PE20060773A1 - Derivados de oligosacarido que comprenden un residuo de biotina como inhibidores duales antitromboticos - Google Patents
Derivados de oligosacarido que comprenden un residuo de biotina como inhibidores duales antitromboticosInfo
- Publication number
- PE20060773A1 PE20060773A1 PE2005001503A PE2005001503A PE20060773A1 PE 20060773 A1 PE20060773 A1 PE 20060773A1 PE 2005001503 A PE2005001503 A PE 2005001503A PE 2005001503 A PE2005001503 A PE 2005001503A PE 20060773 A1 PE20060773 A1 PE 20060773A1
- Authority
- PE
- Peru
- Prior art keywords
- residue
- oligosacaride
- biotin
- activity
- dual inhibitors
- Prior art date
Links
Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- 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
- A61K47/62—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 a protein, peptide or polyamino acid
- A61K47/66—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 a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
-
- 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
- A61K47/62—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 a protein, peptide or polyamino acid
- A61K47/66—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 a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
- A61K47/665—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 a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells the pre-targeting system, clearing therapy or rescue therapy involving biotin-(strept) avidin systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- 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
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- 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
-
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Biotechnology (AREA)
- Cell Biology (AREA)
- Nanotechnology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biophysics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Cardiology (AREA)
- Medical Informatics (AREA)
- General Engineering & Computer Science (AREA)
- Urology & Nephrology (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pulmonology (AREA)
- Vascular Medicine (AREA)
- Surgery (AREA)
- Oncology (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
REFERIDA A UN COMPUESTO DE FORMULA (I) TAL COMO OLIGOSACARIDO-ESPACIADOR-A, DONDE EL OLIGOSACARIDO ES UN RESIDUO DE OLIGOSACARIDO CARGADO NEGATIVAMENTE QUE COMPRENDE DE 2 A 25 UNIDADES DE MONOSACARIDOS, QUE TIENE ACTIVIDAD ANTI-Xa Y DONDE LA CARGA ESTA COMPENSADA POR CONTRAIONES CARGADOS POSITIVAMENTE; EL ESPACIADOR ES UN RESIDUO ENLAZADOR FLEXIBLE QUE ES FARMACOLOGICAMENTE INACTIVO Y TIENE UNA LONGITUD DE CADENA DE 10 A 70 ATOMOS; A ES EL RESIDUO -CH[NH-SO2-R1][CO-NR2-CH(4-BENZAMIDINA)-CO-NR3R4], DONDE R1 ES FENILO, NAFTILO, 1,2,3,4-TETRAHIDRONAFTILO, ENTRE OTROS, R2 Y R3 SON H O ALQUILO C1-C8, R4 ES ALQUILO C1-C8, CICLOALQUILO C3-C8, ENTRE OTROS. EL COMPUESTO DE FORMULA (I) COMPRENDE UN ENLACE COVALENTE CON UN RESIDUO DE BIOTINA O UN ANALOGO DE LA MISMA. TAMBIEN SE REFIERE A UNA COMPOSICION FARMACEUTICA. DICHOS COMPUESTOS SON INHIBIDORES DUALES TANTO DE LA ACTIVIDAD ANTITROMBINA (FACTOR IIA) COMO DE LA ACTIVIDAD ANTI-Xa MEDIADA POR ANTITROMBINA III Y SON UTILES EN EL TRATAMIENTO O PREVENCION DE TROMBOSIS O EMBOLIA VENOSA POSTOPERATORIA, ATEROESCLEROSIS, ENTRE OTRAS
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP04106964 | 2004-12-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PE20060773A1 true PE20060773A1 (es) | 2006-09-01 |
Family
ID=35160114
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PE2005001503A PE20060773A1 (es) | 2004-12-23 | 2005-12-16 | Derivados de oligosacarido que comprenden un residuo de biotina como inhibidores duales antitromboticos |
Country Status (29)
| Country | Link |
|---|---|
| US (3) | US8168595B2 (es) |
| EP (1) | EP1830887B1 (es) |
| JP (2) | JP5130051B2 (es) |
| KR (1) | KR101284922B1 (es) |
| CN (1) | CN101087622A (es) |
| AR (1) | AR053657A1 (es) |
| AT (1) | ATE500846T1 (es) |
| AU (1) | AU2005318134B2 (es) |
| BR (1) | BRPI0518560A2 (es) |
| CA (1) | CA2592436C (es) |
| DE (1) | DE602005026859D1 (es) |
| DK (1) | DK1830887T3 (es) |
| ES (1) | ES2361921T3 (es) |
| HK (1) | HK1106712A1 (es) |
| HR (1) | HRP20110330T1 (es) |
| IL (2) | IL183713A (es) |
| MX (1) | MX2007007837A (es) |
| MY (1) | MY146121A (es) |
| NO (1) | NO20072878L (es) |
| NZ (1) | NZ555739A (es) |
| PE (1) | PE20060773A1 (es) |
| PL (1) | PL1830887T3 (es) |
| PT (1) | PT1830887E (es) |
| RU (1) | RU2403259C2 (es) |
| SI (1) | SI1830887T1 (es) |
| TW (1) | TWI403334B (es) |
| UA (1) | UA88793C2 (es) |
| WO (1) | WO2006067173A2 (es) |
| ZA (1) | ZA200705088B (es) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI403334B (zh) * | 2004-12-23 | 2013-08-01 | Merck Sharp & Dohme | 包含生物素殘基之抗血栓雙重抑制劑 |
| JP6109574B2 (ja) | 2009-12-18 | 2017-04-05 | カタラン、フランス、バインハイム、ソシエテ、アノニムＣａｔａｌｅｎｔ Ｆｒａｎｃｅ Ｂｅｉｎｈｅｉｍ Ｓａ | 合成オリゴサッカリドを含有する医薬経口剤形 |
| FR2974478A1 (fr) | 2011-04-28 | 2012-11-02 | Endotis Pharma | Conjugues d'oligosaccharides en prevention des lesions d'ischemie-reperfusion |
| EP2721044B1 (en) | 2011-06-17 | 2015-11-18 | Carbomimetics | Synthetic pentasaccharides having short half-life and high activity |
| WO2013007762A1 (en) | 2011-07-11 | 2013-01-17 | Endotis Pharma | Combination of an anticoagulant and avidin useful in surgical intervention and clinical procedure |
| US10660973B2 (en) | 2015-04-28 | 2020-05-26 | Duke University | Thrombus imaging aptamers and methods of using same |
| CN109982707A (zh) | 2016-09-16 | 2019-07-05 | 杜克大学 | 血管性血友病因子（vwf）靶向剂及其使用方法 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4252951A (en) * | 1979-10-09 | 1981-02-24 | Eli Lilly And Company | Isolation of syn-7-(2-amino-4-thiazolyl)-(methoxyimino)acetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid |
| DK0454220T3 (da) | 1990-04-23 | 1993-11-22 | Sanofi Elf | Carbohydratderivater omfattende en trisaccharidenhed |
| IL102758A (en) | 1991-08-23 | 1997-03-18 | Akzo Nv | Glycosaminoglycanoid derivatives, their preparation and pharmaceutical compositions comprising them |
| ATE190619T1 (de) | 1993-09-01 | 2000-04-15 | Akzo Nobel Nv | Biskonjugate, die zwei saccharide und einen spacer enthalten |
| FR2749849B1 (fr) * | 1996-06-14 | 1998-09-04 | Sanofi Sa | Polysaccharides synthetiques, procede pour leur preparation et compositions pharmaceutiques les contenant |
| FR2751334B1 (fr) | 1996-07-19 | 1998-10-16 | Sanofi Sa | Polysaccharides synthetiques, procede pour leur preparation et compositions pharmaceutiques les contenant |
| FR2773804B1 (fr) | 1998-01-19 | 2000-02-18 | Sanofi Sa | Polysaccharides de synthese, procede pour leur preparation et compositions pharmaceutiques le contenant |
| FR2773801B1 (fr) * | 1998-01-19 | 2000-05-12 | Sanofi Sa | Nouveaux pentasaccharides, procedes pour leurs preparations et compositions pharmaceutiques les contenant |
| CN1261450C (zh) * | 1998-06-17 | 2006-06-28 | 阿克佐诺贝尔公司 | 抗血栓形成化合物 |
| TWI289566B (en) * | 1999-12-07 | 2007-11-11 | N.V.Organon | Antithrombotic compound |
| FR2814463B1 (fr) | 2000-09-22 | 2002-11-15 | Sanofi Synthelabo | Nouveaux polysaccharides a activite antithrombotique comprenant au moins une liaison covalente avec la biotine ou un derive de la biotine |
| TWI403334B (zh) * | 2004-12-23 | 2013-08-01 | Merck Sharp & Dohme | 包含生物素殘基之抗血栓雙重抑制劑 |
| CN101312747B (zh) * | 2005-10-10 | 2013-03-20 | Msd欧斯股份有限公司 | 包括生物素标记的抗血栓形成双重抑制剂 |
-
2005
- 2005-12-14 TW TW094144361A patent/TWI403334B/zh not_active IP Right Cessation
- 2005-12-16 PE PE2005001503A patent/PE20060773A1/es not_active Application Discontinuation
- 2005-12-20 MY MYPI20056026A patent/MY146121A/en unknown
- 2005-12-21 BR BRPI0518560-2A patent/BRPI0518560A2/pt not_active IP Right Cessation
- 2005-12-21 DK DK05821769.6T patent/DK1830887T3/da active
- 2005-12-21 WO PCT/EP2005/057011 patent/WO2006067173A2/en active Application Filing
- 2005-12-21 AT AT05821769T patent/ATE500846T1/de active
- 2005-12-21 AU AU2005318134A patent/AU2005318134B2/en active Active
- 2005-12-21 PT PT05821769T patent/PT1830887E/pt unknown
- 2005-12-21 JP JP2007547509A patent/JP5130051B2/ja active Active
- 2005-12-21 KR KR1020077017005A patent/KR101284922B1/ko not_active IP Right Cessation
- 2005-12-21 ES ES05821769T patent/ES2361921T3/es active Active
- 2005-12-21 NZ NZ555739A patent/NZ555739A/en not_active IP Right Cessation
- 2005-12-21 RU RU2007127859/04A patent/RU2403259C2/ru not_active IP Right Cessation
- 2005-12-21 EP EP05821769A patent/EP1830887B1/en active Active
- 2005-12-21 CN CNA2005800444919A patent/CN101087622A/zh active Pending
- 2005-12-21 DE DE602005026859T patent/DE602005026859D1/de active Active
- 2005-12-21 PL PL05821769T patent/PL1830887T3/pl unknown
- 2005-12-21 SI SI200531279T patent/SI1830887T1/sl unknown
- 2005-12-21 US US11/722,444 patent/US8168595B2/en active Active
- 2005-12-21 CA CA2592436A patent/CA2592436C/en active Active
- 2005-12-21 MX MX2007007837A patent/MX2007007837A/es active IP Right Grant
- 2005-12-21 UA UAA200706654A patent/UA88793C2/ru unknown
- 2005-12-22 AR ARP050105472A patent/AR053657A1/es not_active Application Discontinuation
-
2007
- 2007-06-06 IL IL183713A patent/IL183713A/en not_active IP Right Cessation
- 2007-06-06 NO NO20072878A patent/NO20072878L/no not_active Application Discontinuation
- 2007-06-13 ZA ZA200705088A patent/ZA200705088B/xx unknown
-
2008
- 2008-01-10 HK HK08100324.9A patent/HK1106712A1/xx not_active IP Right Cessation
-
2011
- 2011-05-06 HR HR20110330T patent/HRP20110330T1/hr unknown
- 2011-12-18 IL IL217047A patent/IL217047A0/en unknown
-
2012
- 2012-04-04 US US13/439,012 patent/US20120238512A1/en not_active Abandoned
- 2012-04-04 US US13/438,905 patent/US8445450B2/en active Active
- 2012-09-14 JP JP2012202307A patent/JP5632886B2/ja active Active
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FG | Grant, registration | ||
| FD | Application declared void or lapsed |