Granted Patent
B2
US 12,203,113 · App. 17/379,504 · Granted Jan 21, 2025
Long-acting coagulation factors and methods of producing same
Assignee:
OPKO BIOLOGICS LTD.
C12N9/6437C07K14/505C07K14/59C07K14/745C12N9/644C12N9/96C12Y304/21021A61K38/00A61K38/4846A61K39/395C07K16/46C07K2319/31
View Patent ↗
Loading inventors, assignments & file history…
Abstract
Polypeptides comprising at least one carboxy-terminal peptide (CTP) of chorionic gonadotrophin attached to the carboxy terminus but not to the amino terminus of a coagulation factor and polynucleotides encoding the same are disclosed. Pharmaceutical compositions comprising the polypeptides and polynucleotides of the invention and methods of using and producing same are also disclosed.
Claims (22)
1. A method of increasing patient compliance in the use of a coagulation factor therapy in a human subject, comprising administering to a subject in need thereof a chorionic gonadotropin carboxy terminal peptide (CTP)-modified coagulation Factor VII (FVII) polypeptide selected from;
a. a CTP-modified coagulation FVII polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 25 and amino acids 39-528 of SEQ ID NO: 25, or
b. an activated CTP-modified Factor VII (FVIIa) polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 25 and amino acids 39-528 of SEQ ID NO: 25,
wherein said increasing patient compliance is achieved by reducing the frequency of administration of said coagulation factor polypeptide in a coagulation factor therapy, as compared to an unmodified coagulation factor.
2. The method of claim 1 , wherein said coagulation factor therapy is for treating Hemophilia or Hemophilia A.
3. The method of claim 1 , wherein at least one CTP consists of an amino acid sequence selected from the group consisting of: SEQ ID NO: 1 and SEQ ID NO: 2.
4. The method of claim 1 , wherein at least one CTP is glycosylated.
5. The method of claim 1 , wherein at least one CTP is truncated.
6. The method of claim 1 , wherein at least one CTP is attached to said coagulation Factor VII polypeptide via a linker, wherein said linker is a peptide bond.
7. The method of claim 1 , wherein the sequence of said CTP-modified Factor VII (FVII) is selected from the group consisting of SEQ ID NO: 25 and SEQ ID NO: 46.
8. The method of claim 1 , wherein said CTP-modified coagulation Factor VII as a signal peptide.
9. The method of claim 8 , wherein said signal peptide is set forth in SEQ ID NO: 47.
10. The method of claim 1 , wherein said coagulation FVII polypeptide is an activated coagulation Factor VII (FVIIa) polypeptide.
11. The method of claim 10 , wherein the sequence of said CTP-modified activated coagulation Factor VII is set forth in SEQ ID NO: 46.
12. The method of claim 10 , wherein said activated coagulation FVII polypeptide is in the form of a disulfide-linked two chain heterodimer.
13. The method of claim 12 , wherein said two chains comprise a light chain consisting of amino acids 1-152 and a heavy chain consisting of amino acids 153-490 of SEQ ID NO: 46.
14. The method of claim 12 , wherein, wherein said heavy and the light chain domains are separated and migrate as separated bands of molecular weights 55 kDa and 25 kDa.
15. The method of claim 1 , wherein CTP-modified coagulation FVII is administered to said subject in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
16. The method of claim 15 , wherein said administration is once a week.
17. The method of claim 15 , wherein said administration is subcutaneous or intravenous.
18. The method of claim 15 , wherein said subject is a hemophilic subject or is a subject suffering from a vitamin K deficiency or a liver disease.
19. The method of claim 15 , wherein said subject is a child.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 15, 2021
From: FIMA, UDI EYAL; HART, GILI
To: OPKO BIOLOGICS, LTD.
Reel/Frame 058110/0755 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 15, 2021
From: FIMA, UDI EYAL; HART, GILI
To: OPKO BIOLOGICS, LTD.
Reel/Frame 058111/0629 →
Continuity (9)
Provisional Application
61224366
· Jul 9, 2009
References Cited (400)
US 3791932A
· Schuurs et al.
· 1974
[cited by applicant]
US 3839153A
· Schuurs et al.
· 1974
[cited by applicant]
US 3850578A
· MacConnell
· 1974
[cited by applicant]
US 3850752A
· Schuurs et al.
· 1974
[cited by applicant]
US 3853987A
· Dreyer
· 1974
[cited by applicant]
US 3867517A
· Ling
· 1975
[cited by applicant]
US 3879262A
· Schuurs et al.
· 1975
[cited by applicant]
US 3901654A
· Gross
· 1975
[cited by applicant]
US 3935074A
· Rubenstein et al.
· 1976
[cited by applicant]
US 3984533A
· Uzgiris
· 1976
[cited by applicant]
US 3996345A
· Ullman et al.
· 1976
[cited by applicant]
US 4034074A
· Miles
· 1977
[cited by applicant]
US 4098876A
· Piasio et al.
· 1978
[cited by applicant]
US 4400316A
· Katsuragi et al.
· 1983
[cited by applicant]
US 4666828A
· Gusella
· 1987
[cited by applicant]
US 4683202A
· Mullis
· 1987
[cited by applicant]
US 4801531A
· Frossard
· 1989
[cited by applicant]
US 4853332A
· Mark et al.
· 1989
[cited by applicant]
US 4873316A
· Meade et al.
· 1989
[cited by applicant]
US 4879219A
· Wands et al.
· 1989
[cited by applicant]
US 4911691A
· Aniuk et al.
· 1990
[cited by applicant]
US 5011771A
· Bellet et al.
· 1991
[cited by applicant]
US 5118666A
· Habener
· 1992
[cited by applicant]
US 5177193A
· Boime et al.
· 1993
[cited by applicant]
US 5192659A
· Simons
· 1993
[cited by applicant]
US 5272057A
· Smulson et al.
· 1993
[cited by applicant]
US 5281521A
· Trojanowski et al.
· 1994
[cited by applicant]
US 5338835A
· Boime
· 1994
[cited by applicant]
US 5405945A
· Boime et al.
· 1995
[cited by applicant]
US 5464764A
· Capecchi et al.
· 1995
[cited by applicant]
US 5487992A
· Capecchi et al.
· 1996
[cited by applicant]
US 5585345A
· Boime
· 1996
[cited by applicant]
US 5597797A
· Clark
· 1997
[cited by applicant]
US 5643575A
· Martinez et al.
· 1997
[cited by applicant]
US 5681567A
· Martinez et al.
· 1997
[cited by applicant]
US 5705478A
· Boime
· 1998
[cited by applicant]
US 5712122A
· Boime et al.
· 1998
[cited by applicant]
US 5759818A
· Boime
· 1998
[cited by applicant]
US 5792460A
· Boime
· 1998
[cited by applicant]
US 5824642A
· Attie et al.
· 1998
[cited by applicant]
US 5919455A
· Greenwald et al.
· 1999
[cited by applicant]
US 5929028A
· Skrabanja et al.
· 1999
[cited by applicant]
US 5932447A
· Siegall
· 1999
[cited by applicant]
US 5935924A
· Bunting et al.
· 1999
[cited by applicant]
US 5958737A
· Boime et al.
· 1999
[cited by applicant]
US 6028177A
· Boime
· 2000
[cited by applicant]
US 6083725A
· Selden et al.
· 2000
[cited by applicant]
US 6103501A
· Boime et al.
· 2000
[cited by applicant]
US 6113906A
· Greenwald et al.
· 2000
[cited by applicant]
US 6225449B1
· Boime
· 2001
[cited by applicant]
US 6238890B1
· Boime
· 2001
[cited by applicant]
US 6242580B1
· Boime et al.
· 2001
[cited by applicant]
US 6306654B1
· Boime et al.
· 2001
[cited by applicant]
US 6310183B1
· Johannessen et al.
· 2001
[cited by applicant]
US 6340742B1
· Burg et al.
· 2002
[cited by applicant]
US 6514729B1
· Bentzien
· 2003
[cited by applicant]
US 6897039B2
· Graversen et al.
· 2005
[cited by applicant]
US 7081446B2
· Lustbader
· 2006
[cited by applicant]
US 7091326B2
· Lee et al.
· 2006
[cited by applicant]
US 7094566B2
· Medlock et al.
· 2006
[cited by applicant]
US 7141547B2
· Rosen et al.
· 2006
[cited by applicant]
US 7202215B2
· Lustbader
· 2007
[cited by applicant]
US 7217689B1
· Elliot et al.
· 2007
[cited by applicant]
US 7371372B2
· Chaturvedi et al.
· 2008
[cited by applicant]
US 7371373B2
· Shirley et al.
· 2008
[cited by applicant]
US 7425539B2
· Donovan et al.
· 2008
[cited by applicant]
US 7442684B2
· Lustbader et al.
· 2008
[cited by applicant]
US 7459429B2
· Klima et al.
· 2008
[cited by applicant]
US 7459435B2
· Lehmann et al.
· 2008
[cited by applicant]
US 7459436B2
· Lehmann et al.
· 2008
[cited by applicant]
US 7553940B2
· Fares et al.
· 2009
[cited by applicant]
US 7553941B2
· Fares et al.
· 2009
[cited by applicant]
US 7585837B2
· Shechter et al.
· 2009
[cited by applicant]
US 7649084B2
· Ferguson
· 2010
[cited by applicant]
US 7666835B2
· Bloom et al.
· 2010
[cited by applicant]
US 7795210B2
· Defrees et al.
· 2010
[cited by applicant]
US 8008454B2
· Lee et al.
· 2011
[cited by applicant]
US 8048846B2
· Chahal et al.
· 2011
[cited by applicant]
US 8048848B2
· Fares et al.
· 2011
[cited by applicant]
US 8048849B2
· Fares et al.
· 2011
[cited by applicant]
US 8063015B2
· Defrees et al.
· 2011
[cited by applicant]
US 8097435B2
· Fares et al.
· 2012
[cited by applicant]
US 8110376B2
· Fares et al.
· 2012
[cited by applicant]
US 8114836B2
· Fares et al.
· 2012
[cited by applicant]
US 8129330B2
· Martinez et al.
· 2012
[cited by applicant]
US 8304386B2
· Fares et al.
· 2012
[cited by applicant]
US 8426166B2
· Fares et al.
· 2013
[cited by applicant]
US 8450269B2
· Fares et al.
· 2013
[cited by applicant]
US 8465958B2
· Lopez De Leon et al.
· 2013
[cited by applicant]
US 8746234B2
· Samaniego et al.
· 2014
[cited by applicant]
US 8759292B2
· Fima et al.
· 2014
[cited by applicant]
US 8946155B2
· Fares et al.
· 2015
[cited by applicant]
US 9249407B2
· Fima et al.
· 2016
[cited by applicant]
US 20010007757A1
· Boime et al.
· 2001
[cited by applicant]
US 20010028895A1
· Bisgaier et al.
· 2001
[cited by applicant]
US 20020127652A1
· Schambye et al.
· 2002
[cited by applicant]
US 20040009902A1
· Boime et al.
· 2004
[cited by applicant]
US 20060088595A1
· Asakawa et al.
· 2006
[cited by applicant]
US 20060160177A1
· Okkels et al.
· 2006
[cited by applicant]
US 20070184530A1
· Fares et al.
· 2007
[cited by applicant]
US 20070298041A1
· Tomlinson
· 2007
[cited by applicant]
US 20080064856A1
· Warne et al.
· 2008
[cited by applicant]
US 20080206270A1
· Minev et al.
· 2008
[cited by applicant]
US 20110004172A1
· Eckstein et al.
· 2011
[cited by applicant]
US 20110034374A1
· Bloom et al.
· 2011
[cited by applicant]
US 20110166063A1
· Bossard et al.
· 2011
[cited by applicant]
US 20120264920A1
· Wang et al.
· 2012
[cited by applicant]
US 20140113860A1
· Fima et al.
· 2014
[cited by applicant]
US 20140170728A1
· DeFrees et al.
· 2014
[cited by applicant]
US 20150038413A1
· Fares et al.
· 2015
[cited by applicant]
US 20150133636A1
· Xenopoulos et al.
· 2015
[cited by applicant]
US 20150158926A1
· Fares et al.
· 2015
[cited by applicant]
US 20150295072A1
· Rezanezhad Gatabi
· 2015
[cited by applicant]
US 20150368630A9
· Fima et al.
· 2015
[cited by applicant]
US 20160168588A1
· Hershkovitz et al.
· 2016
[cited by applicant]
CA 2641342
· 2007
[cited by applicant]
CN 1528787A
· 2004
[cited by applicant]
CN 1528894A
· 2006
[cited by applicant]
EP 0167825
· 1986
[cited by applicant]
EP 0264166
· 1988
[cited by applicant]
EP 0394788A1
· 1990
[cited by applicant]
EP 01319712A2
· 2003
[cited by applicant]
EP 2532674
· 2012
[cited by applicant]
EP 2420251
· 2013
[cited by applicant]
JP H8509218
· 1996
[cited by applicant]
JP 2002226365A
· 2002
[cited by applicant]
JP 2002255857A
· 2002
[cited by applicant]
JP 2004269516A
· 2004
[cited by applicant]
KR 20030037598A
· 2003
[cited by applicant]
WO WO198910756
· 1989
[cited by applicant]
WO WO1993006844
· 1993
[cited by applicant]
WO WO199424148A1
· 1994
[cited by applicant]
WO WO200023472A2
· 2000
[cited by applicant]
WO WO2002036169A2
· 2002
[cited by applicant]
WO WO200248194A1
· 2002
[cited by applicant]
WO WO2003038100A1
· 2003
[cited by applicant]
WO WO2002085311A2
· 2003
[cited by applicant]
WO WO2004006756
· 2004
[cited by applicant]
WO WO2004089280A2
· 2004
[cited by applicant]
WO WO2004111242
· 2004
[cited by applicant]
WO WO2005035761
· 2005
[cited by applicant]
WO WO2005080544
· 2005
[cited by applicant]
WO WO2006018204
· 2006
[cited by applicant]
WO WO2006134340
· 2006
[cited by applicant]
WO WO2007094985
· 2007
[cited by applicant]
WO WO2007149406A2
· 2007
[cited by applicant]
WO WO2010007622
· 2010
[cited by applicant]
WO WO2010097077
· 2010
[cited by applicant]
WO WO2011004361A2
· 2011
[cited by applicant]
WO WO2011087672
· 2011
[cited by applicant]
WO WO2012011752
· 2012
[cited by applicant]
WO WO2012167251
· 2012
[cited by applicant]
WO WO2012173422
· 2012
[cited by applicant]
WO WO2013009627A2
· 2013
[cited by applicant]
WO WO2013018098
· 2013
[cited by applicant]
WO WO2003048210A1
· 2013
[cited by applicant]
WO WO2013096386
· 2013
[cited by applicant]
WO WO2013121416
· 2013
[cited by applicant]
WO WO2013121416A1
· 2013
[cited by applicant]
WO WO2013152351A2
· 2013
[cited by applicant]
WO WO2013157002
· 2013
[cited by applicant]
WO WO2013183052
· 2013
[cited by applicant]
WO WO2014080401
· 2014
[cited by applicant]
WO WO2016092549
· 2016
[cited by applicant]
WO WO2016092549A1
· 2016
[cited by applicant]
WO WO2016092550
· 2016
[cited by applicant]
WO WO2016203482
· 2016
[cited by applicant]
U.S. Appl. No. 60/764,761, filed Feb. 3, 2006, Fares et al.
[cited by applicant]
U.S. Appl. No. 61/224,366, filed Jul. 9, 2009, Fima et al.
[cited by applicant]
U.S. Appl. No. 11/700,910, filed Feb. 1, 2007, Fares et al.
[cited by applicant]
U.S. Appl. No. 11/700,911, filed Feb. 1, 2007, Fares et al.
[cited by applicant]
U.S. Appl. No. 11/702,156, filed Feb. 5, 2007, Fares et al.
[cited by applicant]
U.S. Appl. No. 12/216,989, filed Jul. 14, 2008, Fares et al.
[cited by applicant]
U.S. Appl. No. 12/401,746, filed Mar. 11, 2009, Fares et al.
[cited by applicant]
U.S. Appl. No. 12/401,755, filed Mar. 11, 2009, Fares et al.
[cited by applicant]
U.S. Appl. No. 12/476,916, filed Jun. 2, 2009, Fares et al.
[cited by applicant]
Alberts et al. “Molecular biology of the cell”, 5th ed.(Garland Science, 2008). 2002, p. 367.
[cited by applicant]
Ameredes et al. “Growth Hormone Improves Body Mass Recovery with Refeeding after Chronic Undernutrition-Induced Muscle Atrophy in Aging Male Rats” Journal of Nutrition. 129:2264-2270 (1999).
[cited by applicant]
Amirizahdeh et al. “Expression of biologically active recombinant B-domain-deleted human VIII in mammalian cells” Journal of Science, Islamic Republic of Iran. Abstract. 16(2):103-112, (2005).
[cited by applicant]
Anonymous “Corporate Presentation—Lazard Capital Markets Healthcare Conference”, Nov. 15, 2011, pp. 1-19; Retrieved from the Internet: URL:http://web.archive.org/web/20110628023057/http://www.prolor-biotech.com/_Uploads…
[cited by applicant]
Anonymous “Corporate Presentation”, Jun. 1, 2011, pp. 1-35; Retrieved from the Internet: URL;http://web.archive.org/web/20110628023057/http://www.prolor-biotech.com/_Uploads/dbsAttachedFiles/prolorPresentationJune2011In…
[cited by applicant]
Anonymous “Prolor and Yeda enter definitive license agreement for Reversible PEGylation technology”, Jan. 18, 2011, pp. 1-3; Retrieved from the Internet: URL;http://web.archive.org/web/20110123063420/http://www.news-med…
[cited by applicant]
Anonymous “Prolor Biotech Announces Positive Results of its Obesity/Diabetes Drug Candidate in Preclinical Weight Loss Study”, Apr. 17, 2012, pp. 1-2; Retrieved from the Internet: URL;http://web.archive.org/web/20120526…
[cited by applicant]
Anonymous “Prolor Biotech Receives New U.S. Patent Allowance Covering Broad Applications of its CTP Platform for Long Acting Therapeutic Proteins”, Jul. 11, 2011, pp. 1-2; Retrieved from the Internet: URL;http://web.arc…
[cited by applicant]
Anson et al. “The gene structure of human anti-haemophilic factor IX”, The EMBO Journal (1984) 3(5):1053-1060.
[cited by applicant]
Askoy et al., “A study of the intracellular and secreted forms of the MUC2 mucin from the PC/AA intestinal cell line.” Glycobiology 9.7: 739-746 (1999).
[cited by applicant]
Banerji et al. “A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes” Cell 33:729-740 (1983).
[cited by applicant]
Barker et al. “An immunomagnetic-base method for the purification of ovarian cancer cells from patient-derived ascites” (Gynecologic Oncology 82, 57-63, 2001).
[cited by applicant]
Beeley, Glycoprotein and proteoglycan techniques. Elsevier: 69-72 (1985).
[cited by applicant]
Bengtsson et al. “Treatment of adults with growth hormone (GH) deficiency with recombinant human GH” J Clin Endocrinol Metab. Feb. 1993;76(2):309-17.
[cited by applicant]
Berntorp et al. “The pharmacokinetics of clotting factor therapy”; Haemophilia (2003) 9:353-359.
[cited by applicant]
Biller et al. Effects of once-weekly sustained-release growth hormone: a double-blind, placebo-controlled study in adult growth hormone deficiency. The Journal of Clinical Endocrinology & Metabolism. Mar. 16, 2011;96(6)…
[cited by applicant]
Bitter et al. “Expression and secretion vectors for yeast” (1987) Methods in Enzymol. 153:516-544.
[cited by applicant]
Bjorkman et al. Pharmacokinetics of Coagulation Factors Clinical Relevance for Patients with Haemophilia. Clin Pharmacokinet vol. 40 (11): 815-832 (2001).
[cited by applicant]
Bohl et al. “Improvement of erythropoiesis in b-thalassemic mice by continuous erythropoietin delivery from muscle” Blood 95:2793-2798 (2000).
[cited by applicant]
Boissel et al. “Erythropoietin structure-function relationships” The Journal of Biological Chemistry 268(21):15983-15993 (1993).
[cited by applicant]
Booth et al. “The use of a ‘universal’ yeast expression vector to produce an antigenic protein of Mycobacterium leprae” Immunol. Lett. 19:65-70 (1988).
[cited by applicant]
Bouloux et al. “First human exposure to FSH-CTP in hypogonadotrophic hypogonadal males” Human Reproduction. Aug. 1, 2001;16(8):1592-7.
[cited by applicant]
Brisson et al. “Expression of a bacterial gene in plants by using a viral vector” Nature, 310:511-514 (1984).
[cited by applicant]
Broglie et al. “Light-Regulated Expression of a Pea Ribulose-1,5-Bisphosphat Carboxylase Small Subunit Gene in Transformed Plant Cells” Science 224:838-843 (1984).
[cited by applicant]
Brunetti-Pierri et al. “Bioengineered factor IX molecules with increased catalytic activity improve the therapeutic index of gene therapy vectors for hemophilia B.” Human Gene Therapy 20.5: 479-485 (2009).
[cited by applicant]
Buchwald et al. “Long-term, continuous intravenous heparin administration by an implantable infusion pump in ambulatory patients with recurrent venous thrombosis” Surgery 88:507-516 (1980).
[cited by applicant]
Butler et al., “The beta-subunit of human chorionic gonadotrophin exists as a homodimer.” Journal of Molecular Endocrinology 22.2: 185-192 (1999).
[cited by applicant]
Byrne et al. “Multiplex gene regulation: A two-tiered approach to transgene regulation in transgenic mice” Proc. Natl. Acad. Sci USA 86:5473-5477 (1989).
[cited by applicant]
Calame et al. “Transcriptional Controlling Elements in the Immunoglobulin and T Cell Receptor Loci” Adv. Immunol 43:235-275 (1988).
[cited by applicant]
Carles-Bonnet et al. “H-Lys-Arg-Asn-Lys-Asn-Asn-OH is the minimal active structure of oxyntomodulin” Peptides. Dec. 31, 1996;17(3):557-61.
[cited by applicant]
Cawley et al. “Developing long-acting growth hormone formulations”, Clinical Endocrinology (2013) 79, 305-309.
[cited by applicant]
Chan et al. “Plasma Insulin-Like Growth Factor-I and Prostate Cancer Risk: A Prospective Study”, Science vol. 279:563-566, Jan. 1998.
[cited by applicant]
Chen et al. “Recombinant carbohydrate variant of human choriogonadotropin beta-subunit (hCG beta) descarboxyl terminus (115-145). Expression and characterization of carboxyl-terminal deletion mutant of hCG beta in the b…
[cited by applicant]
Chen et al., “Glycoengineering Approach to Half-Life Extension of Recombinant Biotherapeutics.” Bioconjugate Chemistry 23.8: 1524-1533 (2012).
[cited by applicant]
Chen et al., “Modulating antibody pharmacokinetics using hydrophilic polymers.” Expert Opinion on Drug Delivery 8.9: 1221-1236 (2011).
[cited by applicant]
Chihara K. “Clinical aspect of growth hormone deficiency in adults” Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine. Sep. 10, 2000;89(9):2010; with English Abstract.
[cited by applicant]
Claxton et al., A systematic review of the associations between dose regimens and medication compliance. Clinical Therapeutics 23.8: 1296-1310 (2001).
[cited by applicant]
Cohen et al. “Oxyntomodulin suppresses appetite and reduces food intake in humans”, J Clin Endocrinol Metab. Oct. 2003;88(10):4696-701.
[cited by applicant]
Coleman et al., “Dosing frequency and medication adherence in chronic disease.” Journal of managed care pharmacy: JMCP 18.7: 527-539 (2012).
[cited by applicant]
Coruzzi et al. “Tissue-specific and light-regulated expression of a pea nuclear gene encoding the small subunit of ribulose-1,5-bisphosphate carboxylase” The EMBO Journal 3:1671-1680 (1984).
[cited by applicant]
Cutfield et al., “Non-compliance with growth hormone treatment in children is common and impairs linear growth.” PLoS One 6.1: e16223 (2011).
[cited by applicant]
Dalton et al. “Over-expression of secreted proteins from mammalian cell lines” Protein Science. May 1, 2014:23(5):517-25.
[cited by applicant]
Database Geneseq [Online] Apr. 7, 2005, “Human interferon beta (without signal peptide).” XP002664024 retrieved from EBI accession No. GSP: ADW02285, Database accession No. ADW02285.
[cited by applicant]
Davis CG et al. “Deletion of clustered O-linked carbohydrates does not impair function of low density lipoprotein receptor in transfected fibroblasts” J Biol Chem. 261(6):2828-38, Feb. 25, 1986.
[cited by applicant]
Diederichs et al., “Liposome in kosmetika und arzneimitteln.” Pharmazeutische Industrie 56.3: 267-275 (1994).
[cited by applicant]
Diness, et al. Lund-Hansen, and U. Hedner. “Effect of recombinant human FVIIA on warfarin-induced bleeding in rats.” Thrombosis research 59.6 (1990): 921-929.
[cited by applicant]
Dong et al. “The prolonged half-lives of new erythropoietin derivatives via peptide addition” Biochemical Research Communications, 339(1):380-385 (Jan. 6, 2006).
[cited by applicant]
Drake et al. “Optimizing GH therapy in adults and children” Endocr Rev. Aug. 2001;22(4):425-50. Review.
[cited by applicant]
Edlund et al. “Cell-Specific Expression of the Rat Insulin Gene: Evidence for Role of Two Distinct 5′ Flanking Elements” Science 230:912-916 (1985).
[cited by applicant]
Edmunds et al. “Plasma erythropoietin levels and acquired cystic disease of the kidney in patients receiving regular haemodialysis treatment” Br J Haematol. Jun. 1991;78(2):275-7.
[cited by applicant]
Eschbach et al. “Correction of the Anemia of End-Stage Rental Disease with Recombinant Human Erythropoietin”, The New England Journal of Medicine Jan. 8, 1987, vol. 316 No. 2, pp. 73-78.
[cited by applicant]
European Search Report for Application No. 10796803 dated Feb. 28, 2013.
[cited by applicant]
European Search Report for Application No. 12150722.2 Dated Jun. 4, 2012.
[cited by applicant]
European Search Report for Application No. 07749922 dated Oct. 8, 2009.
[cited by applicant]
European Search Report for Application No. 14196333.0 mailed on Mar. 2, 2015.
[cited by applicant]
European Search Report for Application No. 14197286.9 mailed on Mar. 2, 2015.
[cited by applicant]
European Search Report for Application No. 16187710.5 dated Oct. 14, 2016.
[cited by applicant]
European Search Report for Application No. 10796803.4 dated Feb. 28, 2013.
[cited by applicant]
European Search Report for Application No. 12179805 dated Nov. 9, 2012.
[cited by applicant]
European Search Report for Application No. 12179821 dated Nov. 12, 2012.
[cited by applicant]
European Search Report for Application No. 18150731.0 dated Feb. 27, 2018.
[cited by applicant]
European Search Report for Application No. 18198355 dated Mar. 21, 2019.
[cited by applicant]
Extended European Search Report for Application No. 09797630.2, dated Dec. 5, 2011.
[cited by applicant]
Fares “The role of O-linked and N-linked oligosaccharides on the structure-function of glycoprotein hormones: Development of agonists and antagonists”, Biochimica et Biophysica Acta (BBA)-General Subjects 1760.4: 560-56…
[cited by applicant]
Fares et al.g-acting follitropin agonist by fusing the C-terminal sequence of the chorionic gonadotropin beta subunit to the follitropin beta subunit Proc Natl Acad Sci U S A., 89(10):4304-4308, May 15, 1992.
[cited by applicant]
Fares et al. “Designing a long-acting human growth hormone (hGH) by fusing the carboxy-terminal peptide of human chorionic gonadotropin B-subunit to the coding sequence of hGH” Endocrinology 151(9):4410-4417 (2010).
[cited by applicant]
Fares et al. “Growth hormone (GH) retardation of muscle damage due to immobilization in old rats. Possible intervention with a new long-acting recombinant GH” Ann N Y Acad Sci. 786:430-43 (Jun. 15, 1996).
[cited by applicant]
Fares et al. “Designing a Long Acting Erythropoietin by Fusing Three Carboxyl-Terminal Peptides of Human Chorionic Gondotropin [beta] Subunit to the N-Terminal and C-Terminal Coding Sequence”, International Journal of C…
[cited by applicant]
Fares et al., “Development of a long-acting erythropoietin by fusing the carboxyl-terminal peptide of human chorionic gonadotropin B-subunit to the coding sequence of human erythropoietin.” Endocrinology 148.10: 5081-50…
[cited by applicant]
Fayad et al. “Update of the M. D. Anderson Cancer Center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas” Clin Lymphoma Myeloma. Dec. 2007;8 Suppl 2:S57-62.
[cited by applicant]
Final Office Action U.S. Appl. No. 13/372,540, filed Feb. 14, 2012.
[cited by applicant]
Fingl et al., “General Principles.” The Pharmacological Basis of Therapeutics (ed. Goodman, LS & Gilman, A,): 1-46 (1975).
[cited by applicant]
Fogarty, Patrick F. “Biological rationale for new drugs in the bleeding disorders pipeline.” ASH Education Program Book 2011.1 (2011): 397-404.
[cited by applicant]
Freshney “Culture of animal cells: A manual of basic technique” (Culture of Animal Cells, A Manual of Basic Technique, Alan R. Liss, Inc., 1983, New York, p. 4).
[cited by applicant]
Fuentes-Prior et al. “Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex” Nature. Mar. 30, 2000; 404 (6777):518-25.
[cited by applicant]
Furuhashi et al. “Fusing the carboxy-terminal peptide of the chorionic gonadotropin (CG)-subunit to the common alpha-submit:: Retention of O-linked glycosylation and enhanced in vivo bioactivity of chimeric human CG” Mo…
[cited by applicant]
Furuhashi et al. “Processing of O-linked glycosylation in the chimera consisting of alpha-subunit and carboxyl-terminal peptide of the human chorionic gonadotropin beta-subunit is affected by dimer formation with follic…
[cited by applicant]
Gao et al., “Erythropoietin gene therapy leads to autoimmune anemia in macaques” Blood 103(9):3300-3302 (2004).
[cited by applicant]
Garcia-Campayo et al. “Unmasking a new recognition signal for< i> O</i>-linked glycosylation in the chorionic gonadotropin β subunit” Molecular and Cellular Endocrinology 194.1: 63-70 (2002).
[cited by applicant]
Gardella et al. “Expression of Human Parathyroid Hormone-( l-84) in
[cited by applicant]
Gellerfors et al. “Characterisation of a secreted form of recombinant derived human growth hormone, expressed in
[cited by applicant]
Ghosh et al., “Activity and regulation of factor VIIa analogs with increased potency at the endothelial cell surface.” Journal of Thrombosis and Haemostasis 5.2: 336-346 (2007).
[cited by applicant]
Gilboa et al., “Transfer And Expression of Cloned Genes Using Retroviral Vectors”, Biotechniques, vol. 4:504-512, (1986).
[cited by applicant]
Goodson, in “Medical applications of controlled release.” vol. 2: 115-138 (1984).
[cited by applicant]
Guitton et al., “Influence of in vitro non-enzymatic glycosylation on the physicochemical parameters of type I collagen.” Collagen and Related Research 4.4: 253-264 (1984).
[cited by applicant]
Gurley et al. “Upstream Sequences Required for Efficient Expression of a Soybean Heat Shock Gene” Mol.Cell.Biol 6:559-565 (1986).
[cited by applicant]
Hacke et al. “Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS)” JAMA. 1995;274(13):1017-1025.
[cited by applicant]
Hammerling et al. “In vitro bioassay for human erythropoietin based on proliferative stimulation of an erythroid cell line and analysis of carbohydrate-dependent microheterogeneity” Journal of Pharm. Biomed. Analysis 14…
[cited by applicant]
Havron et al. “OR2, 8 Phase I PK&PD profile of long acting bio-better CTP modified hGH (MOD-4023) in healthy volunteers” Growth Hormone & IGF Research. Jan. 1, 2010;20:24-5.
[cited by applicant]
Heffernan et al., “Effects of oral administration of a synthetic fragment of human growth hormone on lipid metabolism.” American Journal of Physiology—Endocrinology and Metabolism 279.3: E501-E507 (2000).
[cited by applicant]
Houdebine, L., “The methods to generate transgenic animals and to control transgene expression” Journal of Biotechnology 98:145-160 (2002).
[cited by applicant]
Huston et al. “Protein engineering of antibody binding sites: Recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in
[cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/IL09/00700 dated Jan. 27, 2011.
[cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/US07/02767 dated Aug. 14, 2008.
[cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/IL2010/000532 dated Jan. 19, 2012.
[cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/US07/03014 dated Apr. 2, 2009.
[cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/IL2017/050645 dated Dec. 20, 2018.
[cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/IL2017/050784 dated Jan. 24, 2019.
[cited by applicant]
International Search Report and Written Opinion for PCT Application No. PCT/IL/050645 Mailed Sep. 21, 2017.
[cited by applicant]
International Search Report and Written Opinion for PCT Application No. PCT/IL/050784 Mailed Sep. 22, 2017.
[cited by applicant]
International Search Report and Written Opinion for PCT Application No. PCT/IL09/00700 dated Feb. 4, 2010.
[cited by applicant]
International Search Report and Written Opinion for PCT Application No. PCT/IL10/00532 dated Apr. 11, 2011.
[cited by applicant]
International Search Report and Written Opinion for PCT Application No. PCT/IL13/50107 dated Jul. 10, 2013.
[cited by applicant]
International Search Report and Written Opinion for PCT Application No. PCT/US07/02767 dated Feb. 15, 2008.
[cited by applicant]
International Search Report and Written Opinion for PCT Application No. PCT/US07/03014 dated Sep. 22, 2008.
[cited by applicant]
International Search Report for Application No. PCTIL2014050910 mailed on Jan. 25, 2015.
[cited by applicant]
International Search Report for PCT Application No. PCT/IL 12/50288 mailed Jan. 28, 2013.
[cited by applicant]
Isgaard et al. “Effects of local administration of GH and IGF-1 on longitudinal bone growth in rats” Am J Physiol. Apr. 1986;250(4 Pt 1): E367-72.
[cited by applicant]
Jarrousse et al. “Oxyntomodulin (glucagon-37) and its C-terminal octapeptide inhibit gastric acid secretion”, FEBS Lett. Aug. 19, 1985; 188(1): 81-4.
[cited by applicant]
Joshi et al. “Recombinant thyrotropin containing a beta-subunit chimera with the human chorionic gonadotropin-beta carboxy-terminus is biologically active, with a prolonged plasma half-life: role of carbohydrate in bioa…
[cited by applicant]
Kanda et al. “Genetic Fusion of an a-subunit Gene to the Follicle-Stimulating Hormone and Chorionic Gonadotropin-b Subunit Genes: Production of a Bifunctional Protein”, Molecular Endocrinolog, vol. 13, No. 11, p. 1873-1…
[cited by applicant]
Kelly et al. “Outcomes of patients with Burkitt lymphoma older than age 40 treated with intensive chemotherapeutic regimens.” Clin Lymphoma Myeloma. Aug. 2009;9(4):307-10.
[cited by applicant]
Kessler et al. “Structure and location of the O-glycosidic carbohydrate units of human chorionic gonadotropin” J Biol Chem. 25;254(16):7909-14 , Aug. 1979.
[cited by applicant]
Kessler et al., “Structures of N-Glycosidic Carbohydrate Units of Human Chorionic Gonadotropin” J Biol Chem. Aug. 25, 1979;254(16):7901-8.
[cited by applicant]
Kicman et al., “Human chorionic gonadotrophin and sport.” British Journal of Sports Medicine 25.2 : 73-80 (1991).
[cited by applicant]
Kieffer et al. “Distribution of glucagon receptors on hormone-specific endocrine cells of rat pancreatic islets” Endocrinology. Nov. 1996;137(11):5119-25.
[cited by applicant]
Kontermann, “Half-Life Modulating Strategies—An Introduction.” Therapeutic Proteins: Strategies to Modulate Their Plasma Half-Lives : 1-21 (2012).
[cited by applicant]
Kontermann, “Strategies for extended serum half-life of protein therapeutics.” Current opinion in Biotechnology 22.6: 868-876 (2011).
[cited by applicant]
Kotler et al., “Effects of growth hormone on abnormal visceral adipose tissue accumulation and dyslipidemia in HIV-infected patients.” JAIDS Journal of Acquired Immune Deficiency Syndromes 35.3: 239-252 (2004).
[cited by applicant]
Krantz et al. “Specific binding of erythropoietin to spleen cells infected with the anemia strain of Friend virus” Proc Natl Acad Sci U S A. Dec. 1984;81(23):7574-8.
[cited by applicant]
Langer Robert “New Methods of Drug Delivery” Science 249:1527-1533 (1990).
[cited by applicant]
Larsen et al., “Accumulation of magnetic iron oxide nanoparticles coated with variably sized polyethylene glycol in murine tumors.” Nanoscale 4.7: 2352-2361 (2012).
[cited by applicant]
Le et al., “Improved Vancomycin Dosing in Children Using Area Under the Curve Exposure.” Pediatr Infect Dis J vol. 32, pp. e155-e163 (2013).
[cited by applicant]
Lentz et al., “Posttranslational modification of the carboxy-terminal region of the. beta. subunit of human chorionic gonadotropin.” Biochemistry 23.22: 5330-5337 (1984).
[cited by applicant]
Li et al. “Bioassay of hGH .I. Weight gain of hypophysectomized rats”. Abstract, Yaowu Fenxi Zazhi 15(2), 3-7 (1995).
[cited by applicant]
Lippin et al. “Human erythropoietin gene therapy for patients with chronic renal failure” Blood 106(7):2280-2286 (2005).
[cited by applicant]
Littleword, T.J. “Erythropoietin for the treatment of anemia associated with hematological malignancy” Hematol Oncol. Mar. 2001;19(1):19-30.
[cited by applicant]
Lo et al. “The effects of recombinant human growth hormone on body composition andglucose metabolism in HIV-infected patients with fat accumulation” J Clin Endocrinol Metab. Aug. 2001;86(8):3480-7. PubMed PMID: 11502767.
[cited by applicant]
Lopez-Berenstein, Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 317-327 (1989).
[cited by applicant]
Lopez-Berestein et al. “Treatment of systemic fungal infections with liposomal amphotericin B.” Liposomes in the therapy of infectious diseases and cancer. (1989): 310-327.
[cited by applicant]
Maheshwari et al., “Manipulation of Electrostatic and Saccharide Linker Interactions in the Design of Efficient Glycopolypeptide-Based Cholera Toxin Inhibitors.” Macromolecular bioscience 10.1: 68-81 (2010).
[cited by applicant]
Maston et al., “Chorionic gonadotropin beta subunit [
[cited by applicant]
Matsumoto et al. The measurement of low levels of factor VIII or factor IX in hemophilia A and hemophilia B plasma by clot waveform analysis and thrombin generation assay. Journal of Thrombosis and Haemostasis vol. 4:37…
[cited by applicant]
Matsuo et al. “Thrombolysis by human tissue plasminogen activator and urokinase in rabbits with experimental pulmonary embolus” Nature. Jun. 18, 1981;291(5816):590-1.
[cited by applicant]
Maun et al., “Disulfide locked variants of factor VIIa with a restricted B-strand conformation have enhanced enzymatic activity.” Protein Science 14.5: 1171-1180 (2005).
[cited by applicant]
McAlister et al. “NMR analysis of the N-terminal SRCR domain of human CD5: engineering of a glycoprotein for superior characteristics in NMR experiments.” Protein Engineering 11.10: 847-853 (1998).
[cited by applicant]
Medlock et al. “Epogen signal peptide”, Jan. 6, 2005, XP002685292.
[cited by applicant]
Meulien et al., “Increased biological activity of a recombinant factor IX variant carrying alanine at position+ 1.” Protein Engineering 3.7: 629-633 (1990).
[cited by applicant]
Milton et al. The Delineation of a Decapeptide Gonadotropin-releasing Sequence in the Carboxyl-terminal Extension of the Human Gonadotropin releasing Hormone Precursor. The Journal of Biological Chemistry, vol. 261/36:1…
[cited by applicant]
Morgan et al. “The amino acid sequence of human chorionic gonadotropin. The alpha subunit and beta subunit”, J Biol Chem. Jul. 10, 1975;250(13):5247-58.
[cited by applicant]
Muleo et al. Small doses of recombinant factor Vila in acquired deficiencies of vitamin K dependent factors. Blood Coagulation & Fibrinolysis Abstract, 10(8), 521-522 (1999).
[cited by applicant]
Murray et al. “Dose titration and patient selection increases the efficacy of GH replacement in severely GH deficient adults”, Clinical Endocrinology (1999) 50, pp. 749-757.
[cited by applicant]
Musto “The role of recombinant erythropoietin for the treatment of anemia in multiple myeloma” Leuk Lymphoma. Apr. 1998;29(3-4):283-91.
[cited by applicant]
Mutter et al. “A New Base-Labile Anchoring Group for Polymer-Supported Peptide Synthesis.” Helvetica chimica acta 67.7 (1984): 2009-2016.
[cited by applicant]
Mutter et al. “Evolution versus design: template-directed self-assembly of peptides to artificial proteins (TASP).” CHIMIA International Journal for Chemistry 54.10 (2000): 552-557.
[cited by applicant]
NCBI GenBank Accession No. AAL69702 (Apr. 3, 2002).
[cited by applicant]
Nezu et al. “Treatment of idiopathic pituitary dwarfism with human growth hormone”, Journal of Nara Medical Association 40.1(1989): 16-22; with English Abstract.
[cited by applicant]
Ngo et al. “Computational Complexity, Protein Structure Protein Prediction and the Levinthal Paradox” in Birkhauser The Protein Folding Problem And Tertiary Structure Prediction, pp. 433-440 and 492-495 (1994).
[cited by applicant]
Office Action U.S. Appl. No. 12/826,754, filed Jun. 30, 2010.
[cited by applicant]
Office Action U.S. Appl. No. 13/372,540, filed Feb. 14, 2012.
[cited by applicant]
Office Action for Japanese Application No. 2014-523441 dated May 24, 2016.
[cited by applicant]
Ogle et al. “Renal effects of growth hormone. I. Renal function and kidney growth”, Pediatr. Nephrol. vol. 6:394-398, 1992.
[cited by applicant]
Oosterhof et al. Regulation of whole body energy homeostasis with growth hormone replacement therapy and endurance exercise Physiol Genomics. Jun. 28, 2011;43(12):739-48. doi: 10.1152/physiolgenomics.00034.2010. Epub Ma…
[cited by applicant]
Pedrosa et al., “Selective neoglycosylation increases the structural stability of vicilin, the 7S storage globulin from pea seeds.” Archives of Biochemistry and Biophysics 382.2: 203-210 (2000).
[cited by applicant]
Persson et al. “Recombinant coagulation factor VIIa—from molecular to clinical aspects of a versatile haemostatic agent”, Thrombosis Research (2010) 125:483-489.
[cited by applicant]
Persson et al., “Rational design of coagulation factor VIIa variants with substantially increased intrinsic activity.” Proceedings of the National Academy of Sciences 98.24: 13583-13588 (2001).
[cited by applicant]
Philips A. “The challenge of gene therapy and DNA delivery” J Pharm. Pharmacology 53:1169-1174 (2001).
[cited by applicant]
Pierce et al. “Glycoprotein hormones: structure and function.” Annual review of biochemistry 50.1: 465-495 (1981).
[cited by applicant]
Pinkert et al. “An albumin enhancer located 10 kb upstream functions along with its promoter to direct liver-specific expression in transgenic mice” Genes Dev. 1:268-277 (1987).
[cited by applicant]
Polizzotti et al. “Effects of saccharide spacing and chain extension on toxin inhibition by glycopolypeptides of well-defined architecture”, Macromolecules 40.20: 7103-7110 (2007).
[cited by applicant]
Poreddy et al., “Exogenous fluorescent tracer agents based on pegylated pyrazine dyes for real-time point-of-care measurement of glomerular filtration rate.” Bioorganic & Medicinal Chemistry 20.8: 2490-2497 (2012).
[cited by applicant]
Puett et al. “Structure-Function Relationships of the Luteinizing Hormone Receptor” Annals of the New York Academy of Sciences. Dec. 1, 2005;1061(1):41-54.
[cited by applicant]
Rebois et al., “Hydrodynamic properties of the gonadotropin receptor from a murine Leydig tumor cell line are altered by desensitization.” Biochemistry 26.20: 6422-6428 (1987).
[cited by applicant]
Reichel “Sarcosyl-Page: a new electrophoretic method for the separation and immunological detection of PEGylated proteins.” Protein Electrophoresis. Humana Press 65-79 (2012).
[cited by applicant]
Riddick et al., “A stepwise increase in recombinant human growth hormone dosing during puberty achieves improved pubertal growth: A national cooperative study report”. Journal of Pediatric Endocrinology & Metabolism, 22…
[cited by applicant]
Reiter et al. “A multicenter study of the efficacy and safety of sustained release GH in the treatment of naive pediatric patients with GH deficiency” J Clin Endocrinol Metab. 86(10):4700-6 (Oct. 2001).
[cited by applicant]
Response Final Office Action U.S. Appl. No. 13/372,540, filed Feb. 14, 2012.
[cited by applicant]
Rosario PW. “Normal values of serum IGF-1 in adults: results from a Brazilian population” Arquivos Brasileiros de Endocrinologia & Metabologia. 2010;54(5):447-81.
[cited by applicant]
Ronzi et al. Optimisation of a freeze-drying process of high purity Factor VIII and Factor IX concentrates. Chemical Engineering and Processing. vol. 42:751-757 (2003).
[cited by applicant]
Rudman et al. “Effects of human growth hormone in men over 60 years old” N Engl J Med. Jul. 5, 1990;323(1):1-6.
[cited by applicant]
Russell et al. “Local injections of human or rat growth hormone or of purified human somatomedin-C stimulate unilateral tibial epiphyseal growth in hypophysectomized rats” Endocrinology. Jun. 1985;116(6):2563-7.
[cited by applicant]