Reel/Frame 072254/0251 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 29, 2025
From: BIOGEN MA INC.
To: BIOVERATIV THERAPEUTICS INC.
Reel/Frame 072254/0629 →
CHANGE OF NAME Recorded Jul 29, 2025
From: BIOGEN IDEC MA INC.
To: BIOGEN MA INC.
Reel/Frame 072255/0069 →
Continuity (11)
Division 15455043 · Mar 9, 2017
Division 14213180 · Mar 14, 2014
Provisional Application 61897742 · Oct 30, 2013
Provisional Application 61879955 · Sep 19, 2013
Provisional Application 61876927 · Sep 12, 2013
Provisional Application 61863860 · Aug 8, 2013
Provisional Application 61839477 · Jun 26, 2013
Provisional Application 61829884 · May 31, 2013
Provisional Application 61817085 · Apr 29, 2013
Provisional Application 61800293 · Mar 15, 2013
Related Publication 20210069300A1 · Mar 11, 2021
References Cited (153)
US 4757006A · Toole, Jr. et al. · 1988 [cited by applicant]
US 4868112A · Toole, Jr. · 1989 [cited by applicant]
US 4965199A · Capon et al. · 1990 [cited by applicant]
US 4994371A · Davie et al. · 1991 [cited by applicant]
US 5004803A · Kaufman et al. · 1991 [cited by applicant]
US 5112950A · Meulien et al. · 1992 [cited by applicant]
US 5171844A · Van Ooyen et al. · 1992 [cited by applicant]
US 5364771A · Lollar et al. · 1994 [cited by applicant]
US 5543502A · Nordfang et al. · 1996 [cited by applicant]
US 5595886A · Chapman et al. · 1997 [cited by applicant]
US 5610278A · Nordfang et al. · 1997 [cited by applicant]
US 5712122A · Boime et al. · 1998 [cited by applicant]
US 5733873A · Osterberg · 1998 [cited by examiner]
US 5763401A · Nayar · 1998 [cited by applicant]
US 5789203A · Chapman et al. · 1998 [cited by applicant]
US 5859204A · Lollar · 1999 [cited by applicant]
US 5972885A · Spira et al. · 1999 [cited by applicant]
US 6048720A · Dalborg et al. · 2000 [cited by applicant]
US 6060447A · Chapman et al. · 2000 [cited by applicant]
US 6200560B1 · Couto et al. · 2001 [cited by applicant]
US 6228620B1 · Chapman et al. · 2001 [cited by applicant]
US 6251632B1 · Lillicrap et al. · 2001 [cited by applicant]
US 6316226B1 · Van Ooyen et al. · 2001 [cited by applicant]
US 6346513B1 · Van Ooyen et al. · 2002 [cited by applicant]
US 6376463B1 · Lollar · 2002 [cited by applicant]
US 6458563B1 · Lollar · 2002 [cited by applicant]
US 6686179B2 · Fleer et al. · 2004 [cited by applicant]
US 7041635B2 · Kim et al. · 2006 [cited by applicant]
US 7348004B2 · Peters et al. · 2008 [cited by applicant]
US 7404956B2 · Peters et al. · 2008 [cited by applicant]
US 7592010B2 · Rosen et al. · 2009 [cited by applicant]
US 7632921B2 · Pan et al. · 2009 [cited by applicant]
US 7862820B2 · Peters et al. · 2011 [cited by applicant]
US 8239182B2 · Kanade · 2012 [cited by applicant]
US 8815250B2 · Rivera et al. · 2014 [cited by applicant]
US 9050318B2 · Dumont et al. · 2015 [cited by applicant]
US 9623088B2 · Maloney · 2017 [cited by examiner]
US 10786554B2 · Maloney et al. · 2020 [cited by applicant]
US 20050100990A1 · Saenko et al. · 2005 [cited by applicant]
US 20090087411A1 · Defrees · 2009 [cited by applicant]
US 20090163699A1 · Skerra et al. · 2009 [cited by applicant]
US 20090264627A1 · Oestergaard et al. · 2009 [cited by applicant]
US 20100286067A1 · Defrees · 2010 [cited by applicant]
US 20100292130A1 · Maloney et al. · 2010 [cited by applicant]
US 20120093840A1 · Fares et al. · 2012 [cited by applicant]
US 20140308280A1 · Chamberlain et al. · 2014 [cited by applicant]
US 20170281734A1 · Gillies et al. · 2017 [cited by applicant]
CN 1399560A · 2003 [cited by applicant]
EP 0154316A2 · 1985 [cited by applicant]
EP 0295597A2 · 1988 [cited by applicant]
EP 0401384A1 · 1990 [cited by applicant]
EP 2173890A1 · 2010 [cited by applicant]
EP 2968477A1 · 2016 [cited by applicant]
EP 3666283A1 · 2020 [cited by applicant]
JP H10501522A · 1998 [cited by applicant]
WO WO19870004187A1 · 1987 [cited by applicant]
WO WO19880000831A1 · 1988 [cited by applicant]
WO WO19880003558A1 · 1988 [cited by applicant]
WO WO1988008035A1 · 1988 [cited by applicant]
WO WO1991009122A1 · 1991 [cited by applicant]
WO WO1992016221A1 · 1992 [cited by applicant]
WO WO1993020093A1 · 1993 [cited by applicant]
WO WO1994007510A1 · 1994 [cited by applicant]
WO WO1994011503A2 · 1994 [cited by applicant]
WO WO1995026750A1 · 1995 [cited by applicant]
WO WO1995034326A1 · 1995 [cited by applicant]
WO WO2000048635A1 · 2000 [cited by applicant]
WO WO2003080108A1 · 2003 [cited by applicant]
WO WO2004101740A2 · 2004 [cited by applicant]
WO WO2005058283A2 · 2005 [cited by applicant]
WO WO2006074199A1 · 2006 [cited by applicant]
WO WO2007092772A2 · 2007 [cited by examiner]
WO WO2008077616A1 · 2008 [cited by examiner]
WO WO2008155134A1 · 2008 [cited by applicant]
WO WO2010115866A1 · 2010 [cited by applicant]
WO WO2011069164A2 · 2011 [cited by examiner]
WO WO2013009627A2 · 2013 [cited by applicant]
WO WO2013057219A1 · 2013 [cited by applicant]
WO WO2014026954A1 · 2014 [cited by applicant]
WO WO2014070953A1 · 2014 [cited by applicant]
WO WO2014144795A1 · 2014 [cited by applicant]
U.S. Appl. No. 14/213,180, filed Mar. 14, 2014, Kevin Maloney, 2014/0308280, Oct. 16, 2014, now U.S. Pat. No. 9,623,088, Apr. 18, 2017. [cited by applicant]
U.S. Appl. No. 15/455,043, filed Mar. 9, 2017, Kevin Maloney, 2017/0281734, Oct. 5, 2017, now U.S. Pat. No. 10,786,554, Sep. 29, 2020. [cited by applicant]
U.S. Appl. No. 16/993,979* filed Aug. 14, 2020, Kevin Maloney. [cited by applicant]
Extended European Search Report for European Patent Application No. 22176875.7, mailed Dec. 20, 2022. [cited by applicant]
Armour, et al., “Recombinant Human IgG Molecules Lacking Fc Gamma Receptor I Binding And Monocyte Triggering Activities”, European Journal of Immunology, vol. 29, No. 8, pp. 2613-2624. (Aug. 1999). [cited by applicant]
Bai, et al., “Recombinant Granulocyte Colony-Stimulating Factor-Transferrin Fusion Protein As An Oral Myelopoietic Agent”, Proceedings of the National Academy of Sciences of the United States of America, vol. 102, No. 2… [cited by applicant]
Bobrow, Robert S., “Excess Factor VIII: A Common Cause of Hypercoagulability”, American Board of Family Medicine, United States, pp. 147-149 (Mar. 2005). [cited by applicant]
Brandsma, et al., “Recombinant Human Transferrin: Beyond Iron Binding and Transport”, Biotechnology Advances, vol. 29, No. 2, pp. 230-238. (Mar.-Apr. 2011). [cited by applicant]
Brutlag, et al., “Improved Sensitivity of Biological Sequence Database Searches”, Computer Applications in the Biosciences: CABIOS, vol. 6, No. 3, pp. 237-245. (Aug. 1990). [cited by applicant]
Burmeister, et al., “Crystal Structure of the Complex of Rat Neonatal Fc Receptor with Fc”, Nature, vol. 372, No. 6504, pp. 379-383. (Nov. 24, 1994). [cited by applicant]
Cameron, et al., “The Canine Factor VIII cDNA and 5′ Flanking Sequence”, Journal of Thrombosis and Haemostasis, vol. 79, No. 2, pp. 317-322. (Feb. 1998). [cited by applicant]
Collins, et al., “Factor VIII Requirement to Maintain a Target Plasma Level in Prophylactic Treatment of Severe Hemophilia A: Influences Variance in Pharmacokinetics and Treatment Regimens”, Journal of Thrombosis and Ha… [cited by applicant]
Cutler, et al., “The Identification and Classification Of 41 Novel Mutations In The Factor VIII Gene (F8c)”, Human Mutation, vol. 19, No. 3, pp. 274-278. (Mar. 2002). [cited by applicant]
Dennis, et al., “Albumin Binding as a General Strategy for Improving the Pharmacokinetics of Proteins”, Journal of Biological Chemistry, vol. 277, No. 38, pp. 35035-35043. (Sep. 20, 2002). [cited by applicant]
Dobeli, et al., “Role of the Carboxy-Terminal Sequence on the Biological Activity of Human Immune Interferon (IFN-y)”, Journal of Biotechnology, vol. 7, No. 3, pp. 199-216. (1988). [cited by applicant]
Eaton, et al., “Construction and Characterization of an Active Factor VIII Variant Lacking the Central One-Third of the Molecule”, Biochemistry, vol. 25, No. 26, pp. 8343-8347. (Dec. 1986). [cited by applicant]
Extended European Search Report received for European Application No. 19212900.5, mailed on Apr. 30, 2020. [cited by applicant]
Fatouros, et al., “Recombinant factor VIII SQ-Influence of Oxygen, Metal Ions, pH and lonic Strength on its Stability in Aqueous Solution”, International journal of Phamaceutics, vol. 155, No. 1, pp. 121-131. (1997). [cited by applicant]
Francis, G E., “Protein Modification and Fusion Proteins”, Focus on Growth Factors, vol. 3, No. 2, Mediscript, England, pp. 4-10. (1992). [cited by applicant]
Friend, et al., “Phase I Study of an Engineered Aglycosylated Humanized Cd3 Antibody in Renal Transplant Rejection1”, Transplantation, vol. 68, Issue 11, pp. 1632-1637. (Dec. 15, 1999). [cited by applicant]
Gayle, et al., “Identification Of Regions In Interleukin-1 Alpha Important For Activity”, Journal of Biological Chemistry, vol. 268, No. 29, pp. 22105-22111. (Oct. 15, 1993). [cited by applicant]
Genbank, “ [cited by applicant]
Genbank, “ [cited by applicant]
Genbank, “ [cited by applicant]
Genbank, “ [cited by applicant]
Genbank, “Human Transferrin mRNA, Complete cds”, Accession No. M12530, Retrieved From: <<http://www.ncbi.nlm.nih.gov/nuccore/M12530>> Retrieved on Jan. 15, 2015, 2 Pages. (Jan. 14, 1995). [cited by applicant]
Genbank, “Transferrin [Human, Liver, mRNA, 2347 nt]”, Accession No. S95936, Retrieved From :<<http://www.ncbi.nlm.nih.gov/nuccore/S95936>>, 2 pages. (May 7, 1993). [cited by applicant]
Gitschier, et al., “Characterization Of The Human Factor VIII Gene”, Nature, vol. 312, No. 5992, pp. 326-330. (Nov. 22-28, 1984). [cited by applicant]
Healey, et al., “The cDNA And Derived Amino Acid Sequence Of Porcine Factor VIII”, Blood, vol. 88, No. 11, pp. 4209-4214. (Dec. 1, 1996). [cited by applicant]
Hoeben, et al., “Expression Of Functional Factor VIII In Primary Human Skin Fibroblasts After Retrovirus-Mediated Gene Transfer”, Journal of Biological Chemistry, vol. 265, No. 13, pp. 7318-7323. (May 1990). [cited by applicant]
Holt, et al., “Anti-Serum Albumin Domain Antibodies For Extending The Half-Lives Of Short Lived Drugs”, Protein Engineering, Design and Selection, vol. 21, No. 5, pp. 283-288. (May 2008). [cited by applicant]
International Search Report and Written Opinion received for PCT Patent Application No. PCT/US2014/29354, mailed on Aug. 7, 2014. [cited by applicant]
Kim, et al., “Transferrin Fusion Technology: A Novel Approach To Prolonging Biological Half-Life Of Insulinotropic Peptides”, Journal of Pharmacology and Experimental Therapeutics, vol. 334, No. 3, pp. 682-692. (Sep. 20… [cited by applicant]
Kraulis, et al., “The Serum Albumin-Binding Domain Of Streptococcal Protein G Is A Three-Helical Bundle: A Heteronuclear NMR Study”, FEBS Letters, vol. 378, Issue 2, pp. 190-194. (Jan. 8, 1996). [cited by applicant]
Langner, et al., “Synthesis Of Biologically Active Deletion Mutants Of Human Factor VIII:C”, Behring Institute Mitteilungen, No. 82, pp. 16-25. (Apr. 1988). [cited by applicant]
Li, et al., “The Role Of The Transferrin-Transferrin-Receptor System In Drug Delivery And Targeting”, Trends in Pharmacological Sciences, vol. 23, No. 5, pp. 206-209. (May 2002). [cited by applicant]
Linhult, et al., “Mutational Analysis Of The Interaction Between Albumin-Binding Domain From Streptococcal Protein G And Human Serum Albumin”, Protein Science, vol. 11, No. 2, pp. 206-213. (Feb. 2002). [cited by applicant]
Lollar, et al., “Coagulant Properties Of Hybrid Human/Porcine Factor VIII Molecules”, Journal of Biological chemistry, vol. 267, pp. 23652-23657. (Nov. 25, 1992). [cited by applicant]
Lollar, et al., “Structural Basis For The Deceased Procoagulant Activity Of Human Factor VIII Compared To The Porcine Homolog”, Journal of biological chemistry, vol. 266, No., pp. 12481-12486. (Jul. 5, 1991). [cited by applicant]
Mahlangu, et al., “Phase 3 Study of Recombinant Factor VIII Fe Fusion Protein in Severe Hemophilia A”, Blood, vol. 123, Issue 3, pp. 317-325. (Jan. 2014). [cited by applicant]
Malik, et al., “Polyethylene Glycol (PEG)-Modified Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) With Conserved Biological Activity”, Experimental Hematology, vol. 20, No. 8, pp. 1028-1035. (Sep. 1992). [cited by applicant]
Mannucci, et al., “The Hemophilias—From Royal Genes to Gene Therapy”, New England Journal of Medicine, vol. 344, No. 23, pp. 1773-1779. (Jun. 1, 2001). [cited by applicant]
Mei, et al., “Expression of Human Coagulation Factor VIII in a Human Hybrid Cell Line, HKB11”, Molecular Biotechnology, vol. 34, No. 2, Humana Press Inc., pp. 165-178. (Oct. 2006). [cited by applicant]
Mei, et al., “Rational Design Of A Fully Active, Long-Acting PEGylated Factor VIII For Hemophilia A Treatment”, Blood, vol. 116, No. 2, pp. 270-279. (Jul. 15, 2010). [cited by applicant]
Meulien, et al., “A New Recombinant Procoagulant Protein Derived From The Cdna Encoding Human Factor VIII”, Protein Engineering, Design and Selection, vol. 2, No. 4, pp. 301-306. (Oct. 1, 1988). [cited by applicant]
Muller, et al., “Recombinant Bispecific Antibodies For Cellular Cancer Immunotherapy”, Current opinion in molecular therapeutics, vol. 9, No. 4, pp. 319-326. (Aug. 2007). [cited by applicant]
Neumann, et al., “Gene Transfer Into Mouse Lyoma Cells By Electroporation In High Electric Fields”, The EMBO Journal, vol. 1, No. 7, pp. 841-845. (Jul. 1, 1982). [cited by applicant]
Oganesyan, et al., “Structural Characterization of a Human Fc Fragment Engineered for Extended Serum Half-Life”, Molecular Immunology, vol. 46, No. 8-9, pp. 1750-1755. (May 2009). [cited by applicant]
Osterberg, et al., “Development of a Freeze-Dried Albumin-Free Formulation of Recombinant Factor VIII SQ”, Pharmaceutical Research, vol. 14, Issue 7, pp. 892-898. (Jul. 1997). [cited by applicant]
Peyvandi, et al., “Genetic Diagnosis of Haemophilia and Other Inherited Bleeding Disorders”, Haemophilia, vol. 12, Suppl 3, pp. 82-89. (Jul. 2006). [cited by applicant]
Powell, et al., “Safety And Prolonged Activity Of Recombinant Factor VIII Fc fusion protein in Hemophilia A Patients”, Blood, vol. 119, No. 13, pp. 3031-3037. (Mar. 29, 2012). [cited by applicant]
Rodriguez-Merchan, Carlos E., “Management Of Musculoskeletal Complications Of Hemophilia”, Seminars in Thrombosis and Hemostasis., vol. 29, No. 01, pp. 87-96. (2003). [cited by applicant]
Ron, et al., “Expression of Biologically Active Recombinant Keratinocyte Growth Factor. Structure/Function Analysis Of Amino-Terminal Truncation Mutants”, Journal of Biological Chemistry, vol. 268, No. 4, pp. 2984-2988.… [cited by applicant]
Roovers, et al., “Efficient Inhibition Of EGFR Signaling And Of Tumour Growth By Antagonistic anti-EFGR Nanobodies”, Cancer Immunology, Immunotherapy, vol. 56, No. 3, pp. 303-317. (Mar. 2007). [cited by applicant]
Routledge, et al., “The Effect Of Aglycosylation On The Immunogenicity Of A Humanized Therapeutic CD3 Monoclonal Antibody”, Transplantation, vol. 60, No. 8, pp. 847-853. (Oct. 1, 1995). [cited by applicant]
Sarver, et al., “Stable Expression Of Recombinant Factor VIII Molecules Using A Bovine Papillomavirus Vector”, DNA, vol. 6, No. 6, pp. 553-564. (Dec. 1987). [cited by applicant]
Schulte, Stefan, “Half-Life Extension Through Albumin Fusion Technologies”, Thrombosis Research, vol. 124, Supplement 2, pp. S6-S8. (Dec. 2009). [cited by applicant]
Shields, et al., “High Resolution Mapping of the Binding Site on Human IgG1 for Fc Gamma RI, Fc Gamma RII, Fc Gamma RIII, and FcRn and Design of IgG1 Variants with Improved Binding to the Fc Gamma R”, Journal of Biologi… [cited by applicant]
Sommermeyer, et al., “Klinisch verwendete Hydroxyethylstärke: physikalischchemische Charakterisierung”, Krankenhauspharmazie, vol. 8, No. 8, Deutscher Apotheker Verlag, Birkenwaldstr, Germany, pp. 271-278. (1987). [cited by applicant]
Story, et al., “A Major Histocompatibility Complex Class I-like Fc Receptor Cloned from Human Placenta: Possible Role in Transfer of Immunoglobulin G from Mother to Fetus”, Journal of Experimental Medicine, vol. 180, No… [cited by applicant]
Toole, et al., “A Large Region (Approximately Equal To 95 kDa) Of Human Factor VIII Is Dispensable For In Vitro Procoagulant Activity”, Proceedings of the National Academy of Sciences, vol. 83, No. 16, pp. 5939-5942. (A… [cited by applicant]
Toole, et al., “Molecular Cloning Of a cDNA Encoding Human Antihaemophilic Factor”, Nature, vol. 312, No. 5992, pp. 342-347. (Nov. 22-28, 1984). [cited by applicant]
Trussel, et al., “New Strategy For The Extension Of The Serum Half-Life Of Antibody Fragments”, Bioconjugate Chemistry, vol. 20, No. 12, pp. 2286-2292. (Dec. 2009). [cited by applicant]
Vaccaro, et al., “Engineering the Fc Region of Immunoglobulin G to Modulate in Vivo Antibody Levels”, Nature Biotechnology, vol. 23, No. 10, pp. 1283-1288. (Oct. 2005). [cited by applicant]
Valentino, et al., “A Randomized Comparison of Two Prophylaxis Regimens and a Paired Comparison of on-Demand and Prophylaxis Treatments in Hemophilia A Management”, Journal of Thrombosis and Haemostasis, vol. 10, No. 3,… [cited by applicant]
Vehar, et al., “Structure Of Human Factor VIII”, Nature, vol. 312, No. 5992, pp. 337-342. (Nov. 1984). [cited by applicant]
Wakabayashi, et al., “Residues 110-126 in the A1 Domain of Factor VIII Contain a Ca2+ Binding Site Required for Cofactor Activity”, The Journal of Biological Chemistry, vol. 279, pp. 12677-12684. (Jan. 13, 2004). [cited by applicant]
Wang, et al., “Receptor-Mediated Activation of a Proinsulin-Transferrin Fusion Protein in Hepatoma Cells”, Journal of Controlled Release, vol. 155, No. 3, pp. 386-392. (Nov. 7, 2011). [cited by applicant]
Ward, et al., “The Effector Functions Of Immunoglobulins: Implications For Therapy”, Therapeutic immunology, vol. 2, No. 2, pp. 77-94. (Apr. 1995). [cited by applicant]
Weidler, et al., “Pharmacokinetic Parameters As Criteria For Clinical Use Of Hydroxyethyl Starch Preparations”, Arzneimittelforschung/Drug Research, vol. 41, No. 5, pp. 494-498. (May 1991). [cited by applicant]
Wigler, et al., “Biochemical Transfer of Single-Copy Eucaryotic Genes using Total Cellular DNA as Donor”, Cell, vol. 14, No. 3, pp. 725-731. (Jul. 1978). [cited by applicant]
Wood, et al., “Expression of Active Human Factor VIII From Recombinant DNA Clones”, Nature, vol. 312, No. 5992, pp. 330-337. (Nov. 22-28, 1984). [cited by applicant]