YU45533B - Process for obtaining polypeptides of the ifn-alpha type - Google Patents

Process for obtaining polypeptides of the ifn-alpha type

Info

Publication number
YU45533B
YU45533B YU26/81A YU2681A YU45533B YU 45533 B YU45533 B YU 45533B YU 26/81 A YU26/81 A YU 26/81A YU 2681 A YU2681 A YU 2681A YU 45533 B YU45533 B YU 45533B
Authority
YU
Yugoslavia
Prior art keywords
ifn
alpha type
obtaining polypeptides
polypeptides
obtaining
Prior art date
Application number
YU26/81A
Other languages
English (en)
Other versions
YU2681A (en
Inventor
C Weissmann
Original Assignee
Biogen Nv
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27224760&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=YU45533(B) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to SI8110026A priority Critical patent/SI8110026A8/xx
Application filed by Biogen Nv filed Critical Biogen Nv
Publication of YU2681A publication Critical patent/YU2681A/xx
Publication of YU45533B publication Critical patent/YU45533B/xx
Priority to HRP940047 priority patent/HRP940047A2/xx
Priority to BA960096D priority patent/BA96096B1/bs

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00—Preparation of peptides or proteins
    • C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
    • 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
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/555—Interferons [IFN]
    • C07K14/56—IFN-alpha
    • 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
    • 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
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/811—Interferon
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/832—Bacillus
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/832—Bacillus
    • Y10S435/839—Bacillus subtilis
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/848—Escherichia
    • Y10S435/849—Escherichia coli

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Physics & Mathematics (AREA)
  • Plant Pathology (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
YU26/81A 1980-01-08 1981-01-18 Process for obtaining polypeptides of the ifn-alpha type YU45533B (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
SI8110026A SI8110026A8 (en) 1980-01-08 1981-01-08 PROCESS FOR PREPARING OF IFN-alfa-type POLIPEPTIDES.
HRP940047 HRP940047A2 (en) 1980-01-08 1994-01-27 Process for the preparation of alpha-type polypeptides
BA960096D BA96096B1 (bs) 1980-01-08 1996-03-03 Postupak za dobivanje polipeptida ifn - tipa

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP80300079 1980-01-08
EP80301100 1980-04-03
GB8031737 1980-10-02

Publications (2)

Publication Number Publication Date
YU2681A YU2681A (en) 1983-12-31
YU45533B true YU45533B (en) 1992-05-28

Family

ID=27224760

Family Applications (1)

Application Number Title Priority Date Filing Date
YU26/81A YU45533B (en) 1980-01-08 1981-01-18 Process for obtaining polypeptides of the ifn-alpha type

Country Status (22)

Country Link
EP (1) EP0032134B2 (show.php)
JP (1) JP2501889B2 (show.php)
AU (1) AU553400B2 (show.php)
CA (1) CA1341567C (show.php)
CY (1) CY1346A (show.php)
DD (2) DD159782A5 (show.php)
DE (1) DE3165463D1 (show.php)
DK (2) DK170236B1 (show.php)
ES (2) ES8308534A1 (show.php)
FI (1) FI86558C (show.php)
GR (1) GR73557B (show.php)
HU (1) HU194305B (show.php)
IE (1) IE54096B1 (show.php)
MY (1) MY8700559A (show.php)
NO (2) NO164037C (show.php)
NZ (1) NZ195980A (show.php)
OA (1) OA06717A (show.php)
PH (1) PH21848A (show.php)
PL (1) PL148434B1 (show.php)
PT (1) PT72322B (show.php)
SG (1) SG77286G (show.php)
YU (1) YU45533B (show.php)

Families Citing this family (66)

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FI77877C (fi) * 1979-04-20 1989-05-10 Technobiotic Ltd Foerfarande foer framstaellning och rening av human le-formig interferonprotein.
DE3005897A1 (de) * 1980-02-16 1981-09-03 Hoechst Ag, 6000 Frankfurt Genprodukt eines hoeheren organismus aus einem dieses gen enhtaltenden mikroorganismus
DE3005843A1 (de) * 1980-02-16 1981-09-10 Hoechst Ag, 6000 Frankfurt Genprodukt eines hoeheren organismus aus einem dieses gen enthaltenden mikroorganismus
IL62552A0 (en) 1980-04-03 1981-06-29 Biogen Nv Dna sequences,recombinant dna molecules and processes for producing human fibroblast interferon-like polypeptides
ATE25985T1 (de) * 1980-06-12 1987-04-15 Japan Found Cancer Plasmid.
CH651308A5 (de) * 1980-07-01 1985-09-13 Hoffmann La Roche Interferone und deren herstellung.
ES8302778A1 (es) * 1980-11-10 1983-02-01 Genentech Inc Un procedimiento para producir un polipeptido antiviral.
DE3280127D1 (de) * 1981-03-27 1990-04-12 Ici Plc Genetisch modifizierte mikroorganismen.
EP0085693A1 (en) * 1981-08-14 1983-08-17 A/S Alfred Benzon Subjects relating to human inteferon-alpha subtype proteins and corresponding antibodies
GB2108510B (en) * 1981-10-03 1984-12-12 Ciba Geigy Ag Dnas, recombinant dnas, hosts containing them, polypeptides and processes for the production thereof
US4973479A (en) * 1982-01-15 1990-11-27 Cetus Corporation Interferon-α61
US4975276A (en) * 1982-01-15 1990-12-04 Cetus Corporation Interferon-alpha 54
US5098703A (en) * 1982-01-15 1992-03-24 Cetus Corporation Interferon-alpha 76
US5827694A (en) * 1982-03-08 1998-10-27 Genentech, Inc. DNA encoding non-human animal interferons, vectors and hosts therefor, and recombinant production of IFN polypeptides
IE54592B1 (en) * 1982-03-08 1989-12-06 Genentech Inc Anumal interferons, processes involved in their production, compositions containing them, dna sequences coding therefor and espression vehicles containing such sequences and cells transformed thereby
DE3220116A1 (de) * 1982-05-28 1983-12-01 Dr. Karl Thomae Gmbh, 7950 Biberach Mikrobiologisch hergestellte (alpha)- und ss-interferone, dna-sequenzen, die fuer diese interferone codieren, mikroorganismen, die diese genetische information enthalten, und verfahren zu ihrer herstellung
US5831023A (en) * 1982-11-01 1998-11-03 Genentech, Inc. Recombinant animal interferon polypeptides
GB8315980D0 (en) * 1983-06-10 1983-07-13 Biogen Nv Producing hybrid dna sequences
EP0146903A3 (en) * 1983-12-19 1987-07-22 Schering Corporation Production of a vector encoding a novel hybrid interferon species
US4892743A (en) * 1983-12-21 1990-01-09 Schering Corporation Novel hybrid interferon species
FR2560212B1 (fr) * 1984-02-24 1989-12-29 Unicet Anticorps monoclonaux contre l'interferon a2 et hybridomes produisant de tels anticorps
US5231176A (en) * 1984-08-27 1993-07-27 Genentech, Inc. Distinct family DNA encoding of human leukocyte interferons
ATE47864T1 (de) * 1984-08-27 1989-11-15 Genentech Inc Verschiedenartige familie von menschlichen leukozyten-interferonen, zusammensetzungen, die diese enthalten, verfahren zu ihrer herstellung, sowie dna und transfektierte wirte hierfuer.
IL76360A0 (en) * 1984-09-26 1986-01-31 Takeda Chemical Industries Ltd Mutual separation of proteins
EP0194006B1 (en) * 1985-02-01 1992-04-29 Imperial Chemical Industries Plc Analogous interferon polypeptides, process for their preparation and pharmaceutical compositions containing them
SE8502430L (sv) * 1985-05-15 1986-11-16 Kabivitrum Ab En cdna-molekyl som kodar for expressionen av en polypeptid av typen interferon alfa, en bakteriell eller celluler verd transformerad med en sadan molekyl och en polypeptid som uppvisar interferonaktivetet framstelld me
US4885166A (en) * 1985-06-11 1989-12-05 Ciba-Geigy Corporation Hybrid interferons
ATE93541T1 (de) * 1985-07-03 1993-09-15 Genencor Int Hybride polypeptide und verfahren zu deren herstellung.
US4846782A (en) * 1986-03-14 1989-07-11 Schering Corporation Treatment of cancer with interferon and radiotherapy
ES2074420T3 (es) 1986-04-15 1995-09-16 Ciba Geigy Ag Anticuerpos monoclonales contra proteina humana inducida por interferon en forma pura y kits de ensayo que contienen dichos anticuerpos.
US5028422A (en) * 1986-05-27 1991-07-02 Schering Corporation Treatment of basal cell carcinoma intralesionally with recombinant human alpha interferon
US4851220A (en) * 1986-11-26 1989-07-25 Schering Corporation Stable oleaginous gel
US5190751A (en) * 1987-01-20 1993-03-02 Schering Corporation Treatment of certain leukemias with a combination of gamma interferon and alpha interferon
US4853218A (en) * 1987-02-24 1989-08-01 Schering Corporation Zinc-protamine-alpha interferon complex
US4871538A (en) * 1987-07-13 1989-10-03 Schering Corporation Insoluble copper-alpha interferon complex
GB8813032D0 (en) * 1988-06-02 1988-07-06 Boehringer Ingelheim Int Antiviral pharmaceutical composition
US5256410A (en) * 1988-12-01 1993-10-26 Schering Corporation Treatment of squamous cell carcinoma intralesionally with recombinant human alpha interferon
FR2686899B1 (fr) 1992-01-31 1995-09-01 Rhone Poulenc Rorer Sa Nouveaux polypeptides biologiquement actifs, leur preparation et compositions pharmaceutiques les contenant.
GB9609932D0 (en) * 1996-05-13 1996-07-17 Hoffmann La Roche Use of IL-12 and IFN alpha for the treatment of infectious diseases
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US6281337B1 (en) 1998-11-12 2001-08-28 Schering Corporation Methods for conversion of protein isoforms
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WO2001079289A2 (en) * 2000-04-14 2001-10-25 Zymogenetics, Inc. Human interferon, zinf2
BR0112119A (pt) * 2000-06-30 2003-05-06 Zymogenetics Inc Polipeptìdeo isolado, molécula de ácido nucléico isolado, vetor, célula hospedeira recombinante, método de produzir a proteìna zcyto21, anticorpo ou fragmento de anticorpo, método de detectar a presença da expressão do gene zcyto21 em uma amostra biológica
US7959910B2 (en) 2000-07-31 2011-06-14 Biolex Therapeutics, Inc. C-terminally truncated interferon alpha variants
FR2823220B1 (fr) 2001-04-04 2003-12-12 Genodyssee Nouveaux polynucleotides et polypeptides de l'erythropoietine (epo)
US6887462B2 (en) 2001-04-09 2005-05-03 Chiron Corporation HSA-free formulations of interferon-beta
US7038032B2 (en) 2001-04-20 2006-05-02 Zymogenetics, Inc. Cytokine protein family
DE60228136D1 (de) * 2001-04-20 2008-09-18 Zymogenetics Inc Cytokin-proteinfamilie
US7910313B2 (en) 2001-04-20 2011-03-22 Zymogenetics, Inc. Cytokine protein family
FR2824333B1 (fr) 2001-05-03 2003-08-08 Genodyssee Nouveaux polynucleotides et polypeptides de l'ifn alpha 5
EP2261250B1 (en) 2001-12-21 2015-07-01 Human Genome Sciences, Inc. GCSF-Albumin fusion proteins
WO2005003296A2 (en) 2003-01-22 2005-01-13 Human Genome Sciences, Inc. Albumin fusion proteins
CA2503305A1 (en) 2002-10-23 2004-05-06 Zymogenetics, Inc. Methods for treating viral infection using il-28 and il-29
WO2004039996A1 (en) * 2002-11-01 2004-05-13 Cadila Healthcare Limited Mthod for producing recombinant human interferon alpha 2b polypeptide in pichia pastoris
ES2405209T3 (es) 2003-08-07 2013-05-30 Zymogenetics, Inc. Preparaciones homogéneas de lL-29
JP4896005B2 (ja) 2004-04-02 2012-03-14 ザイモジェネティクス リミテッド ライアビリティ カンパニー Ｉｌ−２８およびｉｌ−２９システイン変異体を用いるウイルス感染を治療するための方法
JP2008508310A (ja) 2004-07-29 2008-03-21 ザイモジェネティクス， インコーポレイテッド がんおよび自己免疫障害を治療するためのｉｌ−２８およびｉｌ−２９の使用法
US20060024272A1 (en) 2004-07-29 2006-02-02 Large Scale Biology Corporation C-terminally truncated interferon
WO2006095433A1 (ja) * 2005-03-10 2006-09-14 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo ウシの消化器疾患治療剤
WO2007013944A2 (en) 2005-07-20 2007-02-01 Zymogenetics, Inc. Use of truncated cysteine il28 and il29 mutants to treat cancers and autoimmune disorders
EP2207890A4 (en) 2007-10-05 2010-12-15 Barofold Inc HIGH PRESSURE PROCESSING OF AGGREGATED INTERFERONS
CN102264761A (zh) 2008-12-23 2011-11-30 先灵公司 重组生产的干扰素的提纯
WO2019226050A2 (en) * 2018-05-24 2019-11-28 Wageningen Universiteit Novel viral anti-infective reagents

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CA1215921A (en) * 1977-11-08 1986-12-30 Arthur D. Riggs Method and means for microbial polypeptide expression
AU538665B2 (en) * 1979-10-30 1984-08-23 Juridical Foundation, Japanese Foundation For Cancer Research Human interferon dna

Also Published As

Publication number Publication date
YU2681A (en) 1983-12-31
IE54096B1 (en) 1989-06-21
DK170236B1 (da) 1995-07-10
EP0032134A2 (en) 1981-07-15
FI86558C (fi) 1992-09-10
NO164037C (no) 1990-08-22
FI810030L (fi) 1981-07-09
EP0032134B1 (en) 1984-08-15
JPH02131431A (ja) 1990-05-21
DD159782A5 (de) 1983-04-06
PL229123A1 (en) 1983-07-18
MY8700559A (en) 1987-12-31
PT72322B (en) 1982-09-23
DE3165463D1 (en) 1984-09-20
DK5681A (da) 1981-07-09
EP0032134B2 (en) 1993-10-13
GR73557B (show.php) 1984-03-15
IE810025L (en) 1981-07-08
ES8400770A1 (es) 1983-11-01
ES498343A0 (es) 1983-09-01
EP0032134A3 (en) 1981-08-26
HU194305B (en) 1988-01-28
DD203071A5 (de) 1983-10-12
NZ195980A (en) 1984-10-19
NO810041L (no) 1981-07-09
CY1346A (en) 1987-01-16
AU6605781A (en) 1981-07-30
ES8308534A1 (es) 1983-09-01
JP2501889B2 (ja) 1996-05-29
NO850733L (no) 1981-07-09
PH21848A (en) 1988-03-17
OA06717A (fr) 1982-06-30
PT72322A (en) 1981-03-01
SG77286G (en) 1987-02-27
FI86558B (fi) 1992-05-29
DK61595A (da) 1995-05-31
ES509222A0 (es) 1983-11-01
PL148434B1 (en) 1989-10-31
CA1341567C (en) 2008-02-19
AU553400B2 (en) 1986-07-17
NO164037B (no) 1990-05-14

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