AU2017283151A1 - Modified dextran conjugates comprising a lysine-urea-glutamate pharmacophore - Google Patents
Modified dextran conjugates comprising a lysine-urea-glutamate pharmacophore Download PDFInfo
- Publication number
- AU2017283151A1 AU2017283151A1 AU2017283151A AU2017283151A AU2017283151A1 AU 2017283151 A1 AU2017283151 A1 AU 2017283151A1 AU 2017283151 A AU2017283151 A AU 2017283151A AU 2017283151 A AU2017283151 A AU 2017283151A AU 2017283151 A1 AU2017283151 A1 AU 2017283151A1
- Authority
- AU
- Australia
- Prior art keywords
- dextran
- modified dextran
- conjugate according
- conjugate
- psma
- 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
-
- 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
- A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
- A61K51/065—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules conjugates with carriers being macromolecules
-
- 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
- A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K47/54—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 organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
-
- 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
- A61K47/54—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 organic compound
- A61K47/547—Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent
-
- 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
- A61K47/56—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- 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
- A61K47/6835—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
- A61K47/6869—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 the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate
-
- 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
- A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
-
- 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
- A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
-
- 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
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/121—Solutions, i.e. homogeneous liquid formulation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- 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
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Optics & Photonics (AREA)
- Physics & Mathematics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Materials Engineering (AREA)
- Cell Biology (AREA)
- Polymers & Plastics (AREA)
- Urology & Nephrology (AREA)
- Biotechnology (AREA)
- Inorganic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Reproductive Health (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI20165515A FI127538B (en) | 2016-06-22 | 2016-06-22 | MODIFIED Dextran Conjugates |
| FI20165515 | 2016-06-22 | ||
| PCT/EP2017/064929 WO2017220488A1 (en) | 2016-06-22 | 2017-06-19 | Modified dextran conjugates comprising a lysine-urea-glutamate pharmacophore |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2017283151A1 true AU2017283151A1 (en) | 2018-12-06 |
Family
ID=59269989
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2017283151A Abandoned AU2017283151A1 (en) | 2016-06-22 | 2017-06-19 | Modified dextran conjugates comprising a lysine-urea-glutamate pharmacophore |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US20190175767A1 (enExample) |
| EP (1) | EP3475311B1 (enExample) |
| JP (1) | JP6944720B2 (enExample) |
| CN (1) | CN109312004A (enExample) |
| AU (1) | AU2017283151A1 (enExample) |
| CA (1) | CA3027920C (enExample) |
| FI (1) | FI127538B (enExample) |
| IL (1) | IL263886B2 (enExample) |
| WO (1) | WO2017220488A1 (enExample) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL240772B1 (pl) * | 2018-06-11 | 2022-06-06 | Nanothea Spolka Akcyjna | Sposób wytwarzania nanocząstek polimerowych chelatujących izotopy promieniotwórcze do zastosowania w diagnostyce i terapii |
| EP3636635A1 (en) | 2018-10-11 | 2020-04-15 | Academisch Ziekenhuis Leiden h.o.d.n. LUMC | Imaging agents |
| CN113747927B (zh) * | 2019-02-14 | 2024-10-18 | 德国癌症研究中心 | 包含淀粉酶可切割接头的前列腺特异性膜抗原(psma)配体 |
| US20220152231A1 (en) * | 2019-03-19 | 2022-05-19 | Nanothea S.A. | Process of preparing polymeric nanoparticles that chelate radioactive isotopes and have a surface modified with specific molecules targeting the psma receptor and their use |
| CN112209970B (zh) * | 2020-10-21 | 2021-10-29 | 北京师范大学 | 一种锝-99m标记含异腈的谷氨酸-脲衍生物的制备方法和应用 |
| CN121002057A (zh) * | 2023-03-30 | 2025-11-21 | 启德医药科技(苏州)有限公司 | 二糖接头、含有该二糖接头的接头-有效载荷以及聚糖链重构的抗体-药物偶联物及其制备方法和用途 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4822594A (en) * | 1987-01-27 | 1989-04-18 | Gibby Wendell A | Contrast enhancing agents for magnetic resonance images |
| SE9803482D0 (sv) | 1998-10-13 | 1998-10-13 | Anders Holmberg | Ion exchange tumor targeting (IETT) |
| DK2097111T3 (en) * | 2006-11-08 | 2015-08-24 | Molecular Insight Pharm Inc | Heterodimers of glutamic acid |
| FI119513B (fi) * | 2007-03-07 | 2008-12-15 | Dextech Medical Ab | Muokatut hydroksipolymeerikonjugaatit, joilla on tappava vaikutus tuumorisoluihin |
| JP5680409B2 (ja) * | 2007-06-26 | 2015-03-04 | ザ ジョンズ ホプキンス ユニバーシティ | 前立腺特異膜抗原(psma)の標識阻害剤、生物学的評価およびイメージング剤としての使用 |
| WO2009124580A1 (en) * | 2008-04-07 | 2009-10-15 | Dextech Medical Ab | Modified hydroxypolymer conjugates with bone seeking and tumor killing moieties |
| ES2732060T3 (es) * | 2011-08-05 | 2019-11-20 | Molecular Insight Pharm Inc | Inhibidores radiomarcados del antígeno de membrana específico de la próstata |
| CN113149921B (zh) * | 2011-11-30 | 2024-11-29 | 约翰霍普金斯大学 | 前列腺特异性膜抗原(psma)的同源多价抑制剂和异源多价抑制剂以及其用途 |
| US9636413B2 (en) * | 2012-11-15 | 2017-05-02 | Endocyte, Inc. | Conjugates for treating diseases caused by PSMA expressing cells |
| EP2958596B1 (en) * | 2013-02-15 | 2019-12-04 | Case Western Reserve University | Psma ligands and uses thereof |
| US20150110716A1 (en) * | 2013-10-18 | 2015-04-23 | Molecular Insight Pharmaceuticals, Inc. | Methods of using spect/ct analysis for staging cancer |
| CN111285918B (zh) * | 2014-05-06 | 2024-05-31 | 约翰霍普金斯大学 | 用于psma靶向的成像和放射疗法的金属/放射性金属标记的psma抑制物 |
| EP3011976A1 (en) * | 2014-10-20 | 2016-04-27 | Deutsches Krebsforschungszentrum | 18F-tagged inhibitors of prostate specific membrane antigen (PSMA), their use as imaging agents |
-
2016
- 2016-06-22 FI FI20165515A patent/FI127538B/en active IP Right Grant
-
2017
- 2017-06-19 IL IL263886A patent/IL263886B2/en unknown
- 2017-06-19 JP JP2018566546A patent/JP6944720B2/ja active Active
- 2017-06-19 EP EP17734661.6A patent/EP3475311B1/en active Active
- 2017-06-19 AU AU2017283151A patent/AU2017283151A1/en not_active Abandoned
- 2017-06-19 CN CN201780038758.6A patent/CN109312004A/zh active Pending
- 2017-06-19 WO PCT/EP2017/064929 patent/WO2017220488A1/en not_active Ceased
- 2017-06-19 US US16/309,360 patent/US20190175767A1/en not_active Abandoned
- 2017-06-19 CA CA3027920A patent/CA3027920C/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| IL263886A (en) | 2019-01-31 |
| EP3475311B1 (en) | 2020-05-13 |
| WO2017220488A1 (en) | 2017-12-28 |
| FI20165515A7 (fi) | 2017-12-23 |
| IL263886B1 (en) | 2023-05-01 |
| EP3475311A1 (en) | 2019-05-01 |
| IL263886B2 (en) | 2023-09-01 |
| CA3027920A1 (en) | 2017-12-28 |
| US20190175767A1 (en) | 2019-06-13 |
| CN109312004A (zh) | 2019-02-05 |
| JP6944720B2 (ja) | 2021-10-06 |
| CA3027920C (en) | 2023-10-17 |
| JP2019527740A (ja) | 2019-10-03 |
| FI127538B (en) | 2018-08-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK5 | Application lapsed section 142(2)(e) - patent request and compl. specification not accepted |