HUE039906T2 - Alacsony fokú vízben oldható polimer tartalmú módosított vérfaktorok - Google Patents
Alacsony fokú vízben oldható polimer tartalmú módosított vérfaktorokInfo
- Publication number
- HUE039906T2 HUE039906T2 HUE09752930A HUE09752930A HUE039906T2 HU E039906 T2 HUE039906 T2 HU E039906T2 HU E09752930 A HUE09752930 A HU E09752930A HU E09752930 A HUE09752930 A HU E09752930A HU E039906 T2 HUE039906 T2 HU E039906T2
- Authority
- HU
- Hungary
- Prior art keywords
- water soluble
- soluble polymer
- low water
- polymer content
- blood factors
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- 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
- 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
- A61K47/54—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 compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- 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
- 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
- A61K47/56—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
- A61K47/61—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 the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- 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
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
- A61K38/37—Factors VIII
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- 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
- 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
- A61K47/56—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
- 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
-
- 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
-
- 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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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)
-
- 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)
- C12Y304/21022—Coagulation factor IXa (3.4.21.22)
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10642408P | 2008-10-17 | 2008-10-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HUE039906T2 true HUE039906T2 (hu) | 2019-02-28 |
Family
ID=41650072
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HUE09752930A HUE039906T2 (hu) | 2008-10-17 | 2009-10-16 | Alacsony fokú vízben oldható polimer tartalmú módosított vérfaktorok |
Country Status (20)
| Country | Link |
|---|---|
| US (4) | US20100099616A1 (enExample) |
| EP (3) | EP3437661A1 (enExample) |
| JP (2) | JP5785872B2 (enExample) |
| KR (2) | KR101929641B1 (enExample) |
| AU (1) | AU2009305612B2 (enExample) |
| BR (1) | BRPI0920259A8 (enExample) |
| CA (1) | CA2738679A1 (enExample) |
| CY (1) | CY1120921T1 (enExample) |
| DK (1) | DK2349342T3 (enExample) |
| ES (1) | ES2692172T3 (enExample) |
| HR (1) | HRP20181454T1 (enExample) |
| HU (1) | HUE039906T2 (enExample) |
| LT (1) | LT2349342T (enExample) |
| MX (1) | MX2011004085A (enExample) |
| NZ (1) | NZ592688A (enExample) |
| PL (1) | PL2349342T3 (enExample) |
| PT (1) | PT2349342T (enExample) |
| SI (1) | SI2349342T1 (enExample) |
| SM (1) | SMT201800486T1 (enExample) |
| WO (1) | WO2010045568A1 (enExample) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2744370C2 (ru) | 2009-07-27 | 2021-03-05 | Баксалта Инкорпорейтед | Конъюгаты белков свертывания крови |
| JP5914363B2 (ja) | 2010-02-16 | 2016-05-11 | ノヴォ ノルディスク アー／エス | 低減されたｖｗｆ結合を有する因子ｖｉｉｉ分子 |
| GB201007356D0 (en) | 2010-04-30 | 2010-06-16 | Leverton Licence Holdings Ltd | Conjugated factor VIIa |
| US20130183280A1 (en) * | 2010-07-15 | 2013-07-18 | Novo Nordisk A/S | Stabilized factor viii variants |
| MY167234A (en) | 2011-09-23 | 2018-08-14 | Novo Nordisk As | Novel glucagon analogues |
| GB201910190D0 (en) * | 2012-04-16 | 2019-08-28 | Cantab Biopharmaceuticals Patents Ltd | Optimised subsutaneous therapeutic agents |
| MY174727A (en) | 2013-04-18 | 2020-05-11 | Novo Nordisk As | Stable, protracted glp-1/glucagon receptor co-agonists for medical use |
| US10570184B2 (en) | 2014-06-04 | 2020-02-25 | Novo Nordisk A/S | GLP-1/glucagon receptor co-agonists for medical use |
| JP6516829B2 (ja) | 2014-08-04 | 2019-05-22 | シーエスエル、リミテッド | 第ｖｉｉｉ因子製剤 |
| CA2978374A1 (en) | 2015-03-06 | 2016-09-15 | Csl Behring Recombinant Facility Ag | Modified von willebrand factor having improved half-life |
| JP6552286B2 (ja) * | 2015-06-05 | 2019-07-31 | 公立大学法人奈良県立医科大学 | 凝固第ｖｉｉｉ因子の複合体形成能に関する情報の取得方法および試薬キット |
| KR20220029733A (ko) | 2019-07-04 | 2022-03-08 | 체에스엘 베링 렝나우 아게 | 응고 인자 viii의 시험관내 안정성을 증가시키기 위한 절단된 폰 빌레브란트 인자 (vwf) |
| EP4058049A1 (en) | 2019-11-11 | 2022-09-21 | CSL Behring Lengnau AG | Polypeptides for inducing tolerance to factor viii |
Family Cites Families (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4179337A (en) * | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
| US4757006A (en) * | 1983-10-28 | 1988-07-12 | Genetics Institute, Inc. | Human factor VIII:C gene and recombinant methods for production |
| US4970300A (en) * | 1985-02-01 | 1990-11-13 | New York University | Modified factor VIII |
| US6048729A (en) | 1987-05-01 | 2000-04-11 | Transkaryotic Therapies, Inc. | In vivo protein production and delivery system for gene therapy |
| US5122614A (en) * | 1989-04-19 | 1992-06-16 | Enzon, Inc. | Active carbonates of polyalkylene oxides for modification of polypeptides |
| US5252714A (en) | 1990-11-28 | 1993-10-12 | The University Of Alabama In Huntsville | Preparation and use of polyethylene glycol propionaldehyde |
| US6063630A (en) | 1991-11-05 | 2000-05-16 | Transkaryotic Therapies, Inc. | Targeted introduction of DNA into primary or secondary cells and their use for gene therapy |
| US6037452A (en) | 1992-04-10 | 2000-03-14 | Alpha Therapeutic Corporation | Poly(alkylene oxide)-Factor VIII or Factor IX conjugate |
| 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 |
| US5621039A (en) * | 1993-06-08 | 1997-04-15 | Hallahan; Terrence W. | Factor IX- polymeric conjugates |
| US5824784A (en) | 1994-10-12 | 1998-10-20 | Amgen Inc. | N-terminally chemically modified protein compositions and methods |
| US6238908B1 (en) | 1995-06-07 | 2001-05-29 | Aastrom Biosciences, Inc. | Apparatus and method for maintaining and growth biological cells |
| US7074878B1 (en) | 1999-12-10 | 2006-07-11 | Harris J Milton | Hydrolytically degradable polymers and hydrogels made therefrom |
| US20030211094A1 (en) * | 2001-06-26 | 2003-11-13 | Nelsestuen Gary L. | High molecular weight derivatives of vitamin k-dependent polypeptides |
| BR0311978A (pt) * | 2002-06-21 | 2005-03-22 | Novo Nordisk Healthcare Ag | Preparação, método para preparar a mesma, formulação farmacêutica, métodos para tratar de uma sìndrome responsiva ao fator vii, para prevenir hemorragias indesejáveis, para prevenir coagulação sanguìnea indesejável e para prevenir as reações mediadas pelo fator tecidual, e, uso de uma preparação |
| MXPA05006688A (es) | 2002-12-19 | 2006-02-22 | Nektar Therapeutics Al Corp | Conjugados de polimero con una variante de cianovirina. |
| WO2004075923A2 (en) * | 2003-02-26 | 2004-09-10 | Nektar Therapeutics Al, Corporation | Polymer-factor viii moiety conjugates |
| JP2006523211A (ja) * | 2003-03-14 | 2006-10-12 | ネオス テクノロジーズ インコーポレイテッド | 分岐水溶性ポリマーとその複合物 |
| WO2006127896A2 (en) * | 2005-05-25 | 2006-11-30 | Neose Technologies, Inc. | Glycopegylated factor ix |
| CA2571292C (en) * | 2004-06-30 | 2013-05-21 | Nektar Therapeutics Al, Corporation | Polymer-factor ix moiety conjugates |
| KR101468345B1 (ko) * | 2004-11-12 | 2014-12-03 | 바이엘 헬스케어 엘엘씨 | Ｆｖｉｉｉ의 부위 지향 변형 |
| BRPI0519562A2 (pt) | 2004-12-27 | 2009-01-27 | Baxter Int | construÇço proteinÁcea, complexo, mÉtodo para prolongar a meia-vida in vivo de fator viii (fviii) ou um derivado biologicamente ativo do mesmo composiÇço farmacÊutica, e, mÉtodo para formar uma construÇço proteinÁcea |
| US20080188400A1 (en) * | 2005-04-26 | 2008-08-07 | Maxygen Holdings Ltd. | Methods For Treating Bleeding |
| US7645860B2 (en) * | 2006-03-31 | 2010-01-12 | Baxter Healthcare S.A. | Factor VIII polymer conjugates |
| KR20080108147A (ko) | 2006-03-31 | 2008-12-11 | 백스터 인터내셔널 인코포레이티드 | 페질화된 인자 ｖｉｉｉ |
| AU2007333049B2 (en) * | 2006-12-15 | 2014-02-20 | Takeda Pharmaceutical Company Limited | Factor VIIa-(poly)sialic acid conjugate having prolonged in vivo half-life |
| MX2009007145A (es) | 2006-12-27 | 2009-08-27 | Nektar Therapeutics Al Corp | Conjugados de polimero con factor viii y factor de von willebrand que tienen una ligadura liberable. |
-
2009
- 2009-10-16 JP JP2011532289A patent/JP5785872B2/ja active Active
- 2009-10-16 KR KR1020167022913A patent/KR101929641B1/ko active Active
- 2009-10-16 SM SM20180486T patent/SMT201800486T1/it unknown
- 2009-10-16 PT PT09752930T patent/PT2349342T/pt unknown
- 2009-10-16 ES ES09752930.9T patent/ES2692172T3/es active Active
- 2009-10-16 HR HRP20181454TT patent/HRP20181454T1/hr unknown
- 2009-10-16 EP EP18179965.1A patent/EP3437661A1/en not_active Withdrawn
- 2009-10-16 EP EP19189998.8A patent/EP3620177A1/en not_active Withdrawn
- 2009-10-16 NZ NZ592688A patent/NZ592688A/xx unknown
- 2009-10-16 SI SI200931874T patent/SI2349342T1/sl unknown
- 2009-10-16 DK DK09752930.9T patent/DK2349342T3/en active
- 2009-10-16 MX MX2011004085A patent/MX2011004085A/es active IP Right Grant
- 2009-10-16 WO PCT/US2009/061023 patent/WO2010045568A1/en not_active Ceased
- 2009-10-16 AU AU2009305612A patent/AU2009305612B2/en active Active
- 2009-10-16 PL PL09752930T patent/PL2349342T3/pl unknown
- 2009-10-16 LT LTEP09752930.9T patent/LT2349342T/lt unknown
- 2009-10-16 CA CA2738679A patent/CA2738679A1/en not_active Abandoned
- 2009-10-16 EP EP09752930.9A patent/EP2349342B1/en active Active
- 2009-10-16 US US12/580,786 patent/US20100099616A1/en not_active Abandoned
- 2009-10-16 HU HUE09752930A patent/HUE039906T2/hu unknown
- 2009-10-16 BR BRPI0920259A patent/BRPI0920259A8/pt not_active Application Discontinuation
- 2009-10-16 KR KR1020117011049A patent/KR20110071012A/ko not_active Ceased
-
2011
- 2011-09-23 US US13/242,934 patent/US20120076749A1/en not_active Abandoned
-
2015
- 2015-03-20 JP JP2015057790A patent/JP2015110676A/ja active Pending
-
2016
- 2016-01-08 US US14/991,172 patent/US20160199503A1/en not_active Abandoned
-
2018
- 2018-09-24 CY CY181100982T patent/CY1120921T1/el unknown
- 2018-10-30 US US16/175,744 patent/US20190160178A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU2009305612A1 (en) | 2010-04-22 |
| KR20160103173A (ko) | 2016-08-31 |
| ES2692172T3 (es) | 2018-11-30 |
| PT2349342T (pt) | 2018-10-26 |
| CA2738679A1 (en) | 2010-04-22 |
| HRP20181454T1 (hr) | 2018-12-14 |
| EP2349342B1 (en) | 2018-06-27 |
| KR20110071012A (ko) | 2011-06-27 |
| SMT201800486T1 (it) | 2018-11-09 |
| EP2349342A1 (en) | 2011-08-03 |
| US20120076749A1 (en) | 2012-03-29 |
| BRPI0920259A8 (pt) | 2017-09-19 |
| KR101929641B1 (ko) | 2018-12-14 |
| US20160199503A1 (en) | 2016-07-14 |
| WO2010045568A1 (en) | 2010-04-22 |
| EP3437661A1 (en) | 2019-02-06 |
| JP2012505917A (ja) | 2012-03-08 |
| EP3620177A1 (en) | 2020-03-11 |
| MX2011004085A (es) | 2011-09-27 |
| NZ592688A (en) | 2012-12-21 |
| DK2349342T3 (en) | 2018-10-08 |
| BRPI0920259A2 (pt) | 2016-01-05 |
| PL2349342T3 (pl) | 2019-01-31 |
| LT2349342T (lt) | 2018-10-10 |
| JP5785872B2 (ja) | 2015-09-30 |
| US20190160178A1 (en) | 2019-05-30 |
| AU2009305612B2 (en) | 2015-05-21 |
| SI2349342T1 (sl) | 2018-10-30 |
| CY1120921T1 (el) | 2019-12-11 |
| US20100099616A1 (en) | 2010-04-22 |
| JP2015110676A (ja) | 2015-06-18 |
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