ES2386010T3 - Variantes de FVII o FVIIa - Google Patents
Variantes de FVII o FVIIa Download PDFInfo
- Publication number
- ES2386010T3 ES2386010T3 ES09075170T ES09075170T ES2386010T3 ES 2386010 T3 ES2386010 T3 ES 2386010T3 ES 09075170 T ES09075170 T ES 09075170T ES 09075170 T ES09075170 T ES 09075170T ES 2386010 T3 ES2386010 T3 ES 2386010T3
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- Prior art keywords
- variant
- polypeptide
- amino acid
- fvii
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- Prior art date
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- Expired - Lifetime
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Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6437—Coagulation factor VIIa (3.4.21.21)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21021—Coagulation factor VIIa (3.4.21.21)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Wood Science & Technology (AREA)
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- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biotechnology (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Surgery (AREA)
- Dermatology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Fats And Perfumes (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (4)
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| US45654703P | 2003-03-20 | 2003-03-20 | |
| US456547P | 2003-03-20 | ||
| US47970803P | 2003-06-19 | 2003-06-19 | |
| US479708P | 2003-06-19 |
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| ES2386010T3 true ES2386010T3 (es) | 2012-08-07 |
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| ES04722232T Expired - Lifetime ES2327044T3 (es) | 2003-03-20 | 2004-03-22 | Variantes de fvii o fviia. |
| ES09075170T Expired - Lifetime ES2386010T3 (es) | 2003-03-20 | 2004-03-22 | Variantes de FVII o FVIIa |
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| ES04722232T Expired - Lifetime ES2327044T3 (es) | 2003-03-20 | 2004-03-22 | Variantes de fvii o fviia. |
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| US (2) | US7771996B2 (OSRAM) |
| EP (2) | EP1608745B1 (OSRAM) |
| JP (2) | JP4847856B2 (OSRAM) |
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| AU (2) | AU2004221761B2 (OSRAM) |
| CA (1) | CA2519873C (OSRAM) |
| DE (1) | DE602004021099D1 (OSRAM) |
| DK (2) | DK2085470T3 (OSRAM) |
| ES (2) | ES2327044T3 (OSRAM) |
| WO (1) | WO2004083361A2 (OSRAM) |
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| US7247708B2 (en) | 1997-10-23 | 2007-07-24 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| US6747003B1 (en) | 1997-10-23 | 2004-06-08 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| JP2003521930A (ja) * | 2000-02-11 | 2003-07-22 | マキシゲン・エイピーエス | 第ＶＩＩ因子または第ＶＩＩａ因子様分子 |
| US7220837B1 (en) | 2000-04-28 | 2007-05-22 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| US7812132B2 (en) | 2000-04-28 | 2010-10-12 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| US20030211094A1 (en) | 2001-06-26 | 2003-11-13 | Nelsestuen Gary L. | High molecular weight derivatives of vitamin k-dependent polypeptides |
| CN1665925A (zh) * | 2002-04-30 | 2005-09-07 | 马克西根控股公司 | 凝血因子Ⅶ或Ⅶa多肽变体 |
| AU2004221761B2 (en) | 2003-03-20 | 2010-01-07 | Bayer Healthcare Llc | FVII or FVIIa variants |
| EP1644504B8 (en) | 2003-06-19 | 2010-06-02 | Bayer HealthCare LLC | Factor vii or viia gla domain variants |
| DK1781782T3 (da) | 2004-08-17 | 2010-08-23 | Csl Behring Gmbh | Modificerede vitamin K-afhængige polypeptider |
| EP1893230A2 (en) * | 2005-04-26 | 2008-03-05 | Maxygen Holdings Ltd. | Use of modified factor vii for treating bleeding |
| ES2553160T3 (es) | 2005-06-17 | 2015-12-04 | Novo Nordisk Health Care Ag | Reducción y derivatización selectivas de proteínas Factor VII transformadas por ingeniería que comprenden al menos una cisteína no nativa |
| EP1904528B1 (en) | 2005-07-13 | 2012-10-31 | Novo Nordisk Health Care AG | Host cell protein knock-out cells for production of therapeutic proteins |
| EP1924689B1 (en) | 2005-09-01 | 2014-08-13 | Novo Nordisk Health Care AG | Hydrophobic interaction chromatography purification of factor vii polypeptides |
| US20090055942A1 (en) | 2005-09-14 | 2009-02-26 | Novo Nordisk Healthcare A/G | Human Coagulation Factor VII Polypeptides |
| ES2399138T3 (es) * | 2006-03-16 | 2013-03-26 | Stellaris Pharmaceuticals Aps | Tratamiento local con factor VII |
| JP5570809B2 (ja) | 2006-09-01 | 2014-08-13 | ノボ ノルディスク ヘルス ケア アーゲー | 修飾タンパク質 |
| AU2013204377B2 (en) * | 2007-04-13 | 2015-07-16 | Catalyst Biosciences, Inc. | Modified factor vii polypeptides and uses thereof |
| UA101155C2 (ru) * | 2007-04-13 | 2013-03-11 | Каталист Байосайенс, Инк. | Модифицированный полипептид фактора vii (fvii) и его применение |
| TWI465247B (zh) | 2008-04-11 | 2014-12-21 | Catalyst Biosciences Inc | 經修飾的因子ｖｉｉ多肽和其用途 |
| TWI595004B (zh) | 2010-11-03 | 2017-08-11 | 介控生化科技公司 | 經修飾之第九因子多胜肽及其用途 |
| CA3185756A1 (en) | 2012-12-24 | 2014-07-03 | Coagulant Therapeutics Corporation | Short-acting factor vii polypeptides |
| MX2020003351A (es) | 2017-09-27 | 2020-10-12 | Sigilon Therapeutics Inc | Metodos, composiciones y elementos implantables que comprenden celulas activas. |
| IL277713B2 (en) | 2018-04-04 | 2024-09-01 | Sigilon Therapeutics Inc | Implantable particles and related methods |
| WO2019195056A1 (en) | 2018-04-04 | 2019-10-10 | Sigilon Therapeutics, Inc. | Methods, compositions, and implantable elements comprising stem cells |
| UY38389A (es) | 2018-09-27 | 2020-04-30 | Sigilon Therapeutics Inc | Dispositivos implantables para terapia celular y métodos relacionados |
| CN114728044A (zh) | 2019-08-15 | 2022-07-08 | 介控生化科技公司 | 用于皮下施用和按需求治疗的经修饰的因子vii多肽 |
| EP4602155A1 (en) | 2022-10-11 | 2025-08-20 | Sigilon Therapeutics, Inc. | Engineered cells and implantable elements for treatment of disease |
| CN120659872A (zh) | 2022-10-11 | 2025-09-16 | 西吉隆医疗股份有限公司 | 用于治疗疾病的经工程化的细胞和可植入元件 |
Family Cites Families (68)
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| GR860984B (en) | 1985-04-17 | 1986-08-18 | Zymogenetics Inc | Expression of factor vii and ix activities in mammalian cells |
| US5180583A (en) | 1985-11-26 | 1993-01-19 | Hedner Ulla K E | Method for the treatment of bleeding disorders |
| US5258288A (en) | 1986-07-25 | 1993-11-02 | Genzyme Corporation | Vector containing DNA encoding mature human protein S |
| DK323587D0 (da) | 1987-06-25 | 1987-06-25 | Novo Industri As | Protein |
| FI882746A7 (fi) | 1987-06-12 | 1988-12-13 | Hoechst Japan | Hybridiproteiini C ja menetelmä sen valmistamiseksi. |
| US4904584A (en) | 1987-12-23 | 1990-02-27 | Genetics Institute, Inc. | Site-specific homogeneous modification of polypeptides |
| US5648254A (en) | 1988-01-15 | 1997-07-15 | Zymogenetics, Inc. | Co-expression in eukaryotic cells |
| JPH0246296A (ja) | 1988-08-09 | 1990-02-15 | Hoechst Japan Ltd | 雑種プロテインｃ及びその製造方法 |
| US5218092A (en) | 1988-09-29 | 1993-06-08 | Kyowa Hakko Kogyo Co., Ltd. | Modified granulocyte-colony stimulating factor polypeptide with added carbohydrate chains |
| US5041376A (en) | 1988-12-09 | 1991-08-20 | The Board Of Regents Of The University Of Texas System | Method for identifying or shielding functional sites or epitopes of proteins that enter the exocytotic pathway of eukaryotic cells, the mutant proteins so produced and genes encoding said mutant proteins |
| US5047335A (en) | 1988-12-21 | 1991-09-10 | The Regents Of The University Of Calif. | Process for controlling intracellular glycosylation of proteins |
| US5093317A (en) | 1989-06-05 | 1992-03-03 | Cephalon, Inc. | Treating disorders by application of insulin-like growth factor |
| US5077214A (en) | 1989-07-07 | 1991-12-31 | The Texas A&M University System | Use of baculovirus early promoters for expression of foreign genes in stably transformed insect cells |
| US5580560A (en) | 1989-11-13 | 1996-12-03 | Novo Nordisk A/S | Modified factor VII/VIIa |
| US5225537A (en) | 1989-12-29 | 1993-07-06 | Zymogenetics, Inc. | Methods for producing hybrid phospholipid-binding proteins |
| ES2052368T3 (es) | 1990-01-26 | 1994-07-01 | Immuno Ag | Factores sanguineos producidos por recombinacion y el proceso para la expresion de dichos factores, asi como recombinacion del virus de vaccina usados en dicho proceso. |
| JP3330932B2 (ja) | 1990-01-29 | 2002-10-07 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | 抗凝固剤タンパク質 |
| US5583107A (en) | 1990-09-04 | 1996-12-10 | Cor Therapeutics, Inc. | Agents affecting thrombosis and hemostasis |
| US5531916A (en) | 1990-10-03 | 1996-07-02 | E. I. Du Pont De Nemours And Company | Hydrofluorocarbon cleaning compositions |
| EP0785273A1 (en) | 1990-11-26 | 1997-07-23 | Genetics Institute, Inc. | Paired basic amino acid converting enzyme and DNA sequence encoding it |
| US5861374A (en) | 1991-02-28 | 1999-01-19 | Novo Nordisk A/S | Modified Factor VII |
| US5788965A (en) | 1991-02-28 | 1998-08-04 | Novo Nordisk A/S | Modified factor VII |
| HU218890B (hu) | 1991-02-28 | 2000-12-28 | Novo Nordisk A/S | Véralvadást gátló módosított VII faktorok, ezeket kódoló polinukleotid molekulák, polinukleotid molekulával transzfektált emlős sejtek és a véralvadást gátló módosított VII faktorokat tartalmazó gyógyászati készítmények, valamint a készítmények ... |
| US5817788A (en) | 1991-02-28 | 1998-10-06 | Zymogenetics, Inc. | Modified factor VII |
| US5833982A (en) | 1991-02-28 | 1998-11-10 | Zymogenetics, Inc. | Modified factor VII |
| US5504064A (en) | 1991-04-10 | 1996-04-02 | Oklahoma Medical Research Foundation | Treatment of bleeding with modified tissue factor in combination with an activator of FVII |
| JPH0720127A (ja) | 1993-05-07 | 1995-01-24 | Eisai Co Ltd | 各種ｐｉｖｋａの測定方法および測定試薬 |
| PT699075E (pt) | 1993-05-21 | 2002-05-31 | Novo Nordisk As | Factor vii modificado para inibicao de restenose vascular e de deposicao de plaquetas |
| DE19531637A1 (de) | 1995-08-28 | 1997-03-06 | Immuno Ag | Pharmazeutische Zusammensetzung zur Behandlung von Blutgerinnungsstörugnen, Verfahren zur Herstellung derselben und deren Verwendung |
| US5837843A (en) | 1996-11-08 | 1998-11-17 | Oklahoma Medical Research Foundation | Modified protein C |
| JP2001523949A (ja) | 1996-11-08 | 2001-11-27 | オクラホマ メディカル リサーチ ファウンデーション | 改変したプロテインｃおよびその使用方法 |
| BR9806793A (pt) * | 1997-01-22 | 2000-05-16 | Univ Texas | Processos e composições de fator tissular para coagulação e tratamento de tumores. |
| DE69800640T2 (de) | 1997-01-29 | 2001-07-05 | Polymasc Pharmaceuticals Plc, London | Pegylationsverfahren |
| EP1017794A1 (en) | 1997-02-06 | 2000-07-12 | Novo Nordisk A/S | Polypeptide-polymer conjugates having added and/or removed attachment groups |
| US6475725B1 (en) | 1997-06-20 | 2002-11-05 | Baxter Aktiengesellschaft | Recombinant cell clones having increased stability and methods of making and using the same |
| AT407255B (de) | 1997-06-20 | 2001-02-26 | Immuno Ag | Rekombinanter zellklon mit erhöhter stabilität in serum- und proteinfreiem medium und verfahren zur gewinnung des stabilen zellklons |
| ATE375363T1 (de) | 1997-07-14 | 2007-10-15 | Bolder Biotechnology Inc | Derivate des wachstumshormons und verwandte proteine |
| EP1005361B1 (en) | 1997-07-18 | 2010-01-06 | Novo Nordisk Health Care AG | USE OF FVIIa OR FVIIai FOR THE TREATMENT OF ENDOTHELIAL DYSFUNKTION AND FOR THE INHIBITION OF ANGIOGENESIS RESPECTIVELY |
| US6017882A (en) | 1997-10-23 | 2000-01-25 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| US7247708B2 (en) | 1997-10-23 | 2007-07-24 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| US6693075B1 (en) | 1997-10-23 | 2004-02-17 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| US6747003B1 (en) | 1997-10-23 | 2004-06-08 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| JP4574007B2 (ja) | 1998-04-28 | 2010-11-04 | メルク・セローノ・ソシエテ・アノニム | ポリオール−ｉｆｎ−ベータ複体 |
| AT408613B (de) | 1998-06-17 | 2002-01-25 | Immuno Ag | Pharmazeutisches faktor vii-präparat |
| NZ511291A (en) | 1998-10-30 | 2003-08-29 | Novozymes As | A method for selecting a protein variant that has reduced immunogenicity as compared with the parent or wild-type protein |
| AU774156B2 (en) | 1998-10-30 | 2004-06-17 | Novozymes A/S | Glycosylated proteins having reduced allergenicity |
| WO2000028065A1 (en) | 1998-11-06 | 2000-05-18 | Novo Nordisk A/S | Method for the production of fvii |
| WO2000054787A1 (en) | 1999-03-16 | 2000-09-21 | The Children's Hospital Of Philadelphia | Enhanced gamma-carboxylation of recombinant vitamin k-dependent clotting factors |
| JP2003521930A (ja) | 2000-02-11 | 2003-07-22 | マキシゲン・エイピーエス | 第ＶＩＩ因子または第ＶＩＩａ因子様分子 |
| US7220837B1 (en) | 2000-04-28 | 2007-05-22 | Regents Of The University Of Minnesota | Modified vitamin K-dependent polypeptides |
| ES2449224T3 (es) * | 2000-05-03 | 2014-03-18 | Novo Nordisk Health Care Ag | Administración subcutánea del Factor de coagulación VII |
| DE60143292D1 (de) | 2000-05-03 | 2010-12-02 | Novo Nordisk Healthcare Ag | Varianten des menschlichen Koagulationsfaktors VII |
| US7160540B2 (en) | 2000-06-30 | 2007-01-09 | Regents Of The University Of Minnesota | Methods for detecting activity of clottings factors |
| US6423826B1 (en) | 2000-06-30 | 2002-07-23 | Regents Of The University Of Minnesota | High molecular weight derivatives of vitamin K-dependent polypeptides |
| US20030211094A1 (en) | 2001-06-26 | 2003-11-13 | Nelsestuen Gary L. | High molecular weight derivatives of vitamin k-dependent polypeptides |
| PL204888B1 (pl) * | 2000-09-13 | 2010-02-26 | Novo Nordisk Healthcare Ag | Wariant polipeptydu czynnika VII, konstrukcja kwasu nukleinowego, rekombinowana komórka gospodarza, zwierzę transgeniczne, sposób wytwarzania wariantu polipeptydu czynnika VII, kompozycja farmaceutyczna i zastosowanie wariantu polipeptydu czynnika VII |
| BR0113854A (pt) | 2000-09-13 | 2004-07-06 | Novo Nordisk As | Polipeptìdeo do fator vii, construção de ácido nucleìco, célula hospedeira recombinante animal transgênico, planta transgênica, método para produzir o polipeptìdeo do fator vii, composição farmacêutica, uso de um polipeptìdeo do fator vii, e, métodos para o tratamento de episódios de sangramento e para tratamento ou profilaxia de distúrbios de sangramento em um indivìduo ou para a intensificação do sistema hemostático normal |
| EP1325113B1 (en) | 2000-10-02 | 2010-04-21 | Novo Nordisk Health Care AG | Factor vii glycoforms |
| AU2002218029A1 (en) | 2000-11-09 | 2002-05-21 | The Scripps Research Institute | Modified factor viia |
| WO2002077218A1 (en) | 2001-03-22 | 2002-10-03 | Novo Nordisk Health Care Ag | Coagulation factor vii derivatives |
| ES2376694T3 (es) | 2001-09-27 | 2012-03-16 | Novo Nordisk Health Care Ag | Polipã‰ptidos del factor vii de coagulaciã“n humano. |
| AU2002336919A1 (en) | 2001-11-02 | 2003-05-12 | Novo Nordisk Health Care Ag | Human coagulation factor vii polypeptides |
| BR0215216A (pt) | 2001-12-21 | 2004-11-16 | Novo Nordisk Healthcare Ag | Composição aquosa lìquida, método para preparar uma composição aquosa lìquida de um polipeptìdeo de fator vii, uso de uma composição aquosa lìquida, e, método para o tratamento de uma sìndrome de resposta ao fator vii |
| CN1665925A (zh) | 2002-04-30 | 2005-09-07 | 马克西根控股公司 | 凝血因子Ⅶ或Ⅶa多肽变体 |
| ATE505487T1 (de) | 2002-09-30 | 2011-04-15 | Bayer Healthcare Llc | Fvii- oder fviia-varianten mit erhöhter koagulationswirkung |
| AU2004221761B2 (en) | 2003-03-20 | 2010-01-07 | Bayer Healthcare Llc | FVII or FVIIa variants |
| EP1644504B8 (en) * | 2003-06-19 | 2010-06-02 | Bayer HealthCare LLC | Factor vii or viia gla domain variants |
| WO2005023308A1 (en) * | 2003-09-05 | 2005-03-17 | Maxygen Holdings Ltd. | Formulations of vitamin k-dependent polypeptides and sulfoalkyl ether cycloextrins |
-
2004
- 2004-03-22 AU AU2004221761A patent/AU2004221761B2/en not_active Ceased
- 2004-03-22 WO PCT/DK2004/000193 patent/WO2004083361A2/en not_active Ceased
- 2004-03-22 CA CA2519873A patent/CA2519873C/en not_active Expired - Fee Related
- 2004-03-22 EP EP04722232A patent/EP1608745B1/en not_active Expired - Lifetime
- 2004-03-22 DE DE602004021099T patent/DE602004021099D1/de not_active Expired - Lifetime
- 2004-03-22 ES ES04722232T patent/ES2327044T3/es not_active Expired - Lifetime
- 2004-03-22 DK DK09075170.2T patent/DK2085470T3/da active
- 2004-03-22 US US10/549,506 patent/US7771996B2/en not_active Expired - Fee Related
- 2004-03-22 EP EP09075170A patent/EP2085470B1/en not_active Expired - Lifetime
- 2004-03-22 JP JP2006504332A patent/JP4847856B2/ja not_active Expired - Fee Related
- 2004-03-22 DK DK04722232T patent/DK1608745T3/da active
- 2004-03-22 AT AT04722232T patent/ATE431403T1/de not_active IP Right Cessation
- 2004-03-22 ES ES09075170T patent/ES2386010T3/es not_active Expired - Lifetime
-
2010
- 2010-03-25 AU AU2010201201A patent/AU2010201201A1/en not_active Abandoned
- 2010-05-05 US US12/774,560 patent/US20100330669A1/en not_active Abandoned
-
2011
- 2011-07-22 JP JP2011160400A patent/JP2012095641A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| ES2327044T3 (es) | 2009-10-23 |
| CA2519873A1 (en) | 2004-09-30 |
| ATE431403T1 (de) | 2009-05-15 |
| JP2012095641A (ja) | 2012-05-24 |
| AU2004221761A1 (en) | 2004-09-30 |
| DE602004021099D1 (de) | 2009-06-25 |
| US20100330669A1 (en) | 2010-12-30 |
| WO2004083361A3 (en) | 2004-11-04 |
| EP1608745B1 (en) | 2009-05-13 |
| EP1608745A2 (en) | 2005-12-28 |
| US7771996B2 (en) | 2010-08-10 |
| WO2004083361A2 (en) | 2004-09-30 |
| AU2010201201A1 (en) | 2010-04-15 |
| JP2006521098A (ja) | 2006-09-21 |
| DK1608745T3 (da) | 2009-06-15 |
| AU2004221761B2 (en) | 2010-01-07 |
| EP2085470B1 (en) | 2012-05-16 |
| CA2519873C (en) | 2012-12-18 |
| JP4847856B2 (ja) | 2011-12-28 |
| EP2085470A1 (en) | 2009-08-05 |
| DK2085470T3 (da) | 2012-08-06 |
| US20070054366A1 (en) | 2007-03-08 |
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