CA2012993A1 - Monoclonal antibodies (mabs) against tumor-associated antigens, the preparation and use thereof - Google Patents
Monoclonal antibodies (mabs) against tumor-associated antigens, the preparation and use thereofInfo
- Publication number
- CA2012993A1 CA2012993A1 CA002012993A CA2012993A CA2012993A1 CA 2012993 A1 CA2012993 A1 CA 2012993A1 CA 002012993 A CA002012993 A CA 002012993A CA 2012993 A CA2012993 A CA 2012993A CA 2012993 A1 CA2012993 A1 CA 2012993A1
- Authority
- CA
- Canada
- Prior art keywords
- mabs
- associated antigens
- against tumor
- preparation
- monoclonal antibodies
- 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.)
- Granted
Links
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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3076—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties
- C07K16/3084—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells against structure-related tumour-associated moieties against tumour-associated gangliosides
-
- 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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- 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
- A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
-
- 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
- A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6815—Enzymes
-
- 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
- A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6817—Toxins
-
- 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
- A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
- A61K51/1045—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against animal or human tumor cells or tumor cell determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- 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
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Abstract
The invention relates to marine monoclonal anti-bodies (MAbs), A, B, C and D, which are directed against tumor-associated antigens. The nearly complete nucleotide sequences of the v genes of these MAbs are described, so that the relevant variable domains can be put together to give chimeric MAbs, or "humanized" MAbs are obtained by inserting the hypervariable regions (complementarity determining regions = CDR) into a human MAb framework.
Antibody constructs of this type can be employed in human therapy and in vivo diagnosis without the disadvantages observed with marine MAbs.
Antibody constructs of this type can be employed in human therapy and in vivo diagnosis without the disadvantages observed with marine MAbs.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE3909799A DE3909799A1 (en) | 1989-03-24 | 1989-03-24 | MONOCLONAL ANTIBODIES (MAK) AGAINST TUMOR ASSOCIATED ANTIGENS, THEIR PRODUCTION AND USE |
DEP3909799.4 | 1989-03-24 |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2012993A1 true CA2012993A1 (en) | 1990-09-24 |
CA2012993C CA2012993C (en) | 2001-07-03 |
Family
ID=6377161
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002012993A Expired - Lifetime CA2012993C (en) | 1989-03-24 | 1990-03-23 | Monoclonal antibodies (mabs) against tumor-associated antigens, the preparation and use thereof |
Country Status (12)
Country | Link |
---|---|
US (3) | US6926896B2 (en) |
EP (3) | EP0727435B1 (en) |
JP (1) | JP3043772B2 (en) |
KR (1) | KR100189046B1 (en) |
AT (3) | ATE140486T1 (en) |
AU (1) | AU628948B2 (en) |
CA (1) | CA2012993C (en) |
DE (4) | DE3909799A1 (en) |
DK (3) | DK0727436T3 (en) |
ES (3) | ES2116790T3 (en) |
GR (1) | GR3020610T3 (en) |
PT (1) | PT93536B (en) |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ229159A (en) * | 1988-05-17 | 1992-11-25 | Soldano Ferrone | Anti-idiotype antibodies which bind to the idiotype of murine antibody 225.28 |
DE3909799A1 (en) * | 1989-03-24 | 1990-09-27 | Behringwerke Ag | MONOCLONAL ANTIBODIES (MAK) AGAINST TUMOR ASSOCIATED ANTIGENS, THEIR PRODUCTION AND USE |
DE3920358A1 (en) | 1989-06-22 | 1991-01-17 | Behringwerke Ag | BISPECIFIC AND OLIGO-SPECIFIC, MONO- AND OLIGOVALENT ANTI-BODY CONSTRUCTS, THEIR PRODUCTION AND USE |
DE4106389A1 (en) * | 1991-02-28 | 1992-09-03 | Behringwerke Ag | FUSION PROTEINS FOR PRODRUG ACTIVATION, THEIR PRODUCTION AND USE |
US6610299B1 (en) | 1989-10-19 | 2003-08-26 | Aventis Pharma Deutschland Gmbh | Glycosyl-etoposide prodrugs, a process for preparation thereof and the use thereof in combination with functionalized tumor-specific enzyme conjugates |
US7241595B2 (en) | 1989-10-20 | 2007-07-10 | Sanofi-Aventis Pharma Deutschland Gmbh | Glycosyl-etoposide prodrugs, a process for preparation thereof and the use thereof in combination with functionalized tumor-specific enzyme conjugates |
DE4033120A1 (en) * | 1990-10-18 | 1992-04-23 | Boehringer Mannheim Gmbh | Genomic DNA fragment encoding antibody variable region prodn. - by attaching primers to hybridoma DNA then subjecting to polymerase chain reaction, for constructing genes encoding chimeric antibodies |
DE4133791A1 (en) * | 1991-10-11 | 1993-04-15 | Behringwerke Ag | MONOCLONAL ANTIBODIES AGAINST TUMOR ASSOCIATED ANTIGENS, METHOD FOR THEIR PRODUCTION AND THEIR USE |
DE4225853A1 (en) * | 1992-08-05 | 1994-02-10 | Behringwerke Ag | Granulocyte-binding antibody fragments, their production and use |
US6030797A (en) * | 1992-10-08 | 2000-02-29 | Dade Behring Marburg Gmbh | Monoclonal antibodies against tumor-associated antigens, processes for the preparation thereof and the use thereof |
GB9525180D0 (en) * | 1995-12-08 | 1996-02-07 | Univ Mcgill | Design of hormone-like antibodies with agonistic and antagonistic fuctions |
US5905027A (en) * | 1995-12-27 | 1999-05-18 | Uab Research Foundation | Method of diagnosing and treating gliomas |
MA24512A1 (en) * | 1996-01-17 | 1998-12-31 | Univ Vermont And State Agrienl | PROCESS FOR THE PREPARATION OF ANTICOAGULATING AGENTS USEFUL IN THE TREATMENT OF THROMBOSIS |
CA2420193A1 (en) * | 2000-08-24 | 2002-02-28 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US20060088899A1 (en) * | 2002-05-31 | 2006-04-27 | Alvarez Vernon L | Combination chemotherapy with chlorotoxin |
AU2009246142A1 (en) | 2008-05-15 | 2009-11-19 | Transmolecular, Inc. | Treatment of metastatic tumors |
CA2774260C (en) * | 2009-09-16 | 2018-10-09 | Immunomedics, Inc. | Class i anti-cea antibodies and uses thereof |
US9018347B2 (en) | 2010-02-04 | 2015-04-28 | Morphotek, Inc. | Chlorotoxin polypeptides and conjugates and uses thereof |
KR101972173B1 (en) | 2010-05-11 | 2019-04-24 | 프레드 헛친슨 켄서 리서치 센터 | Chlorotoxin variants, conjugates, and methods for their use |
WO2011144744A1 (en) | 2010-05-20 | 2011-11-24 | Therapharm Gmbh | Targeted radioactive compound for human cd66 for the treatment of disorders |
US20140179560A1 (en) | 2012-12-10 | 2014-06-26 | Fred Hutchinson Cancer Research Center | Drug discovery methods and platforms |
US11559580B1 (en) | 2013-09-17 | 2023-01-24 | Blaze Bioscience, Inc. | Tissue-homing peptide conjugates and methods of use thereof |
EP3351271A1 (en) | 2017-01-23 | 2018-07-25 | TheraPharm GmbH | Radioimmunoconjugate for use in treating bone marrow associated diseases |
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US3862925A (en) | 1973-07-05 | 1975-01-28 | American Home Prod | Preparation of somatotropin release inhibiting factor and intermediates therefor |
US4349528A (en) | 1979-11-21 | 1982-09-14 | The Wistar Institute | Monocolonal hybridoma antibody specific for high molecular weight carcinoembryonic antigen |
US4331647A (en) | 1980-03-03 | 1982-05-25 | Goldenberg Milton David | Tumor localization and therapy with labeled antibody fragments specific to tumor-associated markers |
US4444744A (en) | 1980-03-03 | 1984-04-24 | Goldenberg Milton David | Tumor localization and therapy with labeled antibodies to cell surface antigens |
US4460561A (en) | 1980-03-03 | 1984-07-17 | Goldenberg M David | Tumor localization and therapy with labeled antibodies specific to intracellular tumor-associated markers |
US4582797A (en) | 1980-09-25 | 1986-04-15 | The Salk Institute For Biological Studies | Monoclonal antibodies specific for human hematopoietic cell surface glycoproteins |
US4446240A (en) | 1981-01-30 | 1984-05-01 | Nerenberg Samuel T | Pancreas specific protein systems |
US4522918A (en) | 1981-12-15 | 1985-06-11 | Jeffery Schlom | Process for producing monoclonal antibodies reactive with human breast cancer |
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EP0160446B1 (en) | 1984-05-01 | 1992-06-17 | Ciba Corning Diagnostics Corp. | Breast tumor-associated antigen and monoclonal antibodies specific thereto |
US4683200A (en) | 1984-05-17 | 1987-07-28 | Setsuo Hirohashi | Monoclonal antibody to human cancer antigen and method for producing same |
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DE3909799A1 (en) * | 1989-03-24 | 1990-09-27 | Behringwerke Ag | MONOCLONAL ANTIBODIES (MAK) AGAINST TUMOR ASSOCIATED ANTIGENS, THEIR PRODUCTION AND USE |
US5580774A (en) * | 1989-07-31 | 1996-12-03 | Eli Lilly And Company | Chimeric antibodies directed against a human glycoprotein antigen |
-
1989
- 1989-03-24 DE DE3909799A patent/DE3909799A1/en not_active Withdrawn
-
1990
- 1990-03-21 DK DK96100443T patent/DK0727436T3/en active
- 1990-03-21 DK DK90105322.3T patent/DK0388914T3/en active
- 1990-03-21 DE DE59010826T patent/DE59010826D1/en not_active Expired - Lifetime
- 1990-03-21 DE DE59010418T patent/DE59010418D1/en not_active Expired - Lifetime
- 1990-03-21 AT AT90105322T patent/ATE140486T1/en not_active IP Right Cessation
- 1990-03-21 ES ES96100443T patent/ES2116790T3/en not_active Expired - Lifetime
- 1990-03-21 DE DE59010825T patent/DE59010825D1/en not_active Expired - Lifetime
- 1990-03-21 EP EP96100442A patent/EP0727435B1/en not_active Expired - Lifetime
- 1990-03-21 AT AT96100442T patent/ATE166882T1/en not_active IP Right Cessation
- 1990-03-21 ES ES96100442T patent/ES2116789T3/en not_active Expired - Lifetime
- 1990-03-21 AT AT96100443T patent/ATE166883T1/en not_active IP Right Cessation
- 1990-03-21 EP EP90105322A patent/EP0388914B1/en not_active Expired - Lifetime
- 1990-03-21 DK DK96100442T patent/DK0727435T3/en active
- 1990-03-21 EP EP96100443A patent/EP0727436B1/en not_active Expired - Lifetime
- 1990-03-21 ES ES90105322T patent/ES2090052T3/en not_active Expired - Lifetime
- 1990-03-22 PT PT93536A patent/PT93536B/en not_active IP Right Cessation
- 1990-03-23 JP JP2075340A patent/JP3043772B2/en not_active Expired - Lifetime
- 1990-03-23 CA CA002012993A patent/CA2012993C/en not_active Expired - Lifetime
- 1990-03-23 AU AU52150/90A patent/AU628948B2/en not_active Expired
- 1990-03-23 KR KR1019900003932A patent/KR100189046B1/en not_active IP Right Cessation
-
1994
- 1994-12-13 US US08/356,791 patent/US6926896B2/en not_active Expired - Fee Related
-
1996
- 1996-07-24 GR GR960401970T patent/GR3020610T3/en unknown
-
2004
- 2004-09-17 US US10/942,929 patent/US20060159682A1/en not_active Abandoned
-
2008
- 2008-02-07 US US12/068,545 patent/US7662383B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
ATE166883T1 (en) | 1998-06-15 |
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