DE69613369D1 - Chinazolin derivate - Google Patents
Chinazolin derivateInfo
- Publication number
- DE69613369D1 DE69613369D1 DE69613369T DE69613369T DE69613369D1 DE 69613369 D1 DE69613369 D1 DE 69613369D1 DE 69613369 T DE69613369 T DE 69613369T DE 69613369 T DE69613369 T DE 69613369T DE 69613369 D1 DE69613369 D1 DE 69613369D1
- Authority
- DE
- Germany
- Prior art keywords
- chinazolin
- derivatives
- chinazolin derivatives
- 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.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9508537.9A GB9508537D0 (en) | 1995-04-27 | 1995-04-27 | Quinazoline derivatives |
PCT/GB1996/000960 WO1996033979A1 (en) | 1995-04-27 | 1996-04-23 | Quinazoline derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
DE69613369D1 true DE69613369D1 (de) | 2001-07-19 |
DE69613369T2 DE69613369T2 (de) | 2002-05-23 |
Family
ID=10773596
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE69613369T Expired - Fee Related DE69613369T2 (de) | 1995-04-27 | 1996-04-23 | Chinazolin derivate |
Country Status (7)
Country | Link |
---|---|
US (1) | US5942514A (de) |
EP (1) | EP0824527B1 (de) |
JP (1) | JPH11504032A (de) |
AU (1) | AU5343296A (de) |
DE (1) | DE69613369T2 (de) |
GB (1) | GB9508537D0 (de) |
WO (1) | WO1996033979A1 (de) |
Families Citing this family (70)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW321649B (de) * | 1994-11-12 | 1997-12-01 | Zeneca Ltd | |
GB9424233D0 (en) * | 1994-11-30 | 1995-01-18 | Zeneca Ltd | Quinazoline derivatives |
GB9508538D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
GB9508535D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivative |
GB9508565D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quiazoline derivative |
GB9508537D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
EP0824525B1 (de) * | 1995-04-27 | 2001-06-13 | AstraZeneca AB | Chinazolin derivate |
GB9624482D0 (en) * | 1995-12-18 | 1997-01-15 | Zeneca Phaema S A | Chemical compounds |
IL125686A (en) | 1996-02-13 | 2002-11-10 | Zeneca Ltd | Quinazoline derivatives, processes for their preparation, pharmaceutical preparations containing them and their use in the manufacture of a drug with an anti-angiogenic effect and / or an effect of reducing vascular permeability |
GB9603097D0 (en) * | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline compounds |
GB9603095D0 (en) | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
DE69709319T2 (de) | 1996-03-05 | 2002-08-14 | Astrazeneca Ab | 4-anilinochinazolin derivate |
DE69710712T3 (de) | 1996-04-12 | 2010-12-23 | Warner-Lambert Co. Llc | Umkehrbare inhibitoren von tyrosin kinasen |
GB9607729D0 (en) * | 1996-04-13 | 1996-06-19 | Zeneca Ltd | Quinazoline derivatives |
GB9718972D0 (en) | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
US6002008A (en) * | 1997-04-03 | 1999-12-14 | American Cyanamid Company | Substituted 3-cyano quinolines |
DE69838172T2 (de) | 1997-08-22 | 2008-04-10 | Astrazeneca Ab | Oxindolylchinazolinderivate als angiogenesehemmer |
BR9914164A (pt) | 1998-09-29 | 2001-06-26 | American Cyanamid Co | Composto, método para o tratamento, inibição do crescimento de, ou erradiacação de um neoplasma, e de doença de rim policìstico, em um mamìfero em necessidade do mesmo, composição farmacêutica, e, processo para preparar um composto |
US6297258B1 (en) | 1998-09-29 | 2001-10-02 | American Cyanamid Company | Substituted 3-cyanoquinolines |
US6288082B1 (en) | 1998-09-29 | 2001-09-11 | American Cyanamid Company | Substituted 3-cyanoquinolines |
AU5003200A (en) | 1999-05-14 | 2000-12-05 | United States Of America As Represented By The Department Of Veterans Affairs, The | Isolation and characterization of epidermal growth factor related protein |
US7049410B2 (en) * | 1999-05-14 | 2006-05-23 | Majumdar Adhip P N | Antibodies to a novel EGF-receptor related protein (ERRP) |
US6432979B1 (en) | 1999-08-12 | 2002-08-13 | American Cyanamid Company | Method of treating or inhibiting colonic polyps and colorectal cancer |
US7173038B1 (en) | 1999-11-05 | 2007-02-06 | Astrazeneca Ab | Quinazoline derivatives as VEGF inhibitors |
AU779695B2 (en) * | 2000-04-07 | 2005-02-10 | Astrazeneca Ab | Quinazoline compounds |
US6924285B2 (en) | 2002-03-30 | 2005-08-02 | Boehringer Ingelheim Pharma Gmbh & Co. | Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them |
GB0309850D0 (en) | 2003-04-30 | 2003-06-04 | Astrazeneca Ab | Quinazoline derivatives |
GB0317665D0 (en) | 2003-07-29 | 2003-09-03 | Astrazeneca Ab | Qinazoline derivatives |
WO2005026150A1 (en) | 2003-09-16 | 2005-03-24 | Astrazeneca Ab | Quinazoline derivatives as tyrosine kinase inhibitors |
GB0322409D0 (en) | 2003-09-25 | 2003-10-29 | Astrazeneca Ab | Quinazoline derivatives |
GB0326459D0 (en) | 2003-11-13 | 2003-12-17 | Astrazeneca Ab | Quinazoline derivatives |
JP5032851B2 (ja) | 2004-02-03 | 2012-09-26 | アストラゼネカ アクチボラグ | キナゾリン誘導体 |
GEP20084551B (en) * | 2004-05-06 | 2008-11-25 | Warner Lambert Co | 4-phenylamino-quinazolin-6-yl-amides |
JO3000B1 (ar) | 2004-10-20 | 2016-09-05 | Genentech Inc | مركبات أجسام مضادة . |
ATE501148T1 (de) | 2004-12-14 | 2011-03-15 | Astrazeneca Ab | Pyrazolopyrimidinverbindungen als antitumormittel |
US7449184B2 (en) | 2005-01-21 | 2008-11-11 | Genentech, Inc. | Fixed dosing of HER antibodies |
TW200640904A (en) | 2005-02-26 | 2006-12-01 | Astrazeneca Ab | Quinazoline derivatives |
ATE488513T1 (de) | 2005-09-20 | 2010-12-15 | Astrazeneca Ab | 4-(1h-indazol-5-ylamino)chinazolinverbindungen als inhibitoren der erbb-rezeptortyrosinkinase zur behandlung von krebs |
US20070231298A1 (en) * | 2006-03-31 | 2007-10-04 | Cell Genesys, Inc. | Cytokine-expressing cancer immunotherapy combinations |
US9243756B2 (en) | 2006-04-20 | 2016-01-26 | Delta Faucet Company | Capacitive user interface for a faucet and method of forming |
US8162236B2 (en) | 2006-04-20 | 2012-04-24 | Masco Corporation Of Indiana | Electronic user interface for electronic mixing of water for residential faucets |
SG174772A1 (en) * | 2006-09-11 | 2011-10-28 | Curis Inc | Multi-functional small molecules as anti-proliferative agents |
US7547781B2 (en) * | 2006-09-11 | 2009-06-16 | Curis, Inc. | Quinazoline based EGFR inhibitors containing a zinc binding moiety |
WO2008033749A2 (en) * | 2006-09-11 | 2008-03-20 | Curis, Inc. | Quinazoline based egfr inhibitors containing a zinc binding moiety |
EP1921070A1 (de) | 2006-11-10 | 2008-05-14 | Boehringer Ingelheim Pharma GmbH & Co. KG | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstelllung |
WO2008095847A1 (de) | 2007-02-06 | 2008-08-14 | Boehringer Ingelheim International Gmbh | Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
ES2526718T3 (es) | 2007-09-10 | 2015-01-14 | Curis, Inc. | Inhibidores de EGFR basados en sales de tartrato o complejos de quinazolina que contienen un resto que se une al cinc |
US8119616B2 (en) * | 2007-09-10 | 2012-02-21 | Curis, Inc. | Formulation of quinazoline based EGFR inhibitors containing a zinc binding moiety |
UA101168C2 (ru) | 2007-10-29 | 2013-03-11 | Натко Фарма Лимитед | 4-(тетразол-5-ил)хиназолиновые производные как противораковые средства |
WO2009098061A1 (de) | 2008-02-07 | 2009-08-13 | Boehringer Ingelheim International Gmbh | Spirocyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
AU2009247782C1 (en) | 2008-05-13 | 2013-09-19 | Astrazeneca Ab | Fumarate salt of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (N-methylcarbamoylmethyl) piperidin- 4-yl] oxy } quinazoline |
JP5539351B2 (ja) | 2008-08-08 | 2014-07-02 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | シクロヘキシルオキシ置換ヘテロ環、これらの化合物を含有する医薬、およびそれらを生成するための方法 |
WO2011107664A1 (en) | 2010-03-04 | 2011-09-09 | Hospital District Of Southwest Finland | Method for selecting patients for treatment with an egfr inhibitor |
EA201400993A1 (ru) | 2012-03-08 | 2015-05-29 | Галозим, Инк. | Антитела против рецептора эпидермального фактора роста, активные в определенных условиях, и способы их применения |
EP2752413B1 (de) | 2012-03-26 | 2016-03-23 | Fujian Institute Of Research On The Structure Of Matter, Chinese Academy Of Sciences | Chinazolinderivat und anwendung davon |
WO2014139326A1 (en) | 2013-03-13 | 2014-09-18 | Genentech, Inc. | Pyrazolo compounds and uses thereof |
SG11201601770YA (en) | 2013-09-12 | 2016-04-28 | Halozyme Inc | Modified anti-epidermal growth factor receptor antibodies and methods of use thereof |
AU2014364606A1 (en) | 2013-12-17 | 2016-07-07 | Genentech, Inc. | Combination therapy comprising OX40 binding agonists and PD-1 axis binding antagonists |
CN106132439A (zh) | 2014-03-31 | 2016-11-16 | 豪夫迈·罗氏有限公司 | 包含抗血管发生剂和ox40结合激动剂的组合疗法 |
JP6702991B2 (ja) | 2014-11-03 | 2020-06-03 | ジェネンテック, インコーポレイテッド | T細胞免疫サブセットを検出するためのアッセイ及びその使用の方法 |
US20160160290A1 (en) | 2014-11-03 | 2016-06-09 | Genentech, Inc. | Methods and biomarkers for predicting efficacy and evaluation of an ox40 agonist treatment |
CN107709364A (zh) | 2015-04-07 | 2018-02-16 | 豪夫迈·罗氏有限公司 | 具有激动剂活性的抗原结合复合体及使用方法 |
ES2953595T3 (es) | 2017-03-01 | 2023-11-14 | Hoffmann La Roche | Procedimientos diagnósticos y terapéuticos para el cáncer |
EP3679159A1 (de) | 2017-09-08 | 2020-07-15 | H. Hoffnabb-La Roche Ag | Diagnose- und therapieverfahren für krebs |
US11673897B2 (en) | 2018-01-26 | 2023-06-13 | Exelixis, Inc. | Compounds for the treatment of kinase-dependent disorders |
WO2019226514A2 (en) | 2018-05-21 | 2019-11-28 | Nanostring Technologies, Inc. | Molecular gene signatures and methods of using same |
EP4204094A1 (de) | 2020-08-27 | 2023-07-05 | Enosi Therapeutics Corporation | Verfahren und zusammensetzungen zur behandlung von autoimmunerkrankungen und krebs |
CA3226019A1 (en) | 2021-07-20 | 2023-01-26 | Ags Therapeutics Sas | Extracellular vesicles from microalgae, their preparation, and uses |
WO2023144127A1 (en) | 2022-01-31 | 2023-08-03 | Ags Therapeutics Sas | Extracellular vesicles from microalgae, their biodistribution upon administration, and uses |
WO2024088808A1 (en) | 2022-10-24 | 2024-05-02 | Ags Therapeutics Sas | Extracellular vesicles from microalgae, their biodistribution upon intranasal administration, and uses thereof |
Family Cites Families (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3266990A (en) * | 1963-09-24 | 1966-08-16 | Warner Lambert Pharmaceutical | Derivatives of quinazoline |
JPS5538325A (en) * | 1978-09-11 | 1980-03-17 | Sankyo Co Ltd | 4-anilinoquinazoline derivative and its preparation |
US4343940A (en) * | 1979-02-13 | 1982-08-10 | Mead Johnson & Company | Anti-tumor quinazoline compounds |
GB2160201B (en) * | 1984-06-14 | 1988-05-11 | Wyeth John & Brother Ltd | Quinazoline and cinnoline derivatives |
ATE110071T1 (de) * | 1988-01-23 | 1994-09-15 | Kyowa Hakko Kogyo Kk | Pyridazinon-derivate und diese enthaltende pharmazeutische zubereitungen. |
US5411963A (en) * | 1988-01-29 | 1995-05-02 | Dowelanco | Quinazoline derivatives |
IL89029A (en) * | 1988-01-29 | 1993-01-31 | Lilly Co Eli | Fungicidal quinoline and cinnoline derivatives, compositions containing them, and fungicidal methods of using them |
JPH06500117A (ja) * | 1991-02-20 | 1994-01-06 | フアイザー・インコーポレイテツド | 抗腫瘍活性を増強させる2,4−ジアミノキナゾリン誘導体 |
DK0584222T3 (da) * | 1991-05-10 | 1998-02-23 | Rhone Poulenc Rorer Int | Bis-mono- og bicycliske aryl- og heteroarylforbindelser, som inhiberer EGF- og/eller PDGF-receptor-tyrosinkinase |
US5710158A (en) * | 1991-05-10 | 1998-01-20 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
US5721237A (en) * | 1991-05-10 | 1998-02-24 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties |
NZ243082A (en) * | 1991-06-28 | 1995-02-24 | Ici Plc | 4-anilino-quinazoline derivatives; pharmaceutical compositions, preparatory processes, and use thereof |
GB9300059D0 (en) * | 1992-01-20 | 1993-03-03 | Zeneca Ltd | Quinazoline derivatives |
DE4208254A1 (de) * | 1992-03-14 | 1993-09-16 | Hoechst Ag | Substituierte pyrimidine, verfahren zu ihrer herstellung und ihre verwendung als schaedlingsbekaempfungsmittel und fungizid |
US5270466A (en) * | 1992-06-11 | 1993-12-14 | American Cyanamid Company | Substituted quinazoline fungicidal agents |
US6177401B1 (en) * | 1992-11-13 | 2001-01-23 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften | Use of organic compounds for the inhibition of Flk-1 mediated vasculogenesis and angiogenesis |
GB9323290D0 (en) * | 1992-12-10 | 1994-01-05 | Zeneca Ltd | Quinazoline derivatives |
GB9314893D0 (en) * | 1993-07-19 | 1993-09-01 | Zeneca Ltd | Quinazoline derivatives |
GB9314884D0 (en) * | 1993-07-19 | 1993-09-01 | Zeneca Ltd | Tricyclic derivatives |
US5661147A (en) * | 1993-09-03 | 1997-08-26 | Kyowa Hakko Kogyo Co., Ltd. | Imidazoquinazoline derivatives |
GB9325217D0 (en) * | 1993-12-09 | 1994-02-09 | Zeneca Ltd | Pyrimidine derivatives |
US5700823A (en) * | 1994-01-07 | 1997-12-23 | Sugen, Inc. | Treatment of platelet derived growth factor related disorders such as cancers |
IL112249A (en) * | 1994-01-25 | 2001-11-25 | Warner Lambert Co | Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds |
IL112248A0 (en) * | 1994-01-25 | 1995-03-30 | Warner Lambert Co | Tricyclic heteroaromatic compounds and pharmaceutical compositions containing them |
AU686843B2 (en) * | 1994-02-23 | 1998-02-12 | Pfizer Inc. | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
WO1995024190A2 (en) * | 1994-03-07 | 1995-09-14 | Sugen, Inc. | Receptor tyrosine kinase inhibitors for inhibiting cell proliferative disorders and compositions thereof |
DK0682027T3 (da) * | 1994-05-03 | 1998-05-04 | Ciba Geigy Ag | Pyrrolopyrimidinderivater med antiproliferativ virkning |
TW414798B (en) * | 1994-09-07 | 2000-12-11 | Thomae Gmbh Dr K | Pyrimido (5,4-d) pyrimidines, medicaments comprising these compounds, their use and processes for their preparation |
GB9510757D0 (en) * | 1994-09-19 | 1995-07-19 | Wellcome Found | Therapeuticaly active compounds |
TW321649B (de) * | 1994-11-12 | 1997-12-01 | Zeneca Ltd | |
GB9424233D0 (en) * | 1994-11-30 | 1995-01-18 | Zeneca Ltd | Quinazoline derivatives |
AU5108196A (en) * | 1995-03-20 | 1996-10-08 | Dr. Karl Thomae Gmbh | Imidazoquinazolines, drugs containing these compounds, their use and process for their preparation |
EP0817775B1 (de) * | 1995-03-30 | 2001-09-12 | Pfizer Inc. | Chinazolinderivate |
NZ304859A (en) * | 1995-04-03 | 2000-01-28 | Novartis Ag | 4-amino-1H-pyrazolo[3,4-d]pyrimidine derivatives, medicaments and processes for the preparation thereof |
GB9508537D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
EP0824525B1 (de) * | 1995-04-27 | 2001-06-13 | AstraZeneca AB | Chinazolin derivate |
GB9508538D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
GB9508535D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivative |
GB9508565D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quiazoline derivative |
IL117923A (en) * | 1995-05-03 | 2000-06-01 | Warner Lambert Co | Anti-cancer pharmaceutical compositions containing polysubstituted pyrido¬2,3-d¾pyrimidine derivatives and certain such novel compounds |
AU716993B2 (en) * | 1995-05-12 | 2000-03-16 | Neurogen Corporation | Novel deazapurine derivatives; a new class of CRF1 specific ligands |
WO1996040648A1 (en) * | 1995-06-07 | 1996-12-19 | Sugen, Inc. | Quinazolines and pharmaceutical compositions |
MX9709867A (es) * | 1995-06-07 | 1998-03-31 | Pfizer | Derivados de pirimidina condensados con un anillo heterociclico, composiciones que contienen los mismos, y uso de los mismos. |
MX9800215A (es) * | 1995-07-06 | 1998-03-31 | Novartis Ag | Pirrolopirimidas y procesos para su preparacion. |
GB9514265D0 (en) * | 1995-07-13 | 1995-09-13 | Wellcome Found | Hetrocyclic compounds |
AR004010A1 (es) * | 1995-10-11 | 1998-09-30 | Glaxo Group Ltd | Compuestos heterociclicos |
GB9520822D0 (en) * | 1995-10-11 | 1995-12-13 | Wellcome Found | Therapeutically active compounds |
PL321296A1 (en) * | 1995-11-14 | 1997-12-08 | Pharmacia & Upjohn Spa | Derivatives of aryl and heteroaryl purine |
US5760041A (en) * | 1996-02-05 | 1998-06-02 | American Cyanamid Company | 4-aminoquinazoline EGFR Inhibitors |
-
1995
- 1995-04-27 GB GBGB9508537.9A patent/GB9508537D0/en active Pending
-
1996
- 1996-04-23 EP EP96910133A patent/EP0824527B1/de not_active Expired - Lifetime
- 1996-04-23 US US08/930,043 patent/US5942514A/en not_active Expired - Fee Related
- 1996-04-23 DE DE69613369T patent/DE69613369T2/de not_active Expired - Fee Related
- 1996-04-23 WO PCT/GB1996/000960 patent/WO1996033979A1/en active IP Right Grant
- 1996-04-23 JP JP8532251A patent/JPH11504032A/ja active Pending
- 1996-04-23 AU AU53432/96A patent/AU5343296A/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
EP0824527B1 (de) | 2001-06-13 |
US5942514A (en) | 1999-08-24 |
AU5343296A (en) | 1996-11-18 |
DE69613369T2 (de) | 2002-05-23 |
EP0824527A1 (de) | 1998-02-25 |
GB9508537D0 (en) | 1995-06-14 |
JPH11504032A (ja) | 1999-04-06 |
WO1996033979A1 (en) | 1996-10-31 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
8364 | No opposition during term of opposition | ||
8339 | Ceased/non-payment of the annual fee |