JP2012532601A5 - - Google Patents

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JP2012532601A5
JP2012532601A5 JP2012519119A JP2012519119A JP2012532601A5 JP 2012532601 A5 JP2012532601 A5 JP 2012532601A5 JP 2012519119 A JP2012519119 A JP 2012519119A JP 2012519119 A JP2012519119 A JP 2012519119A JP 2012532601 A5 JP2012532601 A5 JP 2012532601A5
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JP
Japan
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factor
clotting
ctp
coagulation
coagulation factor
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JP2012519119A
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Japanese (ja)
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JP5823960B2 (ja
JP2012532601A (ja
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Priority claimed from PCT/IL2010/000532 external-priority patent/WO2011004361A2/en
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JP2012519119A 2009-07-09 2010-07-01 長期作用性凝固因子およびそれを製造する方法 Active JP5823960B2 (ja)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US22436609P 2009-07-09 2009-07-09
US61/224,366 2009-07-09
PCT/IL2010/000532 WO2011004361A2 (en) 2009-07-09 2010-07-01 Long-acting coagulation factors and methods of producing same

Related Child Applications (1)

Application Number Title Priority Date Filing Date
JP2015199912A Division JP6162769B2 (ja) 2009-07-09 2015-10-08 長期作用性凝固因子およびそれを製造する方法

Publications (3)

Publication Number Publication Date
JP2012532601A JP2012532601A (ja) 2012-12-20
JP2012532601A5 true JP2012532601A5 (OSRAM) 2013-05-16
JP5823960B2 JP5823960B2 (ja) 2015-11-25

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Family Applications (3)

Application Number Title Priority Date Filing Date
JP2012519119A Active JP5823960B2 (ja) 2009-07-09 2010-07-01 長期作用性凝固因子およびそれを製造する方法
JP2015199912A Active JP6162769B2 (ja) 2009-07-09 2015-10-08 長期作用性凝固因子およびそれを製造する方法
JP2017117769A Active JP6430592B2 (ja) 2009-07-09 2017-06-15 長期作用性凝固因子およびそれを製造する方法

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Application Number Title Priority Date Filing Date
JP2015199912A Active JP6162769B2 (ja) 2009-07-09 2015-10-08 長期作用性凝固因子およびそれを製造する方法
JP2017117769A Active JP6430592B2 (ja) 2009-07-09 2017-06-15 長期作用性凝固因子およびそれを製造する方法

Country Status (19)

Country Link
US (1) US8476234B2 (OSRAM)
EP (2) EP3130346A1 (OSRAM)
JP (3) JP5823960B2 (OSRAM)
KR (3) KR102014844B1 (OSRAM)
CN (2) CN105153314B (OSRAM)
AU (1) AU2010269884B2 (OSRAM)
CA (1) CA2767503C (OSRAM)
CY (1) CY1118733T1 (OSRAM)
DK (1) DK2451473T3 (OSRAM)
ES (1) ES2618209T3 (OSRAM)
HR (1) HRP20170051T1 (OSRAM)
HU (1) HUE032973T2 (OSRAM)
IL (2) IL235377A (OSRAM)
LT (1) LT2451473T (OSRAM)
MX (4) MX346920B (OSRAM)
PL (1) PL2451473T3 (OSRAM)
PT (1) PT2451473T (OSRAM)
SI (1) SI2451473T1 (OSRAM)
WO (1) WO2011004361A2 (OSRAM)

Families Citing this family (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150038413A1 (en) 2006-02-03 2015-02-05 Opko Biologics Ltd. Long-acting polypeptides and methods of producing and administering same
US8304386B2 (en) * 2006-02-03 2012-11-06 Prolor Biotech, Inc. Long-acting growth hormone and methods of producing same
US10351615B2 (en) 2006-02-03 2019-07-16 Opko Biologics Ltd. Methods of treatment with long-acting growth hormone
US20140113860A1 (en) 2006-02-03 2014-04-24 Prolor Biotech Ltd. Long-acting polypeptides and methods of producing and administering same
US9249407B2 (en) 2006-02-03 2016-02-02 Opko Biologics Ltd. Long-acting coagulation factors and methods of producing same
US9458444B2 (en) 2006-02-03 2016-10-04 Opko Biologics Ltd. Long-acting coagulation factors and methods of producing same
US8759292B2 (en) 2006-02-03 2014-06-24 Prolor Biotech, Llc Long-acting coagulation factors and methods of producing same
US10221228B2 (en) 2006-02-03 2019-03-05 Opko Biologics Ltd. Long-acting polypeptides and methods of producing and administering same
US8476234B2 (en) * 2006-02-03 2013-07-02 Prolor Biotech Inc. Long-acting coagulation factors and methods of producing same
WO2007092252A2 (en) 2006-02-03 2007-08-16 Modigene Inc Long-acting polypeptides and methods of producing same
US8450269B2 (en) 2006-02-03 2013-05-28 Prolor Biotech Ltd. Long-acting growth hormone and methods of producing same
US8048849B2 (en) 2006-02-03 2011-11-01 Modigene, Inc. Long-acting polypeptides and methods of producing same
US8946155B2 (en) 2006-02-03 2015-02-03 Opko Biologics Ltd. Long-acting polypeptides and methods of producing and administering same
US12203113B2 (en) 2009-07-09 2025-01-21 Opko Biologics Ltd. Long-acting coagulation factors and methods of producing same
US9663778B2 (en) 2009-07-09 2017-05-30 OPKO Biologies Ltd. Long-acting coagulation factors and methods of producing same
AU2010202125B1 (en) 2010-05-26 2010-09-02 Takeda Pharmaceutical Company Limited A method to produce an immunoglobulin preparation with improved yield
WO2011150284A2 (en) 2010-05-26 2011-12-01 Baxter International Inc. Removal of serine proteases by treatment with finely divided silicon dioxide
CA2807552A1 (en) 2010-08-06 2012-02-09 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
EP3431485B2 (en) 2010-10-01 2024-09-04 ModernaTX, Inc. Engineered nucleic acids and methods of use thereof
WO2012135805A2 (en) 2011-03-31 2012-10-04 modeRNA Therapeutics Delivery and formulation of engineered nucleic acids
US9464124B2 (en) 2011-09-12 2016-10-11 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
EP2763701B1 (en) 2011-10-03 2018-12-19 Moderna Therapeutics, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
CA2851223A1 (en) 2011-10-06 2013-04-11 Hanmi Science Co., Ltd. Blood coagulation factor vii and viia derivatives, conjugates and complexes comprising the same, and use thereof
KR20140102759A (ko) 2011-12-16 2014-08-22 모더나 세라퓨틱스, 인코포레이티드 변형된 뉴클레오사이드, 뉴클레오타이드 및 핵산 조성물
EP3326642B1 (en) * 2012-02-14 2020-11-25 OPKO Biologics Ltd. Long-acting coagulation factors and uses thereof
US9572897B2 (en) 2012-04-02 2017-02-21 Modernatx, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
DE18200782T1 (de) 2012-04-02 2021-10-21 Modernatx, Inc. Modifizierte polynukleotide zur herstellung von proteinen im zusammenhang mit erkrankungen beim menschen
US9878056B2 (en) 2012-04-02 2018-01-30 Modernatx, Inc. Modified polynucleotides for the production of cosmetic proteins and peptides
US9283287B2 (en) 2012-04-02 2016-03-15 Moderna Therapeutics, Inc. Modified polynucleotides for the production of nuclear proteins
WO2013157002A1 (en) * 2012-04-19 2013-10-24 Prolor Biotech Inc. Long-acting oxyntomodulin variants and methods of producing same
EP3970738A1 (en) * 2012-07-25 2022-03-23 Bioverativ Therapeutics Inc. Blood factor monitoring assay and uses thereof
EA033788B1 (ru) * 2012-11-20 2019-11-26 Opko Biologics Ltd Способ увеличения гидродинамического объема полипептида путем присоединения карбоксиконцевого пептида гонадотропина
CA2892529C (en) 2012-11-26 2023-04-25 Moderna Therapeutics, Inc. Terminally modified rna
US9707276B2 (en) * 2012-12-03 2017-07-18 Merck Sharp & Dohme Corp. O-glycosylated carboxy terminal portion (CTP) peptide-based insulin and insulin analogues
LT2956477T (lt) 2013-02-15 2021-02-10 Bioverativ Therapeutics Inc. Optimizuotas faktoriaus viii genas
US20160024181A1 (en) 2013-03-13 2016-01-28 Moderna Therapeutics, Inc. Long-lived polynucleotide molecules
US8980864B2 (en) 2013-03-15 2015-03-17 Moderna Therapeutics, Inc. Compositions and methods of altering cholesterol levels
EA201690675A1 (ru) 2013-10-03 2016-08-31 Модерна Терапьютикс, Инк. Полинуклеотиды, кодирующие рецептор липопротеинов низкой плотности
US20150158926A1 (en) 2013-10-21 2015-06-11 Opko Biologics, Ltd. Long-acting polypeptides and methods of producing and administering same
HRP20201114T1 (hr) * 2013-10-21 2020-10-30 Opko Biologics Ltd. Dugodjelujući polipeptidi i postupci njihove proizvodnje i primjene
EP3160478A4 (en) 2014-06-30 2018-05-16 Bioverativ Therapeutics Inc. Optimized factor ix gene
CN107438623B (zh) * 2014-12-10 2023-07-14 Opko生物科学有限公司 长效的ctp修饰的生长激素多肽的制备方法
HUE055449T2 (hu) 2015-06-19 2021-11-29 Opko Biologics Ltd Hosszú hatástartamú koagulációs faktorok és eljárások ezek elõállítására
CN106397571A (zh) * 2015-07-31 2017-02-15 李金松 一种新型羧基末端肽及长效白介素7
CN106397570B (zh) * 2015-07-31 2019-11-15 袁武梅 一种羧基末端肽及长效干扰素
US11560418B2 (en) 2015-10-20 2023-01-24 The University Of North Carolina At Chapel Hill Methods and compositions for modified factor IX fusion proteins
PL3411478T3 (pl) 2016-02-01 2022-10-03 Bioverativ Therapeutics Inc. Geny zoptymalizowanego czynnika VIII
TW202444744A (zh) 2016-07-11 2024-11-16 以色列商歐科生物製品有限公司 長效型凝血因子及其生產方法
CN107759694B (zh) * 2016-08-19 2023-01-13 安源医药科技(上海)有限公司 双特异性抗体及其制备方法与用途
CN106279436B (zh) * 2016-08-19 2017-10-31 安源医药科技(上海)有限公司 活化的人凝血因子vii融合蛋白及其制备方法与用途
CN106279437B (zh) 2016-08-19 2017-10-31 安源医药科技(上海)有限公司 高糖基化人凝血因子viii融合蛋白及其制备方法与用途
CN110438022A (zh) * 2018-10-10 2019-11-12 福建师范大学 一种前体蛋白Kex2过表达毕赤酵母菌株及其构建方法
WO2020187969A1 (en) 2019-03-19 2020-09-24 CSL Behring Lengnau AG Factor ix variants and uses thereof in therapy
CN112175088B (zh) * 2019-07-02 2023-03-28 江苏晟斯生物制药有限公司 改进的fix融合蛋白、缀合物及其应用
CN115279896A (zh) 2019-09-30 2022-11-01 比奥维拉迪维治疗股份有限公司 慢病毒载体配制品
MX2023000156A (es) 2020-06-24 2023-02-16 Bioverativ Therapeutics Inc Metodos para la eliminacion de factor viii libre de preparaciones de vectores lentivirales modificados para expresar dicha proteina.

Family Cites Families (79)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US130060A (en) * 1872-07-30 Improvement in cotton-presses
US190611A (en) * 1877-05-08 Improvement in protractors
NL154600B (nl) 1971-02-10 1977-09-15 Organon Nv Werkwijze voor het aantonen en bepalen van specifiek bindende eiwitten en hun corresponderende bindbare stoffen.
NL154598B (nl) 1970-11-10 1977-09-15 Organon Nv Werkwijze voor het aantonen en bepalen van laagmoleculire verbindingen en van eiwitten die deze verbindingen specifiek kunnen binden, alsmede testverpakking.
NL154599B (nl) 1970-12-28 1977-09-15 Organon Nv Werkwijze voor het aantonen en bepalen van specifiek bindende eiwitten en hun corresponderende bindbare stoffen, alsmede testverpakking.
US3901654A (en) 1971-06-21 1975-08-26 Biological Developments Receptor assays of biologically active compounds employing biologically specific receptors
US3853987A (en) 1971-09-01 1974-12-10 W Dreyer Immunological reagent and radioimmuno assay
US3867517A (en) 1971-12-21 1975-02-18 Abbott Lab Direct radioimmunoassay for antigens and their antibodies
NL171930C (nl) 1972-05-11 1983-06-01 Akzo Nv Werkwijze voor het aantonen en bepalen van haptenen, alsmede testverpakkingen.
US3850578A (en) 1973-03-12 1974-11-26 H Mcconnell Process for assaying for biologically active molecules
US3935074A (en) 1973-12-17 1976-01-27 Syva Company Antibody steric hindrance immunoassay with two antibodies
US3996345A (en) 1974-08-12 1976-12-07 Syva Company Fluorescence quenching with immunological pairs in immunoassays
US4034074A (en) 1974-09-19 1977-07-05 The Board Of Trustees Of Leland Stanford Junior University Universal reagent 2-site immunoradiometric assay using labelled anti (IgG)
US3984533A (en) 1975-11-13 1976-10-05 General Electric Company Electrophoretic method of detecting antigen-antibody reaction
US4098876A (en) 1976-10-26 1978-07-04 Corning Glass Works Reverse sandwich immunoassay
US4879219A (en) 1980-09-19 1989-11-07 General Hospital Corporation Immunoassay utilizing monoclonal high affinity IgM antibodies
JPS5781447A (en) 1980-11-11 1982-05-21 Toyo Jozo Co Ltd Human chorionic gonadotropic hormone c-terminal fragment
US4853332A (en) 1982-10-19 1989-08-01 Cetus Corporation Structural genes, plasmids and transformed cells for producing cysteine depleted muteins of biologically active proteins
US5011771A (en) 1984-04-12 1991-04-30 The General Hospital Corporation Multiepitopic immunometric assay
DE3421468A1 (de) 1984-06-08 1985-12-19 Dr. Rentschler Arzneimittel Gmbh & Co, 7958 Laupheim Lipidnanopellets als traegersystem fuer arzneimittel zur peroralen anwendung
US4666828A (en) 1984-08-15 1987-05-19 The General Hospital Corporation Test for Huntington's disease
US4683202A (en) 1985-03-28 1987-07-28 Cetus Corporation Process for amplifying nucleic acid sequences
US4801531A (en) 1985-04-17 1989-01-31 Biotechnology Research Partners, Ltd. Apo AI/CIII genomic polymorphisms predictive of atherosclerosis
JP2874751B2 (ja) 1986-04-09 1999-03-24 ジェンザイム・コーポレーション 希望する蛋白質をミルク中へ分泌する遺伝子移植動物
US4873316A (en) 1987-06-23 1989-10-10 Biogen, Inc. Isolation of exogenous recombinant proteins from the milk of transgenic mammals
EP0374257B1 (en) 1988-05-06 1994-08-31 Toray Industries, Inc. STABLE INTERFERON $g(b) COMPOSITION
US5272057A (en) 1988-10-14 1993-12-21 Georgetown University Method of detecting a predisposition to cancer by the use of restriction fragment length polymorphism of the gene for human poly (ADP-ribose) polymerase
US6225449B1 (en) 1991-10-04 2001-05-01 Washington University Hormone analogs with multiple CTP extensions
US5338835A (en) 1989-02-21 1994-08-16 Washington University CTP-extended form of FSH
US5705478A (en) 1989-02-21 1998-01-06 Washington University Covalently linked β subunits of the glycoprotein hormones as antagonists
ATE148171T1 (de) 1989-02-21 1997-02-15 Univ Washington Modifizierte formen von fortpflanzungshormonen
US5792460A (en) * 1989-02-21 1998-08-11 Washington University Modified glycoprotein hormones having a CTP at the amino terminus
US5464764A (en) 1989-08-22 1995-11-07 University Of Utah Research Foundation Positive-negative selection methods and vectors
US5192659A (en) 1989-08-25 1993-03-09 Genetype Ag Intron sequence analysis method for detection of adjacent and remote locus alleles as haplotypes
US7217689B1 (en) 1989-10-13 2007-05-15 Amgen Inc. Glycosylation analogs of erythropoietin
US5126324A (en) 1990-06-07 1992-06-30 Genentech, Inc. Method of enhancing growth in patients using combination therapy
US6028177A (en) 1991-10-04 2000-02-22 Washington University Methods of detecting single-chain forms of the glycoprotein hormone quartet
US5281521A (en) 1992-07-20 1994-01-25 The Trustees Of The University Of Pennsylvania Modified avidin-biotin technique
EP0695307B1 (en) 1993-04-20 1999-12-15 Washington University Modified protein and peptide pharmaceuticals
US6737515B2 (en) 1993-11-19 2004-05-18 Washington University Follicle stimulating hormone-glycosylation analogs
US6238890B1 (en) 1994-02-18 2001-05-29 Washington University Single chain forms of the glycoprotein hormone quartet
US5935924A (en) 1994-04-15 1999-08-10 Genentech, Inc. Treatment of congestive heart failure
US5541110A (en) 1994-05-17 1996-07-30 Bristol-Myers Squibb Cloning and expression of a gene encoding bryodin 1 from Bryonia dioica
BR9506313A (pt) 1994-08-12 1997-08-05 Univ Washington Formas de cadeia simples do quarteto de hormônio de glicoproteína
US6083725A (en) 1996-09-13 2000-07-04 Transkaryotic Therapies, Inc. Tranfected human cells expressing human α-galactosidase A protein
US20050032211A1 (en) 1996-09-26 2005-02-10 Metabogal Ltd. Cell/tissue culturing device, system and method
US6310183B1 (en) 1997-09-10 2001-10-30 Novo Nordisk A/S Coagulation factor VIIa composition
ES2265693T3 (es) 1998-10-16 2007-02-16 Biogen Idec Ma Inc. Proteinas de fusion con interferon-beta y usos.
US6514729B1 (en) 1999-05-12 2003-02-04 Xencor, Inc. Recombinant interferon-beta muteins
JO2291B1 (en) 1999-07-02 2005-09-12 اف . هوفمان لاروش ايه جي Erythropoietin derivatives
US20020127652A1 (en) * 2000-02-11 2002-09-12 Schambye Hans Thalsgard Follicle stimulating hormones
US7094566B2 (en) 2000-03-16 2006-08-22 Amgen Inc., IL-17 receptor like molecules and uses thereof
JP4409135B2 (ja) 2000-12-01 2010-02-03 武田薬品工業株式会社 生理活性物質含有製剤の製造法
ATE416784T1 (de) 2000-12-01 2008-12-15 Takeda Pharmaceutical Verfahren zur herstellung einer zubereitung mit einer bioaktiven substanz
DK1355942T3 (da) 2000-12-07 2008-11-17 Lilly Co Eli GLP-1-fusionsproteiner
KR101229995B1 (ko) 2000-12-11 2013-02-06 씨제이 주식회사 생체내 에리스로포이에틴 활성이 증진된 융합단백질
AU2002222740A1 (en) 2000-12-11 2002-06-24 Cheil Jedang Corporation Fusion protein having the enhanced in vivo activity of erythropoietin
JP5160005B2 (ja) 2000-12-28 2013-03-13 武田薬品工業株式会社 徐放性製剤
EP1356809A4 (en) 2000-12-28 2008-05-14 Takeda Pharmaceutical Sustained release preparations
US6887462B2 (en) 2001-04-09 2005-05-03 Chiron Corporation HSA-free formulations of interferon-beta
GB0121709D0 (en) 2001-09-07 2001-10-31 Imp College Innovations Ltd Food inhibition agent
AU2002364586A1 (en) 2001-12-21 2003-07-30 Delta Biotechnology Limited Albumin fusion proteins
US7081446B2 (en) 2002-01-31 2006-07-25 The Trustees Of Columbia University In The City Of New York Long-acting follicle stimulating hormone analogues and uses thereof
US7173113B2 (en) 2002-01-31 2007-02-06 The Trustees Of Columbia University In The City Of New York Long-acting hormone and growth factor compositions and uses thereof
GB0206048D0 (en) 2002-03-14 2002-04-24 Croda Int Plc Use
US7459435B2 (en) 2002-08-29 2008-12-02 Hoffmann-La Roche Inc. Treatment of disturbances of iron distribution
US7459436B2 (en) 2002-11-22 2008-12-02 Hoffmann-La Roche Inc. Treatment of disturbances of iron distribution
JP4683319B2 (ja) 2003-02-19 2011-05-18 武田薬品工業株式会社 徐放性製剤用の分散剤
EP1595549A4 (en) 2003-02-19 2010-09-22 Takeda Pharmaceutical DISPERSE FOR PREPARATIONS WITH DELAYED RELEASE
WO2005047319A2 (en) 2003-11-12 2005-05-26 The University Of Georgia Research Foundation, Inc. Dna sequence and expressed recombinant glycoproteins related to feline thyrotropin
CA2549486C (en) 2003-12-19 2015-04-14 F. Hoffmann-La Roche Ag Use of erythropoietin in the treatment of disturbances of iron distribution in chronic inflammatory intestinal diseases
ES2357132T3 (es) 2004-03-19 2011-04-19 Baxter International Inc. Factor ixa para el tratamiento de trastornos hemorrágicos.
JP2008509688A (ja) * 2004-08-17 2008-04-03 ツェー・エス・エル・ベーリング・ゲー・エム・ベー・ハー 改変ビタミンk依存性ポリペプチド
EP1728798A1 (en) 2005-06-01 2006-12-06 ZLB Behring GmbH Coagulation factor X polypeptides with modified activation properties
WO2007092252A2 (en) 2006-02-03 2007-08-16 Modigene Inc Long-acting polypeptides and methods of producing same
US8048849B2 (en) 2006-02-03 2011-11-01 Modigene, Inc. Long-acting polypeptides and methods of producing same
US8476234B2 (en) 2006-02-03 2013-07-02 Prolor Biotech Inc. Long-acting coagulation factors and methods of producing same
US8048848B2 (en) 2006-02-03 2011-11-01 Prolor Biotech Ltd. Long-acting interferons and derivatives thereof and methods thereof
US8304386B2 (en) 2006-02-03 2012-11-06 Prolor Biotech, Inc. Long-acting growth hormone and methods of producing same

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