AU2003223158B2 - Polymorphs of sodium 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate - Google Patents
Polymorphs of sodium 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate Download PDFInfo
- Publication number
- AU2003223158B2 AU2003223158B2 AU2003223158A AU2003223158A AU2003223158B2 AU 2003223158 B2 AU2003223158 B2 AU 2003223158B2 AU 2003223158 A AU2003223158 A AU 2003223158A AU 2003223158 A AU2003223158 A AU 2003223158A AU 2003223158 B2 AU2003223158 B2 AU 2003223158B2
- Authority
- AU
- Australia
- Prior art keywords
- sodium
- chloro
- amino
- hydroxybenzoyl
- butanoate
- 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.)
- Ceased
Links
- UQFYDAAKCZKDHS-UHFFFAOYSA-M sodium;4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate Chemical compound [Na+].OC1=CC(Cl)=CC=C1C(=O)NCCCC([O-])=O UQFYDAAKCZKDHS-UHFFFAOYSA-M 0.000 title claims description 131
- 239000011734 sodium Substances 0.000 claims description 101
- 229910052708 sodium Inorganic materials 0.000 claims description 101
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 94
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 93
- 239000000243 solution Substances 0.000 claims description 90
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- -1 4-chloro-2-hydroxybenzoyl Chemical group 0.000 claims description 18
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- GCVGCXMTCJMBHY-UHFFFAOYSA-N 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoic acid Chemical compound OC(=O)CCCNC(=O)C1=CC=C(Cl)C=C1O GCVGCXMTCJMBHY-UHFFFAOYSA-N 0.000 claims description 8
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
- A61K38/22—Hormones
- A61K38/28—Insulins
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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- 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
Landscapes
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US34761002P | 2002-01-09 | 2002-01-09 | |
| US60/347,610 | 2002-01-09 | ||
| PCT/US2003/000878 WO2003057650A2 (en) | 2002-01-09 | 2003-01-09 | Polymorphs of sodium 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate |
Publications (2)
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| AU2003223158A1 AU2003223158A1 (en) | 2003-07-24 |
| AU2003223158B2 true AU2003223158B2 (en) | 2008-01-17 |
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| Country | Link |
|---|---|
| US (5) | US7227033B2 (enExample) |
| EP (2) | EP2272501B1 (enExample) |
| JP (1) | JP4508646B2 (enExample) |
| AU (1) | AU2003223158B2 (enExample) |
| CA (1) | CA2471144C (enExample) |
| ES (2) | ES2412306T3 (enExample) |
| WO (1) | WO2003057650A2 (enExample) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL126318A (en) | 1996-03-29 | 2004-09-27 | Emisphere Tech Inc | Compounds and compositions for delivering active agents and some novel carrier compounds |
| US6991798B1 (en) | 1998-08-07 | 2006-01-31 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| PT1299348E (pt) | 2000-06-29 | 2008-05-12 | Emisphere Tech Inc | Compostos e composições para administração de agentes activos |
| CA2471144C (en) * | 2002-01-09 | 2011-06-07 | Emisphere Technologies, Inc. | Polymorphs of sodium 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate |
| WO2004062587A2 (en) * | 2003-01-06 | 2004-07-29 | Emisphere Technologies, Inc. | Night-time oral insulin therapy |
| US20050203001A1 (en) * | 2004-03-05 | 2005-09-15 | Emisphere Technologies, Inc. | Oral insulin therapies and protocol |
| US20050192298A1 (en) * | 2004-02-27 | 2005-09-01 | Pfizer Inc | Crystal forms of E-2-Methoxy-N-(3-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-allyl)-acetamide |
| US8273794B2 (en) * | 2004-05-14 | 2012-09-25 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| MXPA06013384A (es) | 2004-05-19 | 2007-03-01 | Emisphere Tech Inc | Formulaciones topicas de cromolin. |
| CN1968699B (zh) | 2004-05-19 | 2010-12-15 | 爱密斯菲尔科技公司 | 阿昔洛韦制剂 |
| CA2573856A1 (en) * | 2004-08-03 | 2006-02-16 | Emisphere Technologies, Inc. | Antidiabetic oral insulin-biguanide combination |
| FR2875807B1 (fr) * | 2004-09-30 | 2006-11-17 | Servier Lab | Forme cristalline alpha du ranelate de strontium, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
| GB0427600D0 (en) * | 2004-12-16 | 2005-01-19 | Novartis Ag | Organic compounds |
| GB0427603D0 (en) * | 2004-12-16 | 2005-01-19 | Novartis Ag | Organic compounds |
| CA2591515C (en) * | 2004-12-29 | 2010-06-22 | Emisphere Technologies, Inc. | Pharmaceutical formulations of gallium salts |
| WO2006076692A1 (en) | 2005-01-12 | 2006-07-20 | Emisphere Technologies, Inc. | Compositions for buccal delivery of parathyroid hormone |
| US8030271B2 (en) | 2005-07-05 | 2011-10-04 | Emisphere Technologies, Inc. | Compositions and methods for buccal delivery of human growth hormone |
| US9364502B2 (en) * | 2006-06-28 | 2016-06-14 | Emisphere Technologies, Inc. | Gallium nitrate formulations |
| WO2011017346A2 (en) | 2009-08-03 | 2011-02-10 | Emisphere Technologies, Inc. | Fast-acting naproxen composition with reduced gastrointestinal effects |
| MX375442B (es) | 2012-09-21 | 2025-03-06 | Intensity Therapeutics Inc | Un agente terapéutico y un agente mejorador de la permeación intracelular para usarse en el tratamiento de cáncer. |
| KR102367083B1 (ko) | 2012-11-13 | 2022-02-24 | 아도시아 | 치환된 음이온성 화합물을 포함하는 속효성 인슐린 제형 |
| FR3020947B1 (fr) * | 2014-05-14 | 2018-08-31 | Adocia | Composition aqueuse comprenant au moins une proteine et un agent solubilisant, sa preparation et ses utilisations |
| US9795678B2 (en) | 2014-05-14 | 2017-10-24 | Adocia | Fast-acting insulin composition comprising a substituted anionic compound and a polyanionic compound |
| FR3043557B1 (fr) | 2015-11-16 | 2019-05-31 | Adocia | Composition a action rapide d'insuline comprenant un citrate substitue |
| CN113167568B (zh) * | 2018-11-29 | 2023-04-28 | 日本电气方案创新株式会社 | 坐标计算装置、坐标计算方法和计算机可读记录介质 |
| CN111925298B (zh) * | 2020-09-02 | 2023-05-30 | 无锡紫杉药业有限公司 | 一种4-cnab及其制备方法 |
Family Cites Families (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5811856B2 (ja) * | 1975-07-14 | 1983-03-04 | 中外製薬株式会社 | ２ ４− ビス （２’ − アセトキシベンズアミド ） アンソクコウサンノ イケイケツシヨウノ セイゾウホウ |
| JPS5312417A (en) * | 1976-07-20 | 1978-02-03 | Sumitomo Chem Co Ltd | Preparation of amorphous d rugs |
| US4421685A (en) | 1980-03-27 | 1983-12-20 | Eli Lilly And Company | Process for producing an insulin |
| DE3266360D1 (en) * | 1981-06-16 | 1985-10-24 | Choay Sa | Medicines containing as active ingredients compounds of the arylbenzenesulfonamide-type, and processes for their preparation |
| USRE35862E (en) | 1986-08-18 | 1998-07-28 | Emisphere Technologies, Inc. | Delivery systems for pharmacological agents encapsulated with proteinoids |
| US5629020A (en) | 1994-04-22 | 1997-05-13 | Emisphere Technologies, Inc. | Modified amino acids for drug delivery |
| US5443841A (en) | 1992-06-15 | 1995-08-22 | Emisphere Technologies, Inc. | Proteinoid microspheres and methods for preparation and use thereof |
| US5583020A (en) * | 1992-11-24 | 1996-12-10 | Ribozyme Pharmaceuticals, Inc. | Permeability enhancers for negatively charged polynucleotides |
| US5401516A (en) | 1992-12-21 | 1995-03-28 | Emisphere Technologies, Inc. | Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof |
| EP0696208B1 (en) | 1993-04-22 | 2001-08-22 | Emisphere Technologies, Inc. | Oral drug delivery compositions |
| US5643957A (en) | 1993-04-22 | 1997-07-01 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| US5534488A (en) | 1993-08-13 | 1996-07-09 | Eli Lilly And Company | Insulin formulation |
| JP3462895B2 (ja) * | 1993-11-05 | 2003-11-05 | 三井化学株式会社 | 安息香酸誘導体の多価金属塩の製造方法 |
| US5474978A (en) | 1994-06-16 | 1995-12-12 | Eli Lilly And Company | Insulin analog formulations |
| US5866536A (en) | 1995-03-31 | 1999-02-02 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| US5650386A (en) | 1995-03-31 | 1997-07-22 | Emisphere Technologies, Inc. | Compositions for oral delivery of active agents |
| TW487582B (en) | 1995-08-11 | 2002-05-21 | Nissan Chemical Ind Ltd | Method for converting sparingly water-soluble medical substance to amorphous state |
| US5776888A (en) | 1997-02-07 | 1998-07-07 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| CA2319672C (en) * | 1997-02-07 | 2011-01-04 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| GB9808896D0 (en) * | 1998-04-25 | 1998-06-24 | Smithkline Beecham Plc | Novel compound |
| CZ298170B6 (cs) * | 1998-06-19 | 2007-07-11 | Teijin Limited | Polymorfní a amorfní modifikace 2-(3-kyan-4-isobutoxyfenyl)-4-methyl-5-thiazolkarboxylové kyseliny a zpusob jejich prípravy |
| JP4430235B2 (ja) | 1998-08-07 | 2010-03-10 | エミスフェアー・テクノロジーズ・インク | 活性剤のデリバリーのための化合物及び組成物 |
| BR0008590A (pt) | 1999-01-08 | 2001-10-30 | Emisphere Tech Inc | Agente de entrega polimérico, composição, formade unidade de dosagem, método para administrarum agente biologicamente ativo a um animalnecessitando o agente, método para preparar umacomposição; e composto |
| DE19903275A1 (de) * | 1999-01-28 | 2000-08-03 | Merck Patent Gmbh | Lyophilisate mit verbesserter Rekonstituierbarkeit |
| CA2361716C (en) | 1999-02-05 | 2009-04-28 | Emisphere Technologies, Inc. | Method of preparing alkylated salicylamides |
| AU3378100A (en) | 1999-02-26 | 2000-09-14 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| WO2000059863A1 (en) * | 1999-04-05 | 2000-10-12 | Emisphere Technologies, Inc. | Disodium salts, monohydrates, and ethanol solvates |
| GB9923933D0 (en) * | 1999-10-08 | 1999-12-08 | Smithkline Beecham Lab | Novel pharmaceutical |
| GB9923934D0 (en) * | 1999-10-08 | 1999-12-08 | Smithkline Beecham Plc | Novel pharmaceutical |
| BRPI0015567B8 (pt) | 1999-11-05 | 2021-05-25 | Emisphere Tech Inc | composto, composição farmacêutica, forma de unidade de dosagem, uso da composição farmacêutica e método para preparar uma composição farmacêutica |
| JP2001240581A (ja) * | 2000-02-29 | 2001-09-04 | Senju Pharmaceut Co Ltd | アミノベンズアミド誘導体およびその用途 |
| AU2001281483A1 (en) | 2000-03-21 | 2001-10-03 | Emisphere Technologies, Inc. | Method of preparing alkylated salicylamides via a dicarboxylate intermediate |
| PT1299348E (pt) * | 2000-06-29 | 2008-05-12 | Emisphere Tech Inc | Compostos e composições para administração de agentes activos |
| US6482847B2 (en) * | 2000-10-03 | 2002-11-19 | Hoffmann-La Roche Inc. | Amorphous form of cell cycle inhibitor having improved solubility and bioavailability |
| CA2471144C (en) | 2002-01-09 | 2011-06-07 | Emisphere Technologies, Inc. | Polymorphs of sodium 4-[(4-chloro-2-hydroxybenzoyl)amino]butanoate |
-
2003
- 2003-01-09 CA CA2471144A patent/CA2471144C/en not_active Expired - Lifetime
- 2003-01-09 ES ES10012220T patent/ES2412306T3/es not_active Expired - Lifetime
- 2003-01-09 EP EP10012220A patent/EP2272501B1/en not_active Expired - Lifetime
- 2003-01-09 AU AU2003223158A patent/AU2003223158B2/en not_active Ceased
- 2003-01-09 WO PCT/US2003/000878 patent/WO2003057650A2/en not_active Ceased
- 2003-01-09 EP EP03719286.1A patent/EP1469827B1/en not_active Expired - Lifetime
- 2003-01-09 US US10/501,205 patent/US7227033B2/en not_active Expired - Lifetime
- 2003-01-09 ES ES03719286.1T patent/ES2664189T3/es not_active Expired - Lifetime
- 2003-01-09 JP JP2003557970A patent/JP4508646B2/ja not_active Expired - Fee Related
-
2005
- 2005-07-14 US US11/183,039 patent/US7208178B2/en not_active Expired - Lifetime
-
2007
- 2007-03-14 US US11/686,341 patent/US7462368B2/en not_active Expired - Lifetime
- 2007-04-12 US US11/734,591 patent/US7420085B2/en not_active Expired - Lifetime
-
2008
- 2008-07-02 US US12/167,126 patent/US7893297B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2005520803A (ja) | 2005-07-14 |
| EP2272501A1 (en) | 2011-01-12 |
| ES2664189T3 (es) | 2018-04-18 |
| US20080033204A1 (en) | 2008-02-07 |
| US20070161708A1 (en) | 2007-07-12 |
| CA2471144A1 (en) | 2003-07-17 |
| US7208178B2 (en) | 2007-04-24 |
| AU2003223158A1 (en) | 2003-07-24 |
| US20090010882A1 (en) | 2009-01-08 |
| US7420085B2 (en) | 2008-09-02 |
| US20050250852A1 (en) | 2005-11-10 |
| ES2412306T3 (es) | 2013-07-11 |
| EP1469827A2 (en) | 2004-10-27 |
| EP1469827A4 (en) | 2006-08-16 |
| JP4508646B2 (ja) | 2010-07-21 |
| CA2471144C (en) | 2011-06-07 |
| WO2003057650A2 (en) | 2003-07-17 |
| EP2272501B1 (en) | 2013-03-20 |
| WO2003057650A3 (en) | 2003-10-16 |
| US20050272639A1 (en) | 2005-12-08 |
| US7227033B2 (en) | 2007-06-05 |
| US7893297B2 (en) | 2011-02-22 |
| HK1153136A1 (en) | 2012-03-23 |
| US7462368B2 (en) | 2008-12-09 |
| EP1469827B1 (en) | 2017-12-27 |
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| FGA | Letters patent sealed or granted (standard patent) | ||
| GM | Mortgages registered |
Name of requester: MHR INSTITUTIONAL PARTNERS IIA LP |
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| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |