AU2004274449A1 - Novel gamma secretase inhibitors - Google Patents
Novel gamma secretase inhibitors Download PDFInfo
- Publication number
- AU2004274449A1 AU2004274449A1 AU2004274449A AU2004274449A AU2004274449A1 AU 2004274449 A1 AU2004274449 A1 AU 2004274449A1 AU 2004274449 A AU2004274449 A AU 2004274449A AU 2004274449 A AU2004274449 A AU 2004274449A AU 2004274449 A1 AU2004274449 A1 AU 2004274449A1
- Authority
- AU
- Australia
- Prior art keywords
- alkyl
- substituted
- group
- compound
- pct
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/663,042 US20040171614A1 (en) | 2002-02-06 | 2003-09-16 | Novel gamma secretase inhibitors |
| US10/663,042 | 2003-09-16 | ||
| PCT/US2004/030191 WO2005028440A1 (en) | 2003-09-16 | 2004-09-15 | Novel gamma secretase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2004274449A1 true AU2004274449A1 (en) | 2005-03-31 |
Family
ID=34375807
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2004274449A Abandoned AU2004274449A1 (en) | 2003-09-16 | 2004-09-15 | Novel gamma secretase inhibitors |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US20040171614A1 (https=) |
| EP (1) | EP1663975A1 (https=) |
| JP (1) | JP2007519607A (https=) |
| KR (1) | KR20060106814A (https=) |
| CN (1) | CN101061097A (https=) |
| AR (1) | AR045656A1 (https=) |
| AU (1) | AU2004274449A1 (https=) |
| CA (1) | CA2538590A1 (https=) |
| IL (1) | IL174270A0 (https=) |
| MX (1) | MXPA06003058A (https=) |
| PE (1) | PE20050377A1 (https=) |
| TW (1) | TW200519087A (https=) |
| WO (1) | WO2005028440A1 (https=) |
| ZA (1) | ZA200602193B (https=) |
Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7256186B2 (en) * | 2002-02-06 | 2007-08-14 | Schering Corporation | Gamma secretase inhibitors |
| US20040171614A1 (en) * | 2002-02-06 | 2004-09-02 | Schering-Plough Corporation | Novel gamma secretase inhibitors |
| US7521481B2 (en) | 2003-02-27 | 2009-04-21 | Mclaurin Joanne | Methods of preventing, treating and diagnosing disorders of protein aggregation |
| MXPA06001558A (es) * | 2003-08-08 | 2006-05-15 | Schering Corp | Inhibidores de amina ciclica bace-1 que poseen un sustituyente heterociclico. |
| TWI300410B (en) * | 2004-04-05 | 2008-09-01 | Schering Corp | Novel gamma secretase inhibitors |
| PE20060481A1 (es) * | 2004-06-30 | 2006-06-19 | Schering Corp | N-arilsulfonilaminas heterociclicas sustituidas como inhibidores de gamma-secretasas |
| DE602005007245D1 (https=) * | 2004-07-28 | 2008-07-10 | Schering Corp | |
| WO2008008720A2 (en) | 2006-07-10 | 2008-01-17 | Synapsin Pharmaceuticals, Inc. | Compositions and methods relating to solenopsins and their uses in treating neurological disorders and enhancing physical performance |
| US9259419B2 (en) | 2006-07-10 | 2016-02-16 | Synapsin Pharmaceuticals, Inc. | Compositions and methods relating to solenopsins and their uses in treating neurological disorders and enhancing physical performance |
| EP2383267A1 (de) * | 2006-09-29 | 2011-11-02 | Grünenthal GmbH | Substituierte Sulfonamid-Derivate |
| EP2089383B1 (en) | 2006-11-09 | 2015-09-16 | Probiodrug AG | 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases |
| US9126987B2 (en) | 2006-11-30 | 2015-09-08 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
| AU2008220785B2 (en) | 2007-03-01 | 2013-02-21 | Vivoryon Therapeutics N.V. | New use of glutaminyl cyclase inhibitors |
| JP5667440B2 (ja) | 2007-04-18 | 2015-02-12 | プロビオドルグ エージー | グルタミニルシクラーゼ阻害剤としてのチオ尿素誘導体 |
| JP2010528036A (ja) * | 2007-05-25 | 2010-08-19 | エラン ファーマシューティカルズ,インコーポレイテッド | γセクレターゼの阻害剤としてのピラゾロピロリジン |
| JP2011523655A (ja) * | 2008-06-03 | 2011-08-18 | フレセニウス メディカル ケア ドイッチュランド ゲーエムベーハー | ガンマセクレターゼモジュレータを含む医薬組成物 |
| JP5934645B2 (ja) | 2009-09-11 | 2016-06-15 | プロビオドルグ エージー | グルタミニルシクラーゼ阻害剤としてのヘテロ環式誘導体 |
| WO2011107530A2 (en) | 2010-03-03 | 2011-09-09 | Probiodrug Ag | Novel inhibitors |
| JP5688745B2 (ja) | 2010-03-10 | 2015-03-25 | プロビオドルグ エージー | グルタミニルシクラーゼ(qc、ec2.3.2.5)の複素環阻害剤 |
| WO2011131748A2 (en) | 2010-04-21 | 2011-10-27 | Probiodrug Ag | Novel inhibitors |
| EP2686313B1 (en) | 2011-03-16 | 2016-02-03 | Probiodrug AG | Benzimidazole derivatives as inhibitors of glutaminyl cyclase |
| AU2012338581B2 (en) | 2011-11-18 | 2016-12-08 | Nxera Pharma Uk Limited | Muscarinic M1 receptor agonists |
| WO2014122474A1 (en) | 2013-02-07 | 2014-08-14 | Takeda Pharmaceutical Company Limited | Piperidin-1 -yl and azepin-1 -yl carboxylates as muscarinic m4 receptor agonists |
| GB201404922D0 (en) | 2014-03-19 | 2014-04-30 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB201513743D0 (en) | 2015-08-03 | 2015-09-16 | Heptares Therapeutics Ltd | Muscarinic agonists |
| GB201519352D0 (en) | 2015-11-02 | 2015-12-16 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB201617454D0 (en) | 2016-10-14 | 2016-11-30 | Heptares Therapeutics Limited | Pharmaceutical compounds |
| EP3645008A4 (en) * | 2017-06-30 | 2020-12-09 | Bristol-Myers Squibb Company | SUBSTITUTED QUINOLINYCYCLOHEXYLPROPANAMIDE COMPOUNDS AND IMPROVED METHODS FOR THEIR PRODUCTION |
| ES2812698T3 (es) | 2017-09-29 | 2021-03-18 | Probiodrug Ag | Inhibidores de glutaminil ciclasa |
| GB201810239D0 (en) | 2018-06-22 | 2018-08-08 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB201819960D0 (en) | 2018-12-07 | 2019-01-23 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB201819961D0 (en) | 2018-12-07 | 2019-01-23 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB202020191D0 (en) | 2020-12-18 | 2021-02-03 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9804426D0 (en) * | 1998-03-02 | 1998-04-29 | Pfizer Ltd | Heterocycles |
| US6589978B2 (en) * | 2000-06-30 | 2003-07-08 | Hoffman-La Roche Inc. | 1-sulfonyl pyrrolidine derivatives |
| TW200302717A (en) * | 2002-02-06 | 2003-08-16 | Schering Corp | Novel gamma secretase inhibitors |
| US20040171614A1 (en) * | 2002-02-06 | 2004-09-02 | Schering-Plough Corporation | Novel gamma secretase inhibitors |
-
2003
- 2003-09-16 US US10/663,042 patent/US20040171614A1/en not_active Abandoned
-
2004
- 2004-09-14 TW TW093127793A patent/TW200519087A/zh unknown
- 2004-09-14 PE PE2004000889A patent/PE20050377A1/es not_active Application Discontinuation
- 2004-09-15 WO PCT/US2004/030191 patent/WO2005028440A1/en not_active Ceased
- 2004-09-15 MX MXPA06003058A patent/MXPA06003058A/es not_active Application Discontinuation
- 2004-09-15 EP EP04784148A patent/EP1663975A1/en not_active Withdrawn
- 2004-09-15 KR KR1020067005286A patent/KR20060106814A/ko not_active Withdrawn
- 2004-09-15 AR ARP040103301A patent/AR045656A1/es unknown
- 2004-09-15 CA CA002538590A patent/CA2538590A1/en not_active Abandoned
- 2004-09-15 JP JP2006526994A patent/JP2007519607A/ja active Pending
- 2004-09-15 AU AU2004274449A patent/AU2004274449A1/en not_active Abandoned
- 2004-09-15 CN CNA2004800335264A patent/CN101061097A/zh active Pending
-
2006
- 2006-03-12 IL IL174270A patent/IL174270A0/en unknown
- 2006-03-15 ZA ZA200602193A patent/ZA200602193B/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN101061097A (zh) | 2007-10-24 |
| EP1663975A1 (en) | 2006-06-07 |
| IL174270A0 (en) | 2006-08-01 |
| TW200519087A (en) | 2005-06-16 |
| WO2005028440A1 (en) | 2005-03-31 |
| JP2007519607A (ja) | 2007-07-19 |
| ZA200602193B (en) | 2007-09-26 |
| US20040171614A1 (en) | 2004-09-02 |
| AR045656A1 (es) | 2005-11-02 |
| PE20050377A1 (es) | 2005-05-30 |
| MXPA06003058A (es) | 2006-05-31 |
| KR20060106814A (ko) | 2006-10-12 |
| CA2538590A1 (en) | 2005-03-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PC1 | Assignment before grant (sect. 113) |
Owner name: SCHERING CORPORATION; PHARMACOPEIA, INC. Free format text: FORMER APPLICANT(S): SCHERING CORPORATION; PHARMACOPEIA DRUG DISCOVERY, INC. |
|
| MK5 | Application lapsed section 142(2)(e) - patent request and compl. specification not accepted |