CA2438238A1 - Composition et procede de traitement de troubles inflammatoires - Google Patents
Composition et procede de traitement de troubles inflammatoires Download PDFInfo
- Publication number
- CA2438238A1 CA2438238A1 CA002438238A CA2438238A CA2438238A1 CA 2438238 A1 CA2438238 A1 CA 2438238A1 CA 002438238 A CA002438238 A CA 002438238A CA 2438238 A CA2438238 A CA 2438238A CA 2438238 A1 CA2438238 A1 CA 2438238A1
- Authority
- CA
- Canada
- Prior art keywords
- protein
- antibody
- cells
- subject
- activity
- 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.)
- Abandoned
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
-
- 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
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
- A61P17/06—Antipsoriatics
-
- 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
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
-
- 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
-
- 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
- A61P37/04—Immunostimulants
-
- 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
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- 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
- 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
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
-
- 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
- C07K14/54—Interleukins [IL]
- C07K14/5428—IL-10
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- 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
- C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
- C12N2710/00011—Details
- C12N2710/10011—Adenoviridae
- C12N2710/10041—Use of virus, viral particle or viral elements as a vector
- C12N2710/10043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- 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
- C12N2799/00—Uses of viruses
- C12N2799/02—Uses of viruses as vector
- C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
- C12N2799/022—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from an adenovirus
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Genetics & Genomics (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Zoology (AREA)
- Dermatology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Child & Adolescent Psychology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
Abstract
La présente invention concerne des inhibiteurs de IL-22 ainsi que des compositions pharmaceutiques et de procédés mettant en oeuvre lesdits inhibiteurs. Les inhibiteurs comprennent des anticorps de IL-22 et sont utiles pour le traitement des troubles inflammatoires. FIG. 1 : A PROTOCOLE CIA DANS DES SOURIS DBA. MODELE DE SOURIS POUR LE POLYARTHRITE RHUMATOIDE B REGIME PROPHYLACTIQUE F JOUR 0 IMMUNISATION AVEC DU COLLAGENE BOVIN ET L'ADJUVANT DE FREUND INCOMPLETE 21?e¿ JOUR IMMUNISATION AVEC DU COLLAGENE BOVIN ET L'ADJUVANT COMPLET DE FREUND C REACTIF DE TEST : DEBUT 21?e¿ JOUR, 200 µg/SOURIS, 2 FOIS PAR SEMAINE D PREMIERES INDICATIONS DE MALADIE ENVIRON AU 23?e¿ JOUR G REACTIF DE TEST H REGIME THERAPEUTIQUE I ENVIRON AU 40?e¿ JOUR OU APRES
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US27082301P | 2001-02-23 | 2001-02-23 | |
US60/270,823 | 2001-02-23 | ||
US28135301P | 2001-04-03 | 2001-04-03 | |
US60/281,353 | 2001-04-03 | ||
PCT/US2002/005684 WO2002068476A2 (fr) | 2001-02-23 | 2002-02-25 | Composition et procede de traitement de troubles inflammatoires |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2438238A1 true CA2438238A1 (fr) | 2002-09-06 |
Family
ID=26954516
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002438238A Abandoned CA2438238A1 (fr) | 2001-02-23 | 2002-02-25 | Composition et procede de traitement de troubles inflammatoires |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP1373319A2 (fr) |
JP (2) | JP2005510451A (fr) |
AU (2) | AU2002252097A2 (fr) |
BR (1) | BR0207528A (fr) |
CA (1) | CA2438238A1 (fr) |
MX (1) | MXPA03007413A (fr) |
NZ (1) | NZ527396A (fr) |
WO (1) | WO2002068476A2 (fr) |
ZA (1) | ZA200306071B (fr) |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030170823A1 (en) | 1999-12-23 | 2003-09-11 | Presnell Scott R. | Novel cytokine ZCYTO18 |
JP5015404B2 (ja) | 2000-08-08 | 2012-08-29 | ザイモジェネティクス, インコーポレイテッド | 可溶性zcytor11サイトカイン受容体 |
BR0207528A (pt) * | 2001-02-23 | 2006-01-17 | Inst Genetics Llc | Anticorpo, composição farmacêutica, e, usos de uma quantidade efetiva de um agente, de uma quantidade terapeuticamente efetiva de um anticorpo para il-22, de uma quantidade imunogênica do antìgeno e uma quantidade aumentadora de imunogenicidade de il-22 em combinação, de uma quantidade efetiva do anticorpo ou fragmento do mesmo e de uma quantidade suficiente de anticorpo ou fragmento ligado a antìgeno do mesmo |
US7638604B2 (en) | 2001-02-23 | 2009-12-29 | Genetics Institute, Llc | Monoclonal antibodies against interleukin-22 |
WO2003083062A2 (fr) | 2002-03-22 | 2003-10-09 | Zymogenetics, Inc. | Anticorps anti-il-tif et leurs methodes d'utilisation dans une inflammation |
ATE475673T1 (de) | 2003-03-24 | 2010-08-15 | Zymogenetics Inc | Anti-il-22ra antikörper und bindungspartner und verwendungsmethoden bei entzündung |
KR20060022289A (ko) * | 2003-06-23 | 2006-03-09 | 제네틱스 인스티튜트, 엘엘씨 | 인터류킨-22 에 대한 항체 및 그의 용도 |
AU2005299809B2 (en) | 2004-10-22 | 2010-12-02 | Zymogenetics, Inc. | Anti-IL-22RA antibodies and binding partners and methods of using in inflammation |
CA2596390A1 (fr) | 2005-02-08 | 2006-08-17 | Zymogenetics, Inc. | Anticorps et partenaires de liaison anti-il-20, anti-il-22 et anti-il-22ra, et methodes d'utilisation de ces anticorps et partenaires de liaison dans des processus inflammatoires |
CN105859886A (zh) | 2005-12-02 | 2016-08-17 | 健泰科生物技术公司 | 牵涉与il-22和il-22r结合的抗体的组合物和方法 |
TWI417301B (zh) | 2006-02-21 | 2013-12-01 | Wyeth Corp | 對抗人類介白素-22(il-22)之抗體及其用途 |
TW200744634A (en) | 2006-02-21 | 2007-12-16 | Wyeth Corp | Methods of using antibodies against human IL-22 |
SG11201507429TA (en) | 2013-03-15 | 2015-10-29 | Genentech Inc | Il-22 polypeptides and il-22 fc fusion proteins and methods of use |
SG11202012014UA (en) | 2018-06-05 | 2021-01-28 | Bioatla Inc | Anti-il-22 antibodies, antibody fragments, their immunoconjugates and uses thereof |
WO2023110942A1 (fr) * | 2021-12-14 | 2023-06-22 | Charité-Universitätsmedizin Berlin | Prévention de guérison d'une fracture altérée |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2329274A1 (fr) * | 1998-05-29 | 1999-12-02 | Steven M. Ruben | Interleukine-21 |
BR9914777A (pt) * | 1998-10-26 | 2001-07-03 | Ludwig Inst Cancer Res | Moléculas isoladas de ácido nucléico que codificam os fatores induzìveis por células t (tifs), as proteìnas codificadas e os usos das mesmas |
ES2530857T3 (es) * | 1999-04-28 | 2015-03-06 | Genetics Inst Llc | Proteínas GIL-19/AE289 humanas y polinucleótidos que codifican las mismas |
DE60043944D1 (de) * | 1999-12-23 | 2010-04-15 | Zymogenetics Inc | Zytokin zcyt018 |
BR0207528A (pt) * | 2001-02-23 | 2006-01-17 | Inst Genetics Llc | Anticorpo, composição farmacêutica, e, usos de uma quantidade efetiva de um agente, de uma quantidade terapeuticamente efetiva de um anticorpo para il-22, de uma quantidade imunogênica do antìgeno e uma quantidade aumentadora de imunogenicidade de il-22 em combinação, de uma quantidade efetiva do anticorpo ou fragmento do mesmo e de uma quantidade suficiente de anticorpo ou fragmento ligado a antìgeno do mesmo |
-
2002
- 2002-02-25 BR BR0207528-8A patent/BR0207528A/pt active Search and Examination
- 2002-02-25 WO PCT/US2002/005684 patent/WO2002068476A2/fr active Application Filing
- 2002-02-25 EP EP02721152A patent/EP1373319A2/fr not_active Withdrawn
- 2002-02-25 MX MXPA03007413A patent/MXPA03007413A/es active IP Right Grant
- 2002-02-25 NZ NZ527396A patent/NZ527396A/en not_active IP Right Cessation
- 2002-02-25 CA CA002438238A patent/CA2438238A1/fr not_active Abandoned
- 2002-02-25 AU AU2002252097A patent/AU2002252097A2/en not_active Abandoned
- 2002-02-25 JP JP2002567986A patent/JP2005510451A/ja active Pending
-
2003
- 2003-08-06 ZA ZA2003/06071A patent/ZA200306071B/en unknown
-
2008
- 2008-07-25 AU AU2008203342A patent/AU2008203342B8/en not_active Ceased
-
2009
- 2009-01-07 JP JP2009001211A patent/JP2009137986A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
BR0207528A (pt) | 2006-01-17 |
EP1373319A2 (fr) | 2004-01-02 |
NZ527396A (en) | 2007-12-21 |
AU2002252097A2 (en) | 2002-09-12 |
JP2009137986A (ja) | 2009-06-25 |
MXPA03007413A (es) | 2003-11-18 |
AU2008203342A1 (en) | 2008-08-14 |
WO2002068476A2 (fr) | 2002-09-06 |
WO2002068476A3 (fr) | 2003-08-07 |
AU2008203342B8 (en) | 2011-03-17 |
ZA200306071B (en) | 2005-11-30 |
AU2008203342B2 (en) | 2011-02-17 |
JP2005510451A (ja) | 2005-04-21 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
FZDE | Dead |
Effective date: 20131204 |