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DK1029921T3 - Serpinresistent t-PA, mutanter, gener - Google Patents

Serpinresistent t-PA, mutanter, gener

Info

Publication number
DK1029921T3
DK1029921T3 DK00109138T DK00109138T DK1029921T3 DK 1029921 T3 DK1029921 T3 DK 1029921T3 DK 00109138 T DK00109138 T DK 00109138T DK 00109138 T DK00109138 T DK 00109138T DK 1029921 T3 DK1029921 T3 DK 1029921T3
Authority
DK
Denmark
Prior art keywords
mutants
genes
serine protease
resistant
serpin
Prior art date
Application number
DK00109138T
Other languages
Danish (da)
English (en)
Inventor
Joseph F Sambrook
Edwin L Madison
Elizabeth J Goldsmith
Maryjane H Gething
Robert D Gerard
Original Assignee
Univ Texas
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.)
Filing date
Publication date
Priority claimed from US07/434,748 external-priority patent/US5550042A/en
Application filed by Univ Texas filed Critical Univ Texas
Application granted granted Critical
Publication of DK1029921T3 publication Critical patent/DK1029921T3/da

Links

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
    • 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)
    • C12N9/6456—Plasminogen activators
    • C12N9/6459—Plasminogen activators t-plasminogen activator (3.4.21.68), i.e. tPA
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
    • C07K14/8121—Serpins
    • C07K14/8132—Plasminogen activator inhibitors
    • 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
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/102—Mutagenizing nucleic acids
    • 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
    • C12N15/70—Vectors or expression systems specially adapted for E. coli
    • C12N15/71—Expression systems using regulatory sequences derived from the trp-operon
    • 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
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • 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)
    • 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)
    • C12N9/6427—Chymotrypsins (3.4.21.1; 3.4.21.2); Trypsin (3.4.21.4)
    • 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)
    • C12Y304/21069—Protein C activated (3.4.21.69)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing 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
    • C12N2800/00—Nucleic acids vectors
    • C12N2800/10—Plasmid DNA
    • C12N2800/108—Plasmid DNA episomal vectors
    • 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
    • C12N2830/00—Vector systems having a special element relevant for transcription
    • 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
    • C12N2830/00—Vector systems having a special element relevant for transcription
    • C12N2830/55—Vector systems having a special element relevant for transcription from bacteria
    • 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)
    • C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Biomedical Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • Plant Pathology (AREA)
  • Physics & Mathematics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Hematology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
DK00109138T 1989-03-06 1990-03-01 Serpinresistent t-PA, mutanter, gener DK1029921T3 (da)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US31921289A 1989-03-06 1989-03-06
US07/434,748 US5550042A (en) 1989-03-06 1989-11-13 Serine protease mutants of the chymotrypsin superfamily resistant to inhibition by their cognate inhibitors and genes encoding the same and serine protease inhibitor mutants and genes encoding the same
PCT/US1990/000947 WO1990010649A1 (fr) 1989-03-06 1990-03-01 Proteases de la superfamille de la chymotrypsine resistantes a la serine, notamment resistantes a pai-1 et a +-pa, mutants inhibiteurs complementaires; compositions; genes; expression

Publications (1)

Publication Number Publication Date
DK1029921T3 true DK1029921T3 (da) 2003-02-24

Family

ID=23241316

Family Applications (2)

Application Number Title Priority Date Filing Date
DK00109138T DK1029921T3 (da) 1989-03-06 1990-03-01 Serpinresistent t-PA, mutanter, gener
DK90905081T DK0462207T3 (da) 1989-03-06 1990-03-01 t-Pa mutanter resistente mod deres respektive inhibitorer

Family Applications After (1)

Application Number Title Priority Date Filing Date
DK90905081T DK0462207T3 (da) 1989-03-06 1990-03-01 t-Pa mutanter resistente mod deres respektive inhibitorer

Country Status (10)

Country Link
US (1) US5728564A (fr)
EP (2) EP0462207B1 (fr)
JP (3) JP2991769B2 (fr)
AT (2) ATE226636T1 (fr)
AU (1) AU637791B2 (fr)
CA (1) CA2047702C (fr)
DE (2) DE69034013T2 (fr)
DK (2) DK1029921T3 (fr)
ES (2) ES2154629T3 (fr)
WO (1) WO1990010649A1 (fr)

Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5714145A (en) * 1988-09-02 1998-02-03 Genentech, Inc. Tissue plasminogen activator having zymogenic or fibrin specific properties
US5262170A (en) * 1988-09-02 1993-11-16 Genentech, Inc. Tissue plasminogen activator having zymogenic or fibrin specific properties and substituted at amino acid positions 296-299, DNA molecules encoding them, vectors, and host cells
US5866413A (en) * 1989-03-06 1999-02-02 Board Of Regents Of The University Of Texas System Pai-1 mutants
US5358932A (en) * 1989-12-29 1994-10-25 Zymogenetics, Inc. Hybrid protein C
WO1991009960A1 (fr) * 1989-12-29 1991-07-11 Zymogenetics, Inc. Proteine c hybride
GB9011861D0 (en) * 1990-05-26 1990-07-18 Beecham Group Plc Novel compounds
DE69105213T2 (de) * 1990-12-18 1995-05-18 Genentech, Inc., South San Francisco, Calif. Substitutionsvariante des gewebeplasminogenaktivators.
EP0786257B1 (fr) * 1992-06-03 2003-07-30 Genentech, Inc. Variantes d'activateur de plasminogène tissulaire obtenues par glycosylation, presentant de meilleures propriétés thérapeutiques
GB9216558D0 (en) * 1992-08-04 1992-09-16 British Bio Technology Modified proteases
US5567602A (en) * 1992-08-12 1996-10-22 Arris Pharmaceutical Corporation Recombinant production of chymase
ES2080657B1 (es) * 1993-09-27 1996-11-01 Britisch Bio Technology Limite Proteasas modificadas.
EP0958833A1 (fr) * 1998-05-20 1999-11-24 Erasmus Universiteit Rotterdam Procédé et moyens pour la prévention ou le traitement de l'inflammation
AUPP508798A0 (en) 1998-08-05 1998-08-27 Biotech Australia Pty Limited Method of treating psoriasis
WO2001066771A2 (fr) * 2000-03-03 2001-09-13 Zymogenetics, Inc. Serine-protease humaine
US6673623B1 (en) 2000-09-12 2004-01-06 Novocure, Inc. Methods and compositions that control lipid production
WO2002072786A2 (fr) 2001-03-13 2002-09-19 Corvas International, Inc. Molecules d'acides nucleiques codant pour une serine protease transmembranaire 7, polypeptides codes et procedes associes
CA2441378A1 (fr) 2001-03-22 2002-10-03 Dendreon San Diego Llc Molecules d'acide nucleique codant la serine protease cvsp14, polypeptides codes et procedes
US7105333B2 (en) 2001-03-27 2006-09-12 Deadreon Corporation Nucleic acid molecules encoding a transmembrane serine protease 9, the encoded polypeptides and methods based thereon
JP2005506832A (ja) 2001-05-14 2005-03-10 デンドレオン・サンディエゴ・リミテッド・ライアビリティ・カンパニー トランスメンブランセリンプロテアーゼ１０をコードする核酸分子、コードされるポリペプチドおよびそれに基づく方法
US7001872B2 (en) * 2001-06-11 2006-02-21 Halliburton Energy Services, Inc. Subterranean formation treating fluid and methods of fracturing subterranean formations
US6488091B1 (en) * 2001-06-11 2002-12-03 Halliburton Energy Services, Inc. Subterranean formation treating fluid concentrates, treating fluids and methods
US20050137094A1 (en) * 2001-06-11 2005-06-23 Halliburton Energy Sevices, Inc. Subterranean formation treatment fluids and methods of using such fluids
US20030134298A1 (en) * 2001-07-03 2003-07-17 Madison Edwin L. Nucleic acid molecules encoding a transmembrane serine protease 20, the encoded polypeptides and methods based thereon
US7264953B2 (en) * 2001-07-18 2007-09-04 American National Red Cross Mutant proteinase-inhibitors and uses thereof
RU2247777C2 (ru) * 2001-07-27 2005-03-10 Общество с ограниченной ответственностью "Научно-производственное предприятие "Техноген" Модифицированный активатор плазминогена урокиназного типа, последовательность днк, рекомбинантная плазмида, штамм-продуцент, способ получения модифицированного активатора плазминогена урокиназного типа и фармацевтическая композиция, обладающая тромболитическим действием
WO2003044179A2 (fr) * 2001-11-20 2003-05-30 Dendreon San Diego Llc Molecules d'acide nucleique codant la serine protease 17, polypeptides codes et methodes correspondantes
US20040001801A1 (en) * 2002-05-23 2004-01-01 Corvas International, Inc. Conjugates activated by cell surface proteases and therapeutic uses thereof
CN1798838B (zh) 2003-04-04 2012-01-04 洛桑大学 一种蛋白酶的抑制剂蛋白及其用途
DK2046951T5 (da) 2006-07-05 2012-01-23 Catalyst Biosciences Inc Proteasesreeningsmetoder og proteaser identificeret dermed
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
CN112375131B (zh) * 2020-11-16 2021-10-01 西南大学 Seroin蛋白的截短体及其应用

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5112755A (en) * 1982-04-15 1992-05-12 Genentech, Inc. Preparation of functional human urokinase proteins
IL68561A (en) * 1982-05-05 1991-01-31 Genentech Inc Preparation of polypeptide with human tissue plasminogen activator function,processes for making it,and dna and transformed cell intermediates thereof
AU560584B2 (en) * 1983-07-28 1987-04-09 Bayer Aktiengesellschaft Homologues of aprotinin
US5073494A (en) * 1985-04-22 1991-12-17 Genentech, Inc. Human tissue plasminogen activator substituted at position 275 or at positions 275 and 277
JPH084501B2 (ja) * 1987-03-20 1996-01-24 エーザイ株式会社 糖鎖に関する変異ｔＰＡ
MY103358A (en) * 1987-04-15 1993-06-30 Novartis Ag Process for the production of protiens.
DK275788A (da) * 1987-05-22 1989-02-03 Zymogenetics Inc Fibrinolytiske proteiner
US5200340A (en) * 1987-05-22 1993-04-06 Zymogenetics, Inc. Thrombin-activated tissue plasminogen activators
GB2208511A (en) * 1987-08-07 1989-04-05 Bayer Ag Variants of bovine pancreatic trypsin inhibitor produced by recombinant dna technology
WO1989001513A1 (fr) * 1987-08-19 1989-02-23 Sagami Chemical Research Center Prourokinase a action rapide
WO1989007146A1 (fr) * 1988-02-05 1989-08-10 Integrated Genetics, Inc. Activateurs de plasminogenes tissulaires redisposes et procede de production de tels activateurs
WO1989007145A1 (fr) * 1988-02-05 1989-08-10 Integrated Genetics, Inc. Sequences de genes modifiees codant pour des activateurs de plasminogenes tissulaires modifies et molecules ainsi produites
US5108901A (en) * 1988-09-02 1992-04-28 Genentech, Inc. Tissue plasminogen activator having zymogenic or fibrin specific properties
US5262170A (en) * 1988-09-02 1993-11-16 Genentech, Inc. Tissue plasminogen activator having zymogenic or fibrin specific properties and substituted at amino acid positions 296-299, DNA molecules encoding them, vectors, and host cells

Also Published As

Publication number Publication date
JP2991769B2 (ja) 1999-12-20
EP0462207A4 (en) 1992-06-24
WO1990010649A1 (fr) 1990-09-20
JP2000078990A (ja) 2000-03-21
CA2047702A1 (fr) 1990-09-07
JPH04504952A (ja) 1992-09-03
DE69034013T2 (de) 2003-07-31
JP2000037195A (ja) 2000-02-08
ES2154629T3 (es) 2001-04-16
DE69033699T2 (de) 2001-05-23
JP3076035B2 (ja) 2000-08-14
EP0462207A1 (fr) 1991-12-27
DK0462207T3 (da) 2001-06-18
DE69034013D1 (de) 2002-11-28
JP3076034B2 (ja) 2000-08-14
US5728564A (en) 1998-03-17
ES2185529T3 (es) 2003-05-01
EP0462207B1 (fr) 2001-02-07
ATE199090T1 (de) 2001-02-15
EP1029921A1 (fr) 2000-08-23
AU5278090A (en) 1990-10-09
EP1029921B1 (fr) 2002-10-23
AU637791B2 (en) 1993-06-10
ATE226636T1 (de) 2002-11-15
DE69033699D1 (de) 2001-03-15
CA2047702C (fr) 2000-10-24

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