CA2788505C - Polymer-factor viii moiety conjugates - Google Patents
Polymer-factor viii moiety conjugates Download PDFInfo
- Publication number
- CA2788505C CA2788505C CA2788505A CA2788505A CA2788505C CA 2788505 C CA2788505 C CA 2788505C CA 2788505 A CA2788505 A CA 2788505A CA 2788505 A CA2788505 A CA 2788505A CA 2788505 C CA2788505 C CA 2788505C
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- CA
- Canada
- Prior art keywords
- factor viii
- polymer
- conjugate
- daltons
- poly
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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| US8008252B2 (en) * | 2001-10-10 | 2011-08-30 | Novo Nordisk A/S | Factor VII: remodeling and glycoconjugation of Factor VII |
| US7157277B2 (en) | 2001-11-28 | 2007-01-02 | Neose Technologies, Inc. | Factor VIII remodeling and glycoconjugation of Factor VIII |
| US7173003B2 (en) | 2001-10-10 | 2007-02-06 | Neose Technologies, Inc. | Granulocyte colony stimulating factor: remodeling and glycoconjugation of G-CSF |
| US7214660B2 (en) * | 2001-10-10 | 2007-05-08 | Neose Technologies, Inc. | Erythropoietin: remodeling and glycoconjugation of erythropoietin |
| ATE371680T1 (de) | 2002-01-16 | 2007-09-15 | Biocompatibles Uk Ltd | Polymerkonjugate |
| MXPA04012496A (es) * | 2002-06-21 | 2005-09-12 | Novo Nordisk Healthcare Ag | Glicoformos del factor vii pegilados. |
| GB0301014D0 (en) * | 2003-01-16 | 2003-02-19 | Biocompatibles Ltd | Conjugation reactions |
| AU2004215912B2 (en) * | 2003-02-26 | 2009-03-26 | Nektar Therapeutics | Polymer-factor VIII moiety conjugates |
| SG155777A1 (en) | 2003-04-09 | 2009-10-29 | Neose Technologies Inc | Glycopegylation methods and proteins/peptides produced by the methods |
| US8791070B2 (en) | 2003-04-09 | 2014-07-29 | Novo Nordisk A/S | Glycopegylated factor IX |
| US7947261B2 (en) | 2003-05-23 | 2011-05-24 | Nektar Therapeutics | Conjugates formed from polymer derivatives having particular atom arrangements |
| KR101128320B1 (ko) * | 2003-05-23 | 2012-04-12 | 넥타르 테라퓨틱스 | 아미도카르보네이트 연결기를 갖는 peg 유도체 |
| WO2005012484A2 (en) | 2003-07-25 | 2005-02-10 | Neose Technologies, Inc. | Antibody-toxin conjugates |
| WO2005039641A2 (en) * | 2003-10-15 | 2005-05-06 | The Regents Of The University Of California | Biomacromolecule polymer conjugates |
| US20080305992A1 (en) | 2003-11-24 | 2008-12-11 | Neose Technologies, Inc. | Glycopegylated erythropoietin |
| US20060040856A1 (en) | 2003-12-03 | 2006-02-23 | Neose Technologies, Inc. | Glycopegylated factor IX |
| US6887952B1 (en) * | 2004-02-12 | 2005-05-03 | Biosite, Inc. | N-aryl-carbamic acid ester-derived and valeric acid ester-derived cross-linkers and conjugates, and methods for their synthesis and use |
| US9446139B2 (en) * | 2004-03-15 | 2016-09-20 | Nektar Therapeutics | Polymer-based compositions and conjugates of HIV entry inhibitors |
| US8470315B2 (en) | 2004-04-13 | 2013-06-25 | Quintessence Biosciences, Inc. | Non-natural ribonuclease conjugates as cytotoxic agents |
| US20080300173A1 (en) | 2004-07-13 | 2008-12-04 | Defrees Shawn | Branched Peg Remodeling and Glycosylation of Glucagon-Like Peptides-1 [Glp-1] |
| HUE026826T2 (en) | 2004-10-29 | 2016-07-28 | Ratiopharm Gmbh | Modeling and glycopegylation of fibroblast growth factor (FGF) |
| AU2012203813B2 (en) * | 2004-11-12 | 2013-10-24 | Bayer Healthcare Llc | Site-directed modification of FVIII |
| SI1824988T1 (sl) * | 2004-11-12 | 2017-11-30 | Bayer Healthcare Llc | Usmerjena modifikacija FVIII |
| AU2016203693B2 (en) * | 2004-11-12 | 2018-08-23 | Bayer Healthcare Llc | Site-directed modification of FVIII |
| AU2013203348B2 (en) * | 2004-11-12 | 2016-03-03 | Bayer Healthcare Llc | Site-directed modification of FVIII |
| KR20070092754A (ko) | 2004-12-27 | 2007-09-13 | 백스터 인터내셔널 인코포레이티드 | 중합체 - 폰 빌레브란트 인자 - 접합체 |
| US9029331B2 (en) | 2005-01-10 | 2015-05-12 | Novo Nordisk A/S | Glycopegylated granulocyte colony stimulating factor |
| EP1848461A2 (en) | 2005-02-16 | 2007-10-31 | Nektar Therapeutics Al, Corporation | Conjugates of an epo moiety and a polymer |
| US20060233740A1 (en) * | 2005-03-23 | 2006-10-19 | Bossard Mary J | Conjugates of an hGH moiety and a polymer |
| JP2008534559A (ja) * | 2005-04-01 | 2008-08-28 | 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 | 血液凝固fviii類似体 |
| EP1871795A4 (en) | 2005-04-08 | 2010-03-31 | Biogenerix Ag | COMPOSITIONS AND METHOD FOR PRODUCING GLYCOSYLATION MUTANTS OF A PROTEASE-RESISTANT HUMAN GROWTH HORMONE |
| WO2006110776A2 (en) * | 2005-04-12 | 2006-10-19 | Nektar Therapeutics Al, Corporation | Polyethylene glycol cojugates of antimicrobial agents |
| EP1891231A4 (en) | 2005-05-25 | 2011-06-22 | Novo Nordisk As | GLYCOPEGYLATED FACTOR IX |
| WO2006134173A2 (en) * | 2005-06-17 | 2006-12-21 | Novo Nordisk Health Care Ag | Selective reduction and derivatization of engineered proteins comprising at least one non-native cysteine |
| WO2007019331A2 (en) * | 2005-08-04 | 2007-02-15 | Nektar Therapeutics Al, Corporation | Conjugates of a g-csf moiety and a polymer |
| US20070105755A1 (en) | 2005-10-26 | 2007-05-10 | Neose Technologies, Inc. | One pot desialylation and glycopegylation of therapeutic peptides |
| US20090048440A1 (en) | 2005-11-03 | 2009-02-19 | Neose Technologies, Inc. | Nucleotide Sugar Purification Using Membranes |
| US20070141021A1 (en) * | 2005-12-19 | 2007-06-21 | Perry Rosen | Methylmaleimidyl polymer derivatives |
| EP2001518B1 (en) | 2006-03-30 | 2013-07-10 | Palatin Technologies, Inc. | Cyclic natriuretic peptide constructs |
| US8580746B2 (en) * | 2006-03-30 | 2013-11-12 | Palatin Technologies, Inc. | Amide linkage cyclic natriuretic peptide constructs |
| US7795221B2 (en) * | 2006-03-30 | 2010-09-14 | Palatin Technologies, Inc. | Linear natriuretic peptide constructs |
| NZ572050A (en) | 2006-03-31 | 2011-09-30 | Baxter Int | Factor VIII conjugated to polyethylene glycol |
| US7645860B2 (en) | 2006-03-31 | 2010-01-12 | Baxter Healthcare S.A. | Factor VIII polymer conjugates |
| US7985839B2 (en) | 2006-03-31 | 2011-07-26 | Baxter International Inc. | Factor VIII polymer conjugates |
| US7982010B2 (en) | 2006-03-31 | 2011-07-19 | Baxter International Inc. | Factor VIII polymer conjugates |
| BRPI0712008A2 (pt) * | 2006-05-24 | 2012-01-10 | Novo Nordisk Healthcare Ag | derivados e análogos de fix prolongados |
| JP2009541333A (ja) | 2006-06-23 | 2009-11-26 | クインテセンス バイオサイエンシーズ インコーポレーティッド | 修飾リボヌクレアーゼ |
| EP2049151A4 (en) | 2006-07-17 | 2010-03-24 | Quintessence Biosciences Inc | METHOD AND COMPOSITIONS FOR THE TREATMENT OF CANCER |
| US20080248959A1 (en) | 2006-07-21 | 2008-10-09 | Neose Technologies, Inc. | Glycosylation of peptides via o-linked glycosylation sequences |
| JP2010505874A (ja) | 2006-10-03 | 2010-02-25 | ノヴォ ノルディスク アー/エス | ポリペプチドコンジュゲートの精製方法 |
| CN105838699A (zh) | 2006-12-15 | 2016-08-10 | 巴克斯艾尔塔公司 | 具有延长的体内半衰期的因子VIIa-聚唾液酸结合物 |
| NZ577397A (en) * | 2006-12-27 | 2012-01-12 | Nektar Therapeutics | Factor ix moiety-polymer conjugates having a releasable linkage |
| JP5702066B2 (ja) | 2006-12-27 | 2015-04-15 | ネクター セラピューティクス | 解離可能な連結を有するフォンウィルブランド因子および第viii因子のポリマー共役体 |
| RS52845B (sr) | 2007-04-03 | 2013-12-31 | Biogenerix Ag | Postupci tretmana korišćenjem glikopegiliranog g-csf |
| JP5876649B2 (ja) | 2007-06-12 | 2016-03-02 | ラツィオファルム ゲーエムベーハーratiopharm GmbH | ヌクレオチド糖の改良製造法 |
| US8796248B2 (en) * | 2007-10-05 | 2014-08-05 | Nektar Therapeutics | Oligomer-corticosteroid conjugates |
| CA2702043A1 (en) | 2007-10-08 | 2009-04-16 | Quintessence Biosciences, Inc. | Compositions and methods for ribonuclease-based therapies |
| BRPI0820271A2 (pt) * | 2007-11-09 | 2015-05-26 | Baxter Int | Métodos de aumentar a sobrevivência de uma proteína de coagulação pela inibição da interação com um receptor de depuração, de aumentar a sobrevivência de fator viii que inibe receptores de depruração de proteína de coagulação, de tratar um indivíduo com uma doença de coagulação sanguínea, e de tratar uma doença que tem por característica uma deficiência de fator viii em um indivíduo, e, proteína de ...métodos de aumentar a sobrevivência de uma proteína de coagulação pela inibição da interação com um receptor de depuração, de aumentar a sobrevivência de fator viii pela inibição da interação com um receptor de depuração, de preparar uma composição que inibe receptores de depuração de proteína de coagulação, de tratar um indivíduo com uma doença de coagulação sanguínea, e de tratar uma doença que tem por característica uma deficiência de fator viii em um indivíduo, e, proteína de coagulação modificada. |
| ES2428774T3 (es) * | 2007-12-27 | 2013-11-11 | Baxter International Inc. | Procedimiento y composiciones para detectar específicamente moléculas poliméricas fisiológicamente aceptables |
| ES2476690T3 (es) | 2008-02-27 | 2014-07-15 | Novo Nordisk A/S | Moléculas conjugadas del Factor VIII |
| TWI395593B (zh) | 2008-03-06 | 2013-05-11 | Halozyme Inc | 可活化的基質降解酵素之活體內暫時性控制 |
| JP2011519361A (ja) | 2008-04-14 | 2011-07-07 | ハロザイム インコーポレイテッド | 修飾されたヒアルロニダーゼおよびヒアルロナン関連疾患および状態の治療における使用 |
| TWI394580B (zh) | 2008-04-28 | 2013-05-01 | Halozyme Inc | 超快起作用胰島素組成物 |
| CN102112623A (zh) * | 2008-06-04 | 2011-06-29 | 拜耳医药保健有限公司 | 用于治疗血管性血友病的fviii突变蛋白 |
| CN103739712B (zh) | 2008-06-24 | 2016-10-05 | 德国杰特贝林生物制品有限公司 | 具有延长的体内半衰期的因子viii、冯·维勒布兰德因子或它们的复合物 |
| US8575102B2 (en) | 2008-08-01 | 2013-11-05 | Nektar Therapeutics | Conjugates having a releasable linkage |
| US8653131B2 (en) * | 2008-08-22 | 2014-02-18 | Baxter Healthcare S.A. | Polymeric benzyl carbonate-derivatives |
| EP2334695B1 (en) | 2008-10-01 | 2015-12-23 | Quintessence Biosciences, Inc. | Therapeutic ribonucleases |
| US8143347B2 (en) | 2008-10-15 | 2012-03-27 | Baxter International Inc. | Pegylation of recombinant blood coagulation factors in the presence of bound antibodies |
| HUE039906T2 (hu) * | 2008-10-17 | 2019-02-28 | Baxalta GmbH | Alacsony fokú vízben oldható polimer tartalmú módosított vérfaktorok |
| JP5281358B2 (ja) * | 2008-10-27 | 2013-09-04 | 学校法人常翔学園 | 高分子、経上皮吸収促進剤、及び医薬用製剤 |
| KR20110093775A (ko) * | 2008-11-03 | 2011-08-18 | 바이엘 헬스케어 엘엘씨 | 혈우병 치료 방법 |
| ES2724588T3 (es) | 2008-12-09 | 2019-09-12 | Halozyme Inc | Polipéptidos de PH20 soluble extendida y usos de los mismos |
| US20120121613A1 (en) * | 2009-01-19 | 2012-05-17 | Bayer Healthcare Llc | Protein conjugate having an endopeptidase- cleavable bioprotective moiety |
| WO2010091122A1 (en) | 2009-02-03 | 2010-08-12 | Amunix, Inc. | Extended recombinant polypeptides and compositions comprising same |
| CN102333788A (zh) * | 2009-02-19 | 2012-01-25 | 诺沃—诺迪斯克有限公司 | 因子viii的修饰 |
| EP2437786B1 (en) | 2009-06-01 | 2016-05-18 | Yeda Research and Development Co. Ltd. | Prodrugs containing albumin binding probe |
| PL2459224T3 (pl) | 2009-07-27 | 2017-08-31 | Baxalta GmbH | Koniugaty białka związanego z krzepnięciem krwi |
| EP2459226B1 (en) | 2009-07-27 | 2016-06-29 | Lipoxen Technologies Limited | Glycopolysialylation of proteins other than blood coagulation proteins |
| EP2459224B1 (en) | 2009-07-27 | 2016-06-01 | Baxalta GmbH | Blood coagulation protein conjugates |
| US8809501B2 (en) * | 2009-07-27 | 2014-08-19 | Baxter International Inc. | Nucleophilic catalysts for oxime linkage |
| US8642737B2 (en) | 2010-07-26 | 2014-02-04 | Baxter International Inc. | Nucleophilic catalysts for oxime linkage |
| BR112012004094A2 (pt) | 2009-08-24 | 2016-03-08 | Amunix Operating Inc | composições de fator vii de coagulação e métodos para fazer e usar as mesmas |
| US9084743B2 (en) | 2009-09-17 | 2015-07-21 | Baxter International Inc. | Stable co-formulation of hyaluronidase and immunoglobulin, and methods of use thereof |
| ES2639641T3 (es) * | 2010-04-20 | 2017-10-27 | Octapharma Ag | Nuevo agente estabilizante para proteínas farmacéuticas |
| GB201007356D0 (en) | 2010-04-30 | 2010-06-16 | Leverton Licence Holdings Ltd | Conjugated factor VIIa |
| GB201007357D0 (en) * | 2010-04-30 | 2010-06-16 | Leverton Licence Holdings Ltd | Conjugated factor VIII |
| US9611310B2 (en) | 2010-07-09 | 2017-04-04 | Bioverativ Therapeutics Inc. | Systems for factor VIII processing and methods thereof |
| KR20130125753A (ko) | 2010-07-20 | 2013-11-19 | 할로자임, 아이엔씨 | 항-히알루로난제 투여와 관련된 유해 부작용의 치료 |
| 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 |
| ES2800983T3 (es) | 2010-12-22 | 2021-01-07 | Baxalta GmbH | Materiales y métodos para conjugar un derivado de ácido graso soluble en agua con una proteína |
| ES2634669T3 (es) | 2011-02-08 | 2017-09-28 | Halozyme, Inc. | Composición y formulación lipídica de una enzima de degradación de hialuronano y uso de la misma para el tratamiento de la hiperplasia benigna de próstata |
| US9480751B2 (en) | 2011-04-11 | 2016-11-01 | Yeda Research And Development Co. Ltd. | Albumin binding probes and drug conjugates thereof |
| WO2012140650A2 (en) | 2011-04-12 | 2012-10-18 | Hepacore Ltd. | Conjugates of carboxy polysaccharides with fibroblast growth factors and variants thereof |
| US20130011378A1 (en) | 2011-06-17 | 2013-01-10 | Tzung-Horng Yang | Stable formulations of a hyaluronan-degrading enzyme |
| AU2012271361B2 (en) | 2011-06-17 | 2017-03-02 | Halozyme, Inc. | Continuous subcutaneous insulin infusion methods with a hyaluronan degrading enzyme |
| KR20140043438A (ko) | 2011-06-17 | 2014-04-09 | 할로자임, 아이엔씨 | 히알루로난 분해 효소의 안정한 제형 |
| US20130071394A1 (en) | 2011-09-16 | 2013-03-21 | John K. Troyer | Compositions and combinations of organophosphorus bioscavengers and hyaluronan-degrading enzymes, and methods of use |
| EA030440B1 (ru) | 2011-10-24 | 2018-08-31 | Галозим, Инк. | Сопровождающая диагностика для терапии антигиалуронановым агентом и способы ее применения |
| BR112014016195A2 (pt) | 2011-12-30 | 2020-10-27 | Halozyme, Inc. | variantes de polipeptídio ph20, formulações e usos das mesmas |
| EA035323B1 (ru) | 2012-01-12 | 2020-05-28 | Биовератив Терапьютикс Инк. | Полипептиды химерного фактора viii и их применение |
| ES2651523T3 (es) | 2012-02-15 | 2018-01-26 | Csl Behring Gmbh | Variantes del Factor de von Willebrand que tienen afinidad de unión al Factor VIII mejorada |
| LT2822577T (lt) * | 2012-02-15 | 2019-03-25 | Bioverativ Therapeutics Inc. | Rekombinantiniai faktoriaus viii baltymai |
| HRP20221531T1 (hr) | 2012-02-15 | 2023-02-17 | Bioverativ Therapeutics Inc. | Pripravci faktora viii i postupci dobivanja i korištenja istih |
| CN104411324A (zh) | 2012-04-04 | 2015-03-11 | 哈洛齐梅公司 | 使用抗透明质酸剂和肿瘤靶向紫杉烷的组合疗法 |
| EP2838566A2 (en) * | 2012-04-16 | 2015-02-25 | Cantab Biopharmaceuticals Patents Limited | Optimised subcutaneous therapeutic agents |
| CA2875246A1 (en) | 2012-06-08 | 2013-12-12 | Biogen Idec Ma Inc. | Procoagulant compounds |
| AU2013270683A1 (en) | 2012-06-08 | 2014-12-11 | Biogen Ma Inc. | Chimeric clotting factors |
| US20140017265A1 (en) * | 2012-07-05 | 2014-01-16 | Mersana Therapeutics, Inc. | Terminally Modified Polymers and Conjugates Thereof |
| US10138291B2 (en) | 2012-07-11 | 2018-11-27 | Bioverativ Therapeutics Inc. | Factor VIII complex with XTEN and von Willebrand Factor protein, and uses thereof |
| CN104519912A (zh) * | 2012-08-13 | 2015-04-15 | 诺和诺德A/S(股份有限公司) | 液体因子viii制剂 |
| WO2014062856A1 (en) | 2012-10-16 | 2014-04-24 | Halozyme, Inc. | Hypoxia and hyaluronan and markers thereof for diagnosis and monitoring of diseases and conditions and related methods |
| CA2888806A1 (en) | 2012-10-18 | 2014-04-24 | Biogen Idec Ma Inc. | Methods of using a fixed dose of a clotting factor |
| PT2966083T (pt) | 2013-03-05 | 2019-09-17 | Hanmi Pharm Ind Co Ltd | Método de preparação melhorado para produção de alto rendimento de conjugado de polipéptido fisiologicamente ativo |
| US20160030529A1 (en) * | 2013-03-13 | 2016-02-04 | Emory University | Targeted elimination of factor viii immune cells |
| EA037906B1 (ru) | 2013-03-15 | 2021-06-04 | Биовератив Терапьютикс Инк. | Препараты полипептида фактора ix |
| US20200157159A1 (en) | 2013-04-16 | 2020-05-21 | The Board Of Regents Of The University Of Oklahoma | Peptide compounds and compositions thereof |
| DK2796145T3 (da) | 2013-04-22 | 2018-01-29 | Csl Ltd | Et kovalent kompleks af von Willebrand-faktor og faktor VIII linket af en disulfidbro |
| WO2014210558A1 (en) | 2013-06-28 | 2014-12-31 | Biogen Idec Ma Inc. | Thrombin cleavable linker with xten and its uses thereof |
| TW201534726A (zh) | 2013-07-03 | 2015-09-16 | Halozyme Inc | 熱穩定ph20玻尿酸酶變異體及其用途 |
| EP3033097B1 (en) | 2013-08-14 | 2021-03-10 | Bioverativ Therapeutics Inc. | Factor viii-xten fusions and uses thereof |
| US20160311885A1 (en) | 2013-08-14 | 2016-10-27 | Biogen Ma Inc. | Recombinant factor viii proteins |
| DK3091997T5 (da) | 2014-01-10 | 2024-10-14 | Bioverativ Therapeutics Inc | Kimære faktor viii-proteiner og anvendelser deraf |
| EP3114138B1 (en) | 2014-03-05 | 2021-11-17 | Pfizer Inc. | Improved muteins of clotting factor viii |
| AU2015283822B2 (en) | 2014-07-02 | 2019-10-03 | CSL Behring Lengnau AG | Modified von willebrand factor |
| HRP20190881T1 (hr) | 2014-08-28 | 2019-07-12 | Halozyme, Inc. | Kombinacijska terapija s hijaluronan-razgrađujućim enzimom i inhibitorom imunološke kontrolne točke |
| EP3207130B1 (en) | 2014-10-14 | 2019-08-07 | Halozyme, Inc. | Compositions of adenosine deaminase-2 (ada2), variants thereof and methods of using same |
| MA40835A (fr) | 2014-10-23 | 2017-08-29 | Biogen Ma Inc | Anticorps anti-gpiib/iiia et leurs utilisations |
| MA40861A (fr) | 2014-10-31 | 2017-09-05 | Biogen Ma Inc | Anticorps anti-glycoprotéines iib/iiia |
| DK3265483T3 (da) | 2015-03-06 | 2020-03-02 | CSL Behring Lengnau AG | Modificeret von Willebrand-faktor med forbedret halveringstid |
| SG11201708755WA (en) | 2015-05-22 | 2017-12-28 | Csl Behring Recombinant Facility Ag | Truncated von willebrand factor polypeptides for treating hemophilia |
| CN107810194B (zh) | 2015-05-22 | 2021-10-08 | 康诺贝林伦瑙有限公司 | 用于制备经修饰的血管性血友病因子的方法 |
| MX2018001497A (es) | 2015-08-03 | 2018-05-15 | Bioverativ Therapeutics Inc | Proteinas de fusion de factor ix y metodos para producirlas y usarlas. |
| SG11201805497QA (en) | 2016-01-07 | 2018-07-30 | Csl Behring Recombinant Facility Ag | Mutated truncated von willebrand factor |
| SG10201912857XA (en) | 2016-01-07 | 2020-02-27 | CSL Behring Lengnau AG | Mutated von willebrand factor |
| CN109689683A (zh) * | 2016-06-24 | 2019-04-26 | 财团法人牧岩生命科学研究所 | 重组单链fvⅲ及其化学缀合物 |
| WO2018017923A1 (en) | 2016-07-22 | 2018-01-25 | Nektar Therapeutics | Conjugates of a factor viii moiety having an oxime-containing linkage |
| AU2017358865A1 (en) | 2016-11-11 | 2019-05-09 | CSL Behring Lengnau AG | Truncated von willebrand factor polypeptides for extravascular administration in the treatment or prophylaxis of a blood coagulation disorder |
| TW201828975A (zh) | 2016-11-11 | 2018-08-16 | 瑞士商Csl貝林重組技能公司 | 用於治療血友病之截短型類血友病因子(von Willebrand factor)多肽類 |
| BR112019011198A2 (pt) | 2016-12-02 | 2019-12-17 | Bioverativ Therapeutics Inc | métodos de indução de tolerância imune a fatores de coagulação |
| WO2018102743A1 (en) | 2016-12-02 | 2018-06-07 | Bioverativ Therapeutics Inc. | Methods of treating hemophilic arthropathy using chimeric clotting factors |
| US10781435B2 (en) | 2017-06-22 | 2020-09-22 | Catalyst Biosciences, Inc. | Modified membrane type serine protease 1 (MTSP-1) polypeptides and methods of use |
| US11491212B1 (en) | 2017-09-27 | 2022-11-08 | Catalyst Biosciences, Inc. | Subcutaneous administration of modified factor IX polypeptides and treatment of hemophilia B |
| US20190351031A1 (en) | 2018-05-16 | 2019-11-21 | Halozyme, Inc. | Methods of selecting subjects for combination cancer therapy with a polymer-conjugated soluble ph20 |
| RS66972B1 (sr) | 2018-05-18 | 2025-07-31 | Bioverativ Therapeutics Inc | Metode lečenja hemofilije a |
| AU2019305215A1 (en) * | 2018-07-20 | 2021-02-25 | Hercules Llc | Water soluble or dispersible composition |
| PE20211664A1 (es) | 2018-12-28 | 2021-08-26 | Catalyst Biosciences Inc | Polipeptidos de activador de plasminogeno, tipo urocinasa, modificados y metodos de uso |
| US11613744B2 (en) | 2018-12-28 | 2023-03-28 | Vertex Pharmaceuticals Incorporated | Modified urokinase-type plasminogen activator polypeptides and methods of use |
| WO2021154414A2 (en) | 2020-01-29 | 2021-08-05 | Catalyst Biosciences, Inc. | Gene therapy for hemophilia b with a chimeric aav capsid vector encoding modified factor ix polypeptides |
| US12232007B2 (en) * | 2021-06-03 | 2025-02-18 | Apple Inc. | Systems and methods for emergency service access by reduced capability radio frequency devices |
| WO2025227129A2 (en) | 2024-04-25 | 2025-10-30 | Starrock Pharma Llc | Delivery vehicles comprising proglucagon derived polypeptides and anabolic polypeptides and uses thereof |
Family Cites Families (56)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4179337A (en) | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
| JPS59172425A (ja) | 1983-03-18 | 1984-09-29 | Nippon Chemiphar Co Ltd | 新規な血液凝固因子誘導体およびその製造法ならびにそれを含有する血液凝固促進剤 |
| US4650858A (en) | 1983-03-21 | 1987-03-17 | Nordisk Gentofte A/S | Concentrate of the antihemophilic factor VIII and a process for producing it |
| US4757006A (en) | 1983-10-28 | 1988-07-12 | Genetics Institute, Inc. | Human factor VIII:C gene and recombinant methods for production |
| US4965199A (en) | 1984-04-20 | 1990-10-23 | Genentech, Inc. | Preparation of functional human factor VIII in mammalian cells using methotrexate based selection |
| DK525384D0 (da) | 1984-11-05 | 1984-11-05 | Nordisk Insulinlab | Praeparat paa basis af faktor viii til behandling af haemofili a inhibitorpatienter samt fremgangsmaade til fremstilling af et saadan praeparat |
| US4970300A (en) * | 1985-02-01 | 1990-11-13 | New York University | Modified factor VIII |
| JPH0788399B2 (ja) | 1985-04-12 | 1995-09-27 | ジェネティックス・インスチチュ−ト・インコ−ポレ−テッド | 新規プロコアギュラント蛋白質 |
| AT387234B (de) | 1987-03-05 | 1988-12-27 | Vogelbusch Gmbh | Vorrichtung zur zuechtung von dauerformen insbesondere filamentoeser mikroorganismen |
| US4994439A (en) * | 1989-01-19 | 1991-02-19 | California Biotechnology Inc. | Transmembrane formulations for drug administration |
| SE465222C5 (sv) * | 1989-12-15 | 1998-02-10 | Pharmacia & Upjohn Ab | Ett rekombinant, humant faktor VIII-derivat och förfarande för dess framställning |
| US5397771A (en) | 1990-05-10 | 1995-03-14 | Bechgaard International Research And Development A/S | Pharmaceutical preparation |
| IT1248723B (it) | 1990-06-12 | 1995-01-26 | Scalvo S P A | Processo per la purificazione del fattore viii e fattore viii ottenuto con tale processo |
| US5766897A (en) | 1990-06-21 | 1998-06-16 | Incyte Pharmaceuticals, Inc. | Cysteine-pegylated proteins |
| CA2101918A1 (en) * | 1991-03-18 | 1992-09-19 | Samuel Zalipsky | Hydrazine containing conjugates of polypeptides and glycopolypeptides with polymers |
| DE4111393A1 (de) | 1991-04-09 | 1992-10-15 | Behringwerke Ag | Stabilisierte faktor viii-praeparationen |
| US6376463B1 (en) | 1992-04-07 | 2002-04-23 | Emory University | Modified factor VIII |
| US6037452A (en) * | 1992-04-10 | 2000-03-14 | Alpha Therapeutic Corporation | Poly(alkylene oxide)-Factor VIII or Factor IX conjugate |
| WO1994004193A1 (en) * | 1992-08-21 | 1994-03-03 | Enzon, Inc. | Novel attachment of polyalkylene oxides to bio-effecting substances |
| US5298643A (en) | 1992-12-22 | 1994-03-29 | Enzon, Inc. | Aryl imidate activated polyalkylene oxides |
| WO1994015625A1 (en) | 1993-01-15 | 1994-07-21 | Enzon, Inc. | Factor viii - polymeric conjugates |
| US5321095A (en) | 1993-02-02 | 1994-06-14 | Enzon, Inc. | Azlactone activated polyalkylene oxides |
| US5621039A (en) | 1993-06-08 | 1997-04-15 | Hallahan; Terrence W. | Factor IX- polymeric conjugates |
| SE504074C2 (sv) | 1993-07-05 | 1996-11-04 | Pharmacia Ab | Proteinberedning för subkutan, intramuskulär eller intradermal administrering |
| US5446090A (en) | 1993-11-12 | 1995-08-29 | Shearwater Polymers, Inc. | Isolatable, water soluble, and hydrolytically stable active sulfones of poly(ethylene glycol) and related polymers for modification of surfaces and molecules |
| US5612039A (en) * | 1994-03-14 | 1997-03-18 | Nini E. Policappelli | Dietary supplement |
| WO1996041813A2 (en) * | 1994-11-09 | 1996-12-27 | Offord Robin E | Functionalized polymers for site-specific attachment |
| US5569596A (en) * | 1995-01-04 | 1996-10-29 | The Board Of Regents Of The University Of Oklahoma | Method for bacterial reduction of chromium (VI) |
| US5932462A (en) | 1995-01-10 | 1999-08-03 | Shearwater Polymers, Inc. | Multiarmed, monofunctional, polymer for coupling to molecules and surfaces |
| SE9503380D0 (sv) * | 1995-09-29 | 1995-09-29 | Pharmacia Ab | Protein derivatives |
| US6158888A (en) | 1996-09-05 | 2000-12-12 | University Of Florida | Materials and methods for improved radiography |
| US5804420A (en) | 1997-04-18 | 1998-09-08 | Bayer Corporation | Preparation of recombinant Factor VIII in a protein free medium |
| AU7485398A (en) | 1997-05-14 | 1998-12-08 | Emory University | Antigen-mpeg conjugates suppress humoral and cell mediated immune responses |
| WO2000042175A1 (en) | 1999-01-14 | 2000-07-20 | Bolder Biotechnology Inc. | Methods for making proteins containing free cysteine residues |
| EP0933440B1 (en) | 1997-07-22 | 2003-02-05 | Nippon Steel Corporation | Case hardened steel excellent in the prevention of coarsening of particles during carburizing thereof, method of manufacturing the same, and raw shaped material for carburized parts |
| US5985263A (en) | 1997-12-19 | 1999-11-16 | Enzon, Inc. | Substantially pure histidine-linked protein polymer conjugates |
| US6358703B1 (en) | 1998-12-10 | 2002-03-19 | Bayer Corporation | Expression system for factor VIII |
| US6309633B1 (en) | 1999-06-19 | 2001-10-30 | Nobex Corporation | Amphiphilic drug-oligomer conjugates with hydroyzable lipophile components and methods for making and using the same |
| WO2001062827A2 (en) | 2000-02-22 | 2001-08-30 | Shearwater Corporation | N-maleimidyl polymer derivatives |
| NZ522847A (en) | 2000-05-16 | 2004-11-26 | Bolder Biotechnology Inc | Methods for refolding proteins containing free cysteine residues |
| KR100396983B1 (ko) | 2000-07-29 | 2003-09-02 | 이강춘 | 고반응성의 가지 달린 고분자 유도체 및 고분자와 단백질또는 펩타이드의 접합체 |
| TW593427B (en) * | 2000-12-18 | 2004-06-21 | Nektar Therapeutics Al Corp | Synthesis of high molecular weight non-peptidic polymer derivatives |
| MY137181A (en) * | 2001-05-21 | 2009-01-30 | Nektar Therapeutics | Pulmonary administration of chemically modified insulin |
| US6546159B1 (en) | 2001-08-22 | 2003-04-08 | Avanex Corporation | Method and apparatus for compensating differential group delay |
| ES2284959T3 (es) * | 2001-10-30 | 2007-11-16 | Nektar Therapeutics Al, Corporation | Conjugados polimericos solubles en agua de acido retinoico. |
| GEP20074193B (en) | 2002-09-09 | 2007-09-10 | Nektar Therapeutics Al Corp | Water-soluble polymer alkanals |
| KR100967334B1 (ko) | 2002-09-09 | 2010-07-05 | 넥타르 테라퓨틱스 | 말단 카르복실산을 가진 수용성 중합체 유도체의 제조 방법 |
| MXPA05007165A (es) | 2002-12-31 | 2005-09-21 | Nektar Therapeutics Al Corp | Reactivos polimericos que comprnden una cetona o un grupo funcional relacionado. |
| DE60322111D1 (de) * | 2002-12-31 | 2008-08-21 | Nektar Therapeutics Al Co | Verfahren zur herstellung von hydrogelen aus thiosulfonat-zusammensetzungen und ihre verwendungen |
| ATE485331T1 (de) | 2003-01-06 | 2010-11-15 | Nektar Therapeutics | Thiolselektive wasserlösliche polymerderivate |
| AU2004215912B2 (en) | 2003-02-26 | 2009-03-26 | Nektar Therapeutics | Polymer-factor VIII moiety conjugates |
| MXPA05010411A (es) | 2003-03-28 | 2006-05-31 | Biopolymed Inc | Material activo biologicamente conjugado con polimeros biocompatibles con el complejo 1:1, metodo de preparacion del mismo y composicion farmaceutica que lo contienen. |
| WO2004091499A2 (en) | 2003-04-09 | 2004-10-28 | Neose Technologies, Inc. | Intracellular formation of peptide conjugates |
| SG155777A1 (en) | 2003-04-09 | 2009-10-29 | Neose Technologies Inc | Glycopegylation methods and proteins/peptides produced by the methods |
| KR101128320B1 (ko) | 2003-05-23 | 2012-04-12 | 넥타르 테라퓨틱스 | 아미도카르보네이트 연결기를 갖는 peg 유도체 |
| KR102612902B1 (ko) | 2016-04-22 | 2023-12-18 | 삼성디스플레이 주식회사 | 투명 전도막 및 이를 포함하는 전자 소자 |
-
2004
- 2004-02-26 AU AU2004215912A patent/AU2004215912B2/en not_active Expired
- 2004-02-26 CN CNA2004800084228A patent/CN1767857A/zh active Pending
- 2004-02-26 CA CA2788505A patent/CA2788505C/en not_active Expired - Lifetime
- 2004-02-26 PT PT47151659T patent/PT1596887T/pt unknown
- 2004-02-26 KR KR1020057015960A patent/KR101085375B1/ko not_active Expired - Lifetime
- 2004-02-26 US US10/789,956 patent/US7199223B2/en active Active
- 2004-02-26 ES ES04715165T patent/ES2911435T3/es not_active Expired - Lifetime
- 2004-02-26 CN CN2010105418684A patent/CN102139114A/zh active Pending
- 2004-02-26 SI SI200432519T patent/SI1596887T1/sl unknown
- 2004-02-26 WO PCT/US2004/006034 patent/WO2004075923A2/en not_active Ceased
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- 2004-02-26 EP EP04715165.9A patent/EP1596887B1/en not_active Expired - Lifetime
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- 2004-02-26 EP EP12160605A patent/EP2572733A1/en not_active Withdrawn
- 2004-02-26 HU HUE04715165A patent/HUE058897T2/hu unknown
- 2004-02-26 DK DK04715165.9T patent/DK1596887T3/da active
- 2004-02-26 LT LTEPPCT/US2004/006034T patent/LT1596887T/lt unknown
- 2004-02-26 CA CA2517369A patent/CA2517369C/en not_active Expired - Lifetime
- 2004-02-26 EP EP11152599.4A patent/EP2338523B1/en not_active Expired - Lifetime
- 2004-02-26 EP EP12160604A patent/EP2572732A1/en not_active Withdrawn
- 2004-02-26 BR BRPI0407882-9A patent/BRPI0407882B1/pt not_active IP Right Cessation
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- 2005-08-22 IL IL170424A patent/IL170424A/en active IP Right Grant
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- 2007-02-05 US US11/702,302 patent/US7858749B2/en active Active
-
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- 2008-06-06 US US12/157,072 patent/US7863421B2/en not_active Expired - Lifetime
-
2009
- 2009-04-03 AU AU2009201308A patent/AU2009201308B2/en not_active Expired
- 2009-12-11 US US12/636,635 patent/US8143378B2/en not_active Expired - Lifetime
- 2009-12-11 US US12/636,469 patent/US8133977B2/en not_active Expired - Lifetime
- 2009-12-11 US US12/636,594 patent/US8247536B2/en not_active Expired - Lifetime
-
2011
- 2011-07-15 JP JP2011156978A patent/JP2012025747A/ja not_active Withdrawn
-
2012
- 2012-03-27 US US13/431,844 patent/US8889831B2/en not_active Expired - Lifetime
- 2012-03-27 US US13/431,862 patent/US8618259B2/en not_active Expired - Lifetime
- 2012-03-27 US US13/431,872 patent/US8519102B2/en not_active Expired - Fee Related
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2014
- 2014-10-17 US US14/517,679 patent/US20150038422A1/en not_active Abandoned
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2015
- 2015-12-09 US US14/964,416 patent/US9999657B2/en not_active Expired - Lifetime
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2018
- 2018-05-17 US US15/982,932 patent/US11141465B2/en not_active Expired - Fee Related
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2021
- 2021-09-09 US US17/470,811 patent/US20210401948A1/en not_active Abandoned
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2022
- 2022-06-09 CY CY20221100405T patent/CY1125235T1/el unknown
- 2022-07-01 NL NL301184C patent/NL301184I2/nl unknown
- 2022-08-11 FR FR22C1043C patent/FR22C1043I2/fr active Active
- 2022-09-05 BE BE2022C541C patent/BE2022C541I2/fr unknown
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