ATE232396T1 - Oxydiertes thymosin beta 4 - Google Patents

Oxydiertes thymosin beta 4

Info

Publication number: ATE232396T1
Authority: AT; Austria
Prior art keywords: oxidated; beta; thymosine beta; present; thymosine
Prior art date: 1998-03-28

Application number

AT99913428T

Other languages

English (en)

Inventor

Robert Duncan Stevenson

Anthony John Lawrence

John Young

Darryl John Cecil Pappin

Original Assignee

Univ Glasgow

Imp Cancer Res Technology Icrt

Robert Duncan Stevenson

Priority date (The priority date 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 date listed.)

1998-03-28

Filing date

1999-03-29

Publication date

2003-02-15

1999-03-29 Application filed by Univ Glasgow, Imp Cancer Res Technology Icrt, Robert Duncan Stevenson filed Critical Univ Glasgow

2003-02-15 Application granted granted Critical

2003-02-15 Publication of ATE232396T1 publication Critical patent/ATE232396T1/de

Links

UGPMCIBIHRSCBV-XNBOLLIBSA-N Thymosin beta 4 Chemical compound N([C@@H](CC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O)C(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(C)=O UGPMCIBIHRSCBV-XNBOLLIBSA-N 0.000 abstract 2
102100035000 Thymosin beta-4 Human genes 0.000 abstract 2
108010079996 thymosin beta(4) Proteins 0.000 abstract 2
206010040070 Septic Shock Diseases 0.000 abstract 1
201000010099 disease Diseases 0.000 abstract 1
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
230000028709 inflammatory response Effects 0.000 abstract 1
239000008194 pharmaceutical composition Substances 0.000 abstract 1
239000000546 pharmaceutical excipient Substances 0.000 abstract 1
230000036303 septic shock Effects 0.000 abstract 1
238000002560 therapeutic procedure Methods 0.000 abstract 1

Classifications

- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/67—General methods for enhancing the expression
- 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
- A61K38/22—Hormones
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- 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
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/57581—Thymosin; Related peptides
- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Chemical & Material Sciences (AREA)
Engineering & Computer Science (AREA)
Organic Chemistry (AREA)
Bioinformatics & Cheminformatics (AREA)
Genetics & Genomics (AREA)
General Health & Medical Sciences (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Veterinary Medicine (AREA)
Animal Behavior & Ethology (AREA)
Public Health (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Zoology (AREA)
Chemical Kinetics & Catalysis (AREA)
Biomedical Technology (AREA)
Wood Science & Technology (AREA)
General Engineering & Computer Science (AREA)
Biotechnology (AREA)
Molecular Biology (AREA)
Biochemistry (AREA)
Biophysics (AREA)
Immunology (AREA)
Plant Pathology (AREA)
Microbiology (AREA)
Physics & Mathematics (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Gastroenterology & Hepatology (AREA)
Endocrinology (AREA)
Rheumatology (AREA)
Toxicology (AREA)
Physical Education & Sports Medicine (AREA)
Dermatology (AREA)
Communicable Diseases (AREA)
Heart & Thoracic Surgery (AREA)
Hematology (AREA)
Orthopedic Medicine & Surgery (AREA)
Cardiology (AREA)

AT99913428T 1998-03-28 1999-03-29 Oxydiertes thymosin beta 4 ATE232396T1 (de)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
GBGB9806632.7A GB9806632D0 (en)	1998-03-28	1998-03-28	Peptide factor
PCT/GB1999/000833 WO1999049883A2 (en)	1998-03-28	1999-03-29	Oxidized thymosin beta 4

Publications (1)

Publication Number	Publication Date
ATE232396T1 true ATE232396T1 (de)	2003-02-15

Family

ID=10829414

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
AT99913428T ATE232396T1 (de)	1998-03-28	1999-03-29	Oxydiertes thymosin beta 4

Country Status (15)

Country	Link
US (3)	US6602519B1 (de)
EP (1)	EP1094833B1 (de)
JP (1)	JP2002509893A (de)
KR (1)	KR20010074461A (de)
CN (2)	CN1178695C (de)
AT (1)	ATE232396T1 (de)
AU (1)	AU766493B2 (de)
CA (1)	CA2325984A1 (de)
DE (1)	DE69905368T2 (de)
ES (1)	ES2192839T3 (de)
GB (1)	GB9806632D0 (de)
IL (1)	IL138665A0 (de)
NZ (1)	NZ507642A (de)
WO (1)	WO1999049883A2 (de)
ZA (1)	ZA200005196B (de)

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB9806632D0 (en) *	1998-03-28	1998-05-27	Stevenson Robert	Peptide factor
US20070015698A1 (en) *	1998-07-30	2007-01-18	United States Of America As Represented By The Secretary Of Health	Treatment of skin, and wound repair, with thymosin beta 4
US20060100156A1 (en) *	2004-10-01	2006-05-11	Regenerx Biopharmaceuticals, Inc.	Cell nucleus-entering compositions
EP1100529B2 (de) *	1998-07-30	2010-08-25	The Government of the United States of America, as repres. by the Secretary of Health and Human Services, Nat. Inst. of Health	Thymosin beta 4 stimuliert wundheilung
US20040067227A1 (en) *	2001-11-02	2004-04-08	Goldstein Allan L.	Inhibition or reversal of skin aging by actin-sequestering peptides
US20070191275A1 (en) *	1998-07-30	2007-08-16	Regenerx Biopharmaceuticals, Inc.	Method of treating, preventing, inhibiting or reducing damage to cardiac tissue with thymosin beta 4 fragments
EP1328289B1 (de) *	2000-10-20	2008-09-03	Hamburger Stiftung zur Förderung von Wissenschaft und Kultur	Oxidierte proteine und deren biologische und therapeutische aktivität sowie diagnostische verwendung über die hemmung der interaktion zwischen oxidierten proteinen und cd36
JP4224297B2 (ja)	2000-11-02	2009-02-12	リジェナークス・バイオファーマシューティカルズ・インコーポレイテッド	アクチン隔離ペプチドによる皮膚老化の阻害又は反転
JP2005506293A (ja) *	2001-03-15	2005-03-03	リジェナークス・バイオファーマスーティカルズ・インコーポレイテッド	サイモシンβ４（Ｔβ４）、類似体、アイソホーム、および他の誘導体を用いて眼および周辺組織の疾患を治療するための方法
CN101549148A (zh) *	2001-08-29	2009-10-07	雷根内克斯生物制药有限公司	多肽在制备用于促进心内膜细胞向间质细胞转化的药物中的应用
EP2266595A3 (de) *	2002-02-06	2011-07-06	Regenerx Biopharmaceuticals, Inc.	Behandlung von Infektionen und anderen Erkrankungen
AU2008201749B2 (en) *	2002-02-06	2010-05-13	Regenerx Biopharmaceuticals, Inc.	Treatment of Infections and Other Disorders
US20060264360A1 (en) *	2002-04-12	2006-11-23	Yale University Office Of Cooperstive Research	Anti-inflammatory and wound healing effects of lymphoid thymosin beta-4
US6821524B2 (en) *	2002-06-03	2004-11-23	Jan Marini Skin Research, Inc.	Cosmetic skin care compositions
AU2004229336B2 (en) *	2003-03-31	2008-12-04	Regenerx Biopharmaceuticals, Inc.	Compositions and methods for delivering thymosin beta 4, analogues, isoforms and other derivatives
WO2005027958A1 (en) *	2003-09-19	2005-03-31	Imperial College Innovations Ltd	Thymosin-beta-sulphoxide as an immunosuppressive active agent
CA2550833A1 (en) *	2003-12-22	2005-07-14	Regenerx Biopharmaceuticals, Inc.	Method of treating or preventing biological or immunological responses to a reactive chemical or biological or toxic agent
EP1720904A4 (de) *	2004-03-05	2007-08-22	Regenerx Biopharmaceuticals	Behandlung bzw. prävention des aufbaus einer extrazellulären matrix
WO2006076523A1 (en) *	2005-01-14	2006-07-20	Regenerx Biopharmaceuticals, Inc.	Modified beta thymosin peptides
KR20080018268A (ko)	2005-06-17	2008-02-27	리지너크스 바이오 파마소티컬스, 인코포레이티드	조직 악화, 부상 또는 손상을 치료하거나 또는 예방하기위한 엘케이케이티이티 및/또는 엘케이케이티엔티 조성물들및 그 방법
EP1913013A2 (de) *	2005-07-19	2008-04-23	Grannus Biosciences	Gekürztes oxidiertes thymosin-beta4 und derivate davon
ES2288118B1 (es) *	2006-05-10	2008-11-01	Bcn Peptides, S.A.	Procedimiento para sintetizar timosinas.
CN101297965B (zh) *	2008-06-16	2011-01-05	浙江省中医药研究院	胸腺肽β4在制备防治支气管哮喘药物中的应用
US20100247693A1 (en) *	2009-03-24	2010-09-30	Marini Jan L	Cosmetic formulation to treat rosacea telangiectasia
US8580742B2 (en) *	2010-03-05	2013-11-12	N.V. Perricone Llc	Topical glutathione formulations for menopausal skin
US8609604B2 (en)	2009-12-28	2013-12-17	N.V. Perricone Llc	Methods of improving the appearance of aging skin
US20110160144A1 (en) *	2009-12-28	2011-06-30	Perricone Nicholas V	Topical Acyl Glutathione Formulations
JP5847418B2 (ja)	2011-03-30	2016-01-20	富士フイルム株式会社	細胞接着性タンパク質
US9808654B2 (en)	2013-02-11	2017-11-07	Jan Marini Skin Research	Post procedure skin care gel and methods of use thereof
CN110215513B (zh) *	2018-11-15	2022-02-22	北京诺思兰德生物技术股份有限公司	经修饰的胸腺素β4在治疗放射性肠炎方面的用途

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US388234A (en) *		1888-08-21		Car-brake
US3998798A (en) *	1972-12-22	1976-12-21	The Trustees Of The University Of Pennsylvania	Monellin, a sweet polypeptide derived from fruit of dioscoreophyllum cumminsii
US4297276A (en) *	1979-03-23	1981-10-27	Hoffman-La Roche Inc.	Thymosin beta 3 and beta 4
US4389343A (en) *	1981-12-24	1983-06-21	Hoffmann-La Roche Inc.	Immunopotentiating peptides from thymus
US4388234A (en)	1981-12-28	1983-06-14	Hoffmann-La Roche Inc.	Peptide isolation
US4572798A (en) *	1984-12-06	1986-02-25	Cetus Corporation	Method for promoting disulfide bond formation in recombinant proteins
US5578570A (en) *	1993-10-07	1996-11-26	The George Washington University Medical Center	Method of treating septic shock using thymosin β4
US5593964A (en) *	1993-10-07	1997-01-14	The George Washington University Medical Center	Method of treating septic shock by preventing actin polymerization
US5468729A (en) *	1993-10-26	1995-11-21	Alpha 1 Biomedicals	Method for treatment of autoimmune hepatitis
GB9806632D0 (en) *	1998-03-28	1998-05-27	Stevenson Robert	Peptide factor

1998
- 1998-03-28 GB GBGB9806632.7A patent/GB9806632D0/en not_active Ceased
1999
- 1999-03-29 JP JP2000540846A patent/JP2002509893A/ja active Pending
- 1999-03-29 CA CA002325984A patent/CA2325984A1/en not_active Abandoned
- 1999-03-29 CN CNB998059579A patent/CN1178695C/zh not_active Expired - Fee Related
- 1999-03-29 IL IL13866599A patent/IL138665A0/xx not_active IP Right Cessation
- 1999-03-29 EP EP99913428A patent/EP1094833B1/de not_active Expired - Lifetime
- 1999-03-29 AT AT99913428T patent/ATE232396T1/de not_active IP Right Cessation
- 1999-03-29 AU AU31553/99A patent/AU766493B2/en not_active Ceased
- 1999-03-29 NZ NZ507642A patent/NZ507642A/en unknown
- 1999-03-29 KR KR1020007010794A patent/KR20010074461A/ko not_active Withdrawn
- 1999-03-29 US US09/647,117 patent/US6602519B1/en not_active Expired - Fee Related
- 1999-03-29 WO PCT/GB1999/000833 patent/WO1999049883A2/en not_active Ceased
- 1999-03-29 CN CNA2004100879091A patent/CN1644586A/zh active Pending
- 1999-03-29 ES ES99913428T patent/ES2192839T3/es not_active Expired - Lifetime
- 1999-03-29 DE DE69905368T patent/DE69905368T2/de not_active Expired - Fee Related
2000
- 2000-09-27 ZA ZA200005196A patent/ZA200005196B/en unknown
2003
- 2003-01-09 US US10/339,271 patent/US20040213772A1/en not_active Abandoned
2006
- 2006-06-14 US US11/452,738 patent/US20060229234A1/en not_active Abandoned

Also Published As

Publication number	Publication date
KR20010074461A (ko)	2001-08-04
CN1308543A (zh)	2001-08-15
US6602519B1 (en)	2003-08-05
JP2002509893A (ja)	2002-04-02
IL138665A0 (en)	2001-10-31
DE69905368D1 (en)	2003-03-20
EP1094833A2 (de)	2001-05-02
CN1178695C (zh)	2004-12-08
NZ507642A (en)	2003-10-31
WO1999049883A2 (en)	1999-10-07
CN1644586A (zh)	2005-07-27
GB9806632D0 (en)	1998-05-27
WO1999049883A3 (en)	2001-02-22
US20040213772A1 (en)	2004-10-28
DE69905368T2 (de)	2003-12-18
CA2325984A1 (en)	1999-10-07
AU3155399A (en)	1999-10-18
US20060229234A1 (en)	2006-10-12
AU766493B2 (en)	2003-10-16
EP1094833B1 (de)	2003-02-12
ES2192839T3 (es)	2003-10-16
ZA200005196B (en)	2002-01-02

Legal Events

Date

Code

Title

Description

2003-09-15

UEP

Publication of translation of european patent specification

Ref document number: 1094833

Country of ref document: EP

2008-12-15

REN

Ceased due to non-payment of the annual fee

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