NO325689B1 - Kondenserte pyrrolokarbazoler, samt anvendelser og farmasoytiske preparater - Google Patents
Kondenserte pyrrolokarbazoler, samt anvendelser og farmasoytiske preparater Download PDFInfo
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- NO325689B1 NO325689B1 NO20030845A NO20030845A NO325689B1 NO 325689 B1 NO325689 B1 NO 325689B1 NO 20030845 A NO20030845 A NO 20030845A NO 20030845 A NO20030845 A NO 20030845A NO 325689 B1 NO325689 B1 NO 325689B1
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- inclusive
- carbon atoms
- alkyl
- amino acid
- pyrimidyl
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- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Public Health (AREA)
- Medicinal Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Physical Education & Sports Medicine (AREA)
- Cardiology (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
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- Urology & Nephrology (AREA)
- Orthopedic Medicine & Surgery (AREA)
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Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US22780300P | 2000-08-25 | 2000-08-25 | |
| US27845501P | 2001-03-23 | 2001-03-23 | |
| US09/935,285 US6630500B2 (en) | 2000-08-25 | 2001-08-22 | Selected fused pyrrolocarbazoles |
| PCT/US2001/026266 WO2002017914A2 (en) | 2000-08-25 | 2001-08-23 | Fused pyrrolocarbazoles against inflammation |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO20030845D0 NO20030845D0 (no) | 2003-02-24 |
| NO20030845L NO20030845L (no) | 2003-04-16 |
| NO325689B1 true NO325689B1 (no) | 2008-07-07 |
Family
ID=27397767
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20030845A NO325689B1 (no) | 2000-08-25 | 2003-02-24 | Kondenserte pyrrolokarbazoler, samt anvendelser og farmasoytiske preparater |
Country Status (26)
| Country | Link |
|---|---|
| US (3) | US6630500B2 (ko) |
| EP (1) | EP1311263B1 (ko) |
| JP (1) | JP5399598B2 (ko) |
| KR (1) | KR100810190B1 (ko) |
| CN (1) | CN1298323C (ko) |
| AR (1) | AR034143A1 (ko) |
| AT (1) | ATE306920T1 (ko) |
| AU (1) | AU8520501A (ko) |
| BG (1) | BG66103B1 (ko) |
| BR (1) | BR0113776A (ko) |
| CA (1) | CA2420592C (ko) |
| CZ (1) | CZ303707B6 (ko) |
| DE (1) | DE60114215T2 (ko) |
| DK (1) | DK1311263T3 (ko) |
| EA (1) | EA006371B1 (ko) |
| ES (1) | ES2250463T3 (ko) |
| HK (1) | HK1053989A1 (ko) |
| HU (1) | HU230128B1 (ko) |
| IL (2) | IL154590A0 (ko) |
| MX (1) | MXPA03001562A (ko) |
| NO (1) | NO325689B1 (ko) |
| NZ (1) | NZ524288A (ko) |
| PL (1) | PL212956B1 (ko) |
| SK (1) | SK287498B6 (ko) |
| TW (1) | TWI299731B (ko) |
| WO (1) | WO2002017914A2 (ko) |
Families Citing this family (88)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6811992B1 (en) | 1998-05-14 | 2004-11-02 | Ya Fang Liu | Method for identifying MLK inhibitors for the treatment of neurological conditions |
| DK1556083T3 (da) | 2002-10-08 | 2011-04-04 | Rinat Neuroscience Corp | Fremgangsmåde til behandling af post-operative smerter ved indgivelse af en antistof mod nervevækstfaktor og sammensætning indeholdende samme |
| UA80447C2 (en) | 2002-10-08 | 2007-09-25 | Methods for treating pain by administering nerve growth factor antagonist and opioid analgesic | |
| US9498530B2 (en) | 2002-12-24 | 2016-11-22 | Rinat Neuroscience Corp. | Methods for treating osteoarthritis pain by administering a nerve growth factor antagonist and compositions containing the same |
| US7569364B2 (en) | 2002-12-24 | 2009-08-04 | Pfizer Inc. | Anti-NGF antibodies and methods using same |
| KR101250818B1 (ko) | 2002-12-24 | 2013-04-15 | 리나트 뉴로사이언스 코프. | 항-ｎｇｆ 항체 및 그것을 이용하는 방법 |
| MXPA05008815A (es) | 2003-02-19 | 2006-05-25 | Rinat Neuroscience Corp | Metodos para tratar el dolor al administrar un antagonista del factor de crecimiento de nervios y un farmaco antiinflamatorio no esteroidal y composiciones que contienen los mismos. |
| TW201319088A (zh) | 2003-07-18 | 2013-05-16 | Amgen Inc | 對肝細胞生長因子具專一性之結合劑 |
| US7241779B2 (en) | 2003-12-23 | 2007-07-10 | Cephalon, Inc. | Fused pyrrolocarbazoles |
| US7169802B2 (en) * | 2003-12-23 | 2007-01-30 | Cephalon, Inc. | Fused pyrrolocarbazoles |
| MXPA06011463A (es) | 2004-04-07 | 2007-04-25 | Rinat Neuroscience Corp | Metodos para tratar dolor por cancer de hueso al administrar un antagonista de factor de crecimiento de nervio. |
| JP2008521900A (ja) | 2004-11-30 | 2008-06-26 | アムジエン・インコーポレーテツド | キノリン及びキナゾリン類似体並びにがん治療のための医薬としてのその使用 |
| US20060134174A1 (en) * | 2004-12-22 | 2006-06-22 | Bausch & Lomb Incorporated | Pharmaceutical delivery system and method of use |
| US20060134175A1 (en) * | 2004-12-22 | 2006-06-22 | Stephen Bartels | Drug eluting pharmaceutical delivery system for treatment of ocular disease and method of use |
| US20060134176A1 (en) * | 2004-12-22 | 2006-06-22 | Bausch & Lomb Incorporated | Pharmaceutical delivery system and method of use |
| US20060216288A1 (en) * | 2005-03-22 | 2006-09-28 | Amgen Inc | Combinations for the treatment of cancer |
| WO2007002670A2 (en) * | 2005-06-28 | 2007-01-04 | Bausch & Lomb Incorporated | Method of lowering intraocular pressure |
| AR059066A1 (es) | 2006-01-27 | 2008-03-12 | Amgen Inc | Combinaciones del inhibidor de la angiopoyetina -2 (ang2) y el inhibidor del factor de crecimiento endotelial vascular (vegf) |
| US8217177B2 (en) | 2006-07-14 | 2012-07-10 | Amgen Inc. | Fused heterocyclic derivatives and methods of use |
| PE20080403A1 (es) | 2006-07-14 | 2008-04-25 | Amgen Inc | Derivados heterociclicos fusionados y metodos de uso |
| US20080021013A1 (en) * | 2006-07-21 | 2008-01-24 | Cephalon, Inc. | JAK inhibitors for treatment of myeloproliferative disorders |
| AU2007338792B2 (en) | 2006-12-20 | 2012-05-31 | Amgen Inc. | Substituted heterocycles and methods of use |
| WO2008086014A2 (en) | 2007-01-09 | 2008-07-17 | Amgen Inc. | Bis-aryl amide derivatives useful for the treatment of cancer |
| MX2009008531A (es) | 2007-02-16 | 2009-08-26 | Amgen Inc | Cetonas de heterociclilo que contienen nitrogeno y su uso como inhibidores de c-met. |
| WO2008151323A1 (en) * | 2007-06-08 | 2008-12-11 | University Of Massachusetts | Mixed lineage kinases and metabolic disorders |
| JP5718640B2 (ja) | 2007-08-21 | 2015-05-13 | アムジエン・インコーポレーテツド | ヒトｃ−ｆｍｓ抗原結合性タンパク質 |
| MX2011005055A (es) * | 2008-11-19 | 2011-05-31 | Cephalon Inc | Nuevas formas de un compuesto de indazolo [5,4-a]pirrolo[3,4-c]car bazol. |
| EP2192121A1 (en) | 2008-11-27 | 2010-06-02 | Cephalon France | Regioselective reduction of fused pyrrolocarbazoles-5,7-diones |
| KR101038055B1 (ko) * | 2010-06-10 | 2011-06-01 | 송광섭 | 수중 마사지장치 |
| WO2011161217A2 (en) | 2010-06-23 | 2011-12-29 | Palacký University in Olomouc | Targeting of vegfr2 |
| ES2620521T3 (es) | 2011-03-23 | 2017-06-28 | Amgen Inc. | Inhibidores duales tricíclicos condensados de CDK 4/6 y FLT3 |
| WO2013025939A2 (en) | 2011-08-16 | 2013-02-21 | Indiana University Research And Technology Corporation | Compounds and methods for treating cancer by inhibiting the urokinase receptor |
| AR090263A1 (es) | 2012-03-08 | 2014-10-29 | Hoffmann La Roche | Terapia combinada de anticuerpos contra el csf-1r humano y las utilizaciones de la misma |
| WO2014036022A1 (en) | 2012-08-29 | 2014-03-06 | Amgen Inc. | Quinazolinone compounds and derivatives thereof |
| WO2016112111A1 (en) | 2015-01-08 | 2016-07-14 | The Board Of Trustees Of The Leland Stanford Junior University | Factors and cells that provide for induction of bone, bone marrow, and cartilage |
| MY196830A (en) | 2016-12-22 | 2023-05-03 | Amgen Inc | Kras g12c inhibitors and methods of using the same |
| JOP20190272A1 (ar) | 2017-05-22 | 2019-11-21 | Amgen Inc | مثبطات kras g12c وطرق لاستخدامها |
| EP4141005B1 (en) | 2017-09-08 | 2024-04-03 | Amgen Inc. | Inhibitors of kras g12c and methods of using the same |
| MA52496A (fr) | 2018-05-04 | 2021-03-10 | Amgen Inc | Inhibiteurs de kras g12c et leurs procédés d'utilisation |
| AU2019262589B2 (en) | 2018-05-04 | 2022-07-07 | Amgen Inc. | KRAS G12C inhibitors and methods of using the same |
| EP3790886B1 (en) | 2018-05-10 | 2024-06-26 | Amgen Inc. | Kras g12c inhibitors for the treatment of cancer |
| WO2019232419A1 (en) | 2018-06-01 | 2019-12-05 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| WO2019241157A1 (en) | 2018-06-11 | 2019-12-19 | Amgen Inc. | Kras g12c inhibitors for treating cancer |
| CA3100390A1 (en) | 2018-06-12 | 2020-03-12 | Amgen Inc. | Kras g12c inhibitors encompassing piperazine ring and use thereof in the treatment of cancer |
| JP7516029B2 (ja) | 2018-11-16 | 2024-07-16 | アムジエン・インコーポレーテツド | Ｋｒａｓ ｇ１２ｃ阻害剤化合物の重要な中間体の改良合成法 |
| JP7377679B2 (ja) | 2018-11-19 | 2023-11-10 | アムジエン・インコーポレーテツド | がん治療のためのｋｒａｓｇ１２ｃ阻害剤及び１種以上の薬学的に活性な追加の薬剤を含む併用療法 |
| CA3117222A1 (en) | 2018-11-19 | 2020-05-28 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
| EP3898616B1 (en) | 2018-12-20 | 2024-10-02 | Amgen Inc. | Heteroaryl amides useful as kif18a inhibitors |
| WO2020132651A1 (en) | 2018-12-20 | 2020-06-25 | Amgen Inc. | Kif18a inhibitors |
| US20220002311A1 (en) | 2018-12-20 | 2022-01-06 | Amgen Inc. | Kif18a inhibitors |
| CR20210387A (es) | 2018-12-20 | 2021-08-19 | Amgen Inc | Inhibidores de kif18a |
| KR20210146287A (ko) | 2019-03-01 | 2021-12-03 | 레볼루션 메디슨즈, 인크. | 이환식 헤테로아릴 화합물 및 이의 용도 |
| CN113727758A (zh) | 2019-03-01 | 2021-11-30 | 锐新医药公司 | 双环杂环基化合物及其用途 |
| EP3738593A1 (en) | 2019-05-14 | 2020-11-18 | Amgen, Inc | Dosing of kras inhibitor for treatment of cancers |
| CN118834208A (zh) | 2019-05-21 | 2024-10-25 | 美国安进公司 | 固态形式 |
| WO2021026101A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
| CA3147276A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
| CA3146693A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
| AU2020324406A1 (en) | 2019-08-02 | 2022-03-17 | Amgen Inc. | KIF18A inhibitors |
| EP4048671A1 (en) | 2019-10-24 | 2022-08-31 | Amgen Inc. | Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer |
| KR20220109407A (ko) | 2019-11-04 | 2022-08-04 | 레볼루션 메디슨즈, 인크. | Ras 억제제 |
| AU2020379734A1 (en) | 2019-11-04 | 2022-05-05 | Revolution Medicines, Inc. | Ras inhibitors |
| CN115873020A (zh) | 2019-11-04 | 2023-03-31 | 锐新医药公司 | Ras抑制剂 |
| MX2022005525A (es) | 2019-11-08 | 2022-06-08 | Revolution Medicines Inc | Compuestos de heteroarilo bicíclicos y usos de estos. |
| KR20220101125A (ko) | 2019-11-14 | 2022-07-19 | 암젠 인크 | Kras g12c 억제제 화합물의 개선된 합성 |
| CA3161156A1 (en) | 2019-11-14 | 2021-05-20 | Amgen Inc. | Improved synthesis of kras g12c inhibitor compound |
| EP4065231A1 (en) | 2019-11-27 | 2022-10-05 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
| AU2021206217A1 (en) | 2020-01-07 | 2022-09-01 | Revolution Medicines, Inc. | SHP2 inhibitor dosing and methods of treating cancer |
| AU2021293228A1 (en) | 2020-06-18 | 2023-02-09 | Revolution Medicines, Inc. | Methods for delaying, preventing, and treating acquired resistance to RAS inhibitors |
| CA3187757A1 (en) | 2020-09-03 | 2022-03-24 | Ethan AHLER | Use of sos1 inhibitors to treat malignancies with shp2 mutations |
| JP2023541916A (ja) | 2020-09-15 | 2023-10-04 | レボリューション メディシンズ インコーポレイテッド | がんの治療における、ｒａｓ阻害剤としてのインドール誘導体 |
| AU2021409816A1 (en) | 2020-12-22 | 2023-07-06 | Qilu Regor Therapeutics Inc. | Sos1 inhibitors and uses thereof |
| JP2024516450A (ja) | 2021-05-05 | 2024-04-15 | レボリューション メディシンズ インコーポレイテッド | 共有結合性ｒａｓ阻害剤及びその使用 |
| CN117616031A (zh) | 2021-05-05 | 2024-02-27 | 锐新医药公司 | 用于治疗癌症的ras抑制剂 |
| JP2024517847A (ja) | 2021-05-05 | 2024-04-23 | レボリューション メディシンズ インコーポレイテッド | Ｒａｓ阻害剤 |
| AR127308A1 (es) | 2021-10-08 | 2024-01-10 | Revolution Medicines Inc | Inhibidores ras |
| EP4448526A1 (en) | 2021-12-17 | 2024-10-23 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
| EP4227307A1 (en) | 2022-02-11 | 2023-08-16 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
| WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
| US20230348608A1 (en) | 2022-04-27 | 2023-11-02 | Regeneron Pharmaceuticals, Inc. | Treatment Of Arthropathy Based Upon Stratification Of Osteoarthritis Polygenic Risk Score |
| WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
| WO2024081916A1 (en) | 2022-10-14 | 2024-04-18 | Black Diamond Therapeutics, Inc. | Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives |
| US20240310383A1 (en) | 2023-03-17 | 2024-09-19 | Regeneron Pharmaceuticals, Inc. | Proteomic Risk Score For Osteoarthritis (OA) |
| WO2024206858A1 (en) | 2023-03-30 | 2024-10-03 | Revolution Medicines, Inc. | Compositions for inducing ras gtp hydrolysis and uses thereof |
| WO2024211712A1 (en) | 2023-04-07 | 2024-10-10 | Revolution Medicines, Inc. | Condensed macrocyclic compounds as ras inhibitors |
| WO2024211663A1 (en) | 2023-04-07 | 2024-10-10 | Revolution Medicines, Inc. | Condensed macrocyclic compounds as ras inhibitors |
| US20240352038A1 (en) | 2023-04-14 | 2024-10-24 | Revolution Medicines, Inc. | Crystalline forms of ras inhibitors, compositions containing the same, and methods of use thereof |
| US20240352036A1 (en) | 2023-04-14 | 2024-10-24 | Revolution Medicines, Inc. | Crystalline forms of ras inhibitors, compositions containing the same, and methods of use thereof |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4552842A (en) | 1983-01-28 | 1985-11-12 | Bristol-Myers Company | Process for producing rebeccamycin |
| US5438050A (en) | 1988-02-06 | 1995-08-01 | Godecke Aktiengesellschaft | Indolocarbazole derivatives, processes for their preparation and compositions containing them |
| US5185260A (en) | 1991-08-29 | 1993-02-09 | The United States Of America As Represented By The United States Department Of Energy | Method for distinguishing normal and transformed cells using G1 kinase inhibitors |
| US5594009A (en) | 1994-10-14 | 1997-01-14 | Cephalon, Inc. | Fused pyrrolocarbazoles |
| US5705511A (en) | 1994-10-14 | 1998-01-06 | Cephalon, Inc. | Fused pyrrolocarbazoles |
| US5475110A (en) | 1994-10-14 | 1995-12-12 | Cephalon, Inc. | Fused Pyrrolocarbazoles |
| US5591855A (en) | 1994-10-14 | 1997-01-07 | Cephalon, Inc. | Fused pyrrolocarbazoles |
| US5705711A (en) * | 1995-08-17 | 1998-01-06 | Huntsman Specialty Chemicals Corporation | Manufacture of methyl tertiary butyl ether in reactive distillation column |
| US5808060A (en) | 1995-12-11 | 1998-09-15 | Cephalon, Inc. | Fused isoindolones |
| US5616724A (en) | 1996-02-21 | 1997-04-01 | Cephalon, Inc. | Fused pyrrolo[2,3-c]carbazole-6-ones |
| DE69709407T2 (de) | 1996-08-22 | 2002-05-29 | Bristol-Myers Squibb Co., Wallingford | Zytotoxischer aminozucker und verwandte zuckerderivate von indolopyrrolocarbazolen |
| US6127401A (en) | 1998-06-05 | 2000-10-03 | Cephalon, Inc. | Bridged indenopyrrolocarbazoles |
| JP2002525329A (ja) | 1998-09-25 | 2002-08-13 | セフアロン・インコーポレーテツド | 感覚毛細胞及び蝸牛ニューロンへの損傷を予防する／処置するための方法 |
| US6841567B1 (en) | 1999-02-12 | 2005-01-11 | Cephalon, Inc. | Cyclic substituted fused pyrrolocarbazoles and isoindolones |
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2001
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- 2001-08-23 AT AT01964340T patent/ATE306920T1/de active
- 2001-08-23 BR BR0113776-0A patent/BR0113776A/pt not_active Application Discontinuation
- 2001-08-23 DE DE60114215T patent/DE60114215T2/de not_active Expired - Lifetime
- 2001-08-23 PL PL365683A patent/PL212956B1/pl unknown
- 2001-08-23 AR ARP010104016A patent/AR034143A1/es not_active Application Discontinuation
- 2001-08-23 EP EP01964340A patent/EP1311263B1/en not_active Expired - Lifetime
- 2001-08-23 CZ CZ20030539A patent/CZ303707B6/cs not_active IP Right Cessation
- 2001-08-23 JP JP2002522887A patent/JP5399598B2/ja not_active Expired - Fee Related
- 2001-08-23 MX MXPA03001562A patent/MXPA03001562A/es active IP Right Grant
- 2001-08-23 WO PCT/US2001/026266 patent/WO2002017914A2/en active IP Right Grant
- 2001-08-23 DK DK01964340T patent/DK1311263T3/da active
- 2001-08-23 ES ES01964340T patent/ES2250463T3/es not_active Expired - Lifetime
- 2001-08-23 EA EA200300293A patent/EA006371B1/ru not_active IP Right Cessation
- 2001-08-23 HU HU0303103A patent/HU230128B1/hu not_active IP Right Cessation
- 2001-08-23 TW TW090120678A patent/TWI299731B/zh not_active IP Right Cessation
- 2001-08-23 KR KR1020037002676A patent/KR100810190B1/ko not_active IP Right Cessation
- 2001-08-23 AU AU8520501A patent/AU8520501A/xx active Pending
- 2001-08-23 NZ NZ524288A patent/NZ524288A/en unknown
- 2001-08-23 IL IL15459001A patent/IL154590A0/xx unknown
- 2001-08-23 SK SK219-2003A patent/SK287498B6/sk not_active IP Right Cessation
- 2001-08-23 CN CNB018146333A patent/CN1298323C/zh not_active Expired - Fee Related
- 2001-08-23 CA CA2420592A patent/CA2420592C/en not_active Expired - Fee Related
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2003
- 2003-02-24 NO NO20030845A patent/NO325689B1/no not_active IP Right Cessation
- 2003-03-21 BG BG107659A patent/BG66103B1/bg unknown
- 2003-03-26 US US10/400,136 patent/US7115613B2/en not_active Expired - Fee Related
- 2003-09-09 HK HK03106424A patent/HK1053989A1/xx not_active IP Right Cessation
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2006
- 2006-02-08 US US11/350,170 patent/US7230026B2/en not_active Expired - Fee Related
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2008
- 2008-04-27 IL IL191104A patent/IL191104A0/en unknown
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