DE3381767D1 - Mittel und verfahren zur erzielung einer oertlichen gewichtsabnahme. - Google Patents
Mittel und verfahren zur erzielung einer oertlichen gewichtsabnahme.Info
- Publication number
- DE3381767D1 DE3381767D1 DE8383307525T DE3381767T DE3381767D1 DE 3381767 D1 DE3381767 D1 DE 3381767D1 DE 8383307525 T DE8383307525 T DE 8383307525T DE 3381767 T DE3381767 T DE 3381767T DE 3381767 D1 DE3381767 D1 DE 3381767D1
- Authority
- DE
- Germany
- Prior art keywords
- adrenergic
- alpha
- selected area
- regional
- weight loss
- 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 - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/41—Amines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/06—Preparations for care of the skin for countering cellulitis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Dermatology (AREA)
- Birds (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Input Circuits Of Receivers And Coupling Of Receivers And Audio Equipment (AREA)
- Compositions Of Oxide Ceramics (AREA)
- Ceramic Products (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/448,836 US4525359A (en) | 1982-12-10 | 1982-12-10 | Treatment for selective weight control |
Publications (1)
Publication Number | Publication Date |
---|---|
DE3381767D1 true DE3381767D1 (de) | 1990-08-30 |
Family
ID=23781869
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE8383307525T Expired - Lifetime DE3381767D1 (de) | 1982-12-10 | 1983-12-09 | Mittel und verfahren zur erzielung einer oertlichen gewichtsabnahme. |
Country Status (6)
Country | Link |
---|---|
US (1) | US4525359A (de) |
EP (1) | EP0120165B1 (de) |
JP (1) | JPH0653681B2 (de) |
AT (1) | ATE54823T1 (de) |
CA (1) | CA1228026A (de) |
DE (1) | DE3381767D1 (de) |
Families Citing this family (54)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0244062A3 (de) * | 1986-03-03 | 1990-06-20 | Beecham Group Plc | Verwendung von Arylethanolamin-Derivaten zur Behandlung von Atherosclerose |
US4895845A (en) * | 1986-09-15 | 1990-01-23 | Seed John C | Method of assisting weight loss |
US4829987A (en) * | 1986-12-11 | 1989-05-16 | Easy Tone Body Systems, Inc. | Mineral body wrap combined with exercise for treating cellulite |
DE3815718A1 (de) * | 1988-05-07 | 1989-11-16 | Hoechst Ag | Mittel zur wachstumssteigerung bei tieren |
DK339289D0 (da) * | 1989-07-07 | 1989-07-07 | Dak Lab As | Farmaceutisk praeparat |
IT1239281B (it) * | 1989-10-27 | 1993-10-19 | Indena Spa | Composizioni per la riduzione dei depositi di grasso superfluo a base di principi attivi di origine vegetale ad attivita' agonista dell'adenilato ciclasi o/e ad attivita' antifosfodiesterasica |
FR2655854A1 (fr) * | 1989-12-19 | 1991-06-21 | Poissonnet Claude | Medication nouvelle pour le traitement de surcharges lipidiques. |
FR2669537B1 (fr) * | 1990-11-28 | 1993-02-19 | Oreal | Composition amincissante a base d'alpha-2-bloqueurs. |
FR2671487B1 (fr) * | 1991-01-14 | 1993-03-19 | Oreal | Utilisation d'un facteur de croissance dans une composition amincissante. |
WO1994000432A1 (en) * | 1992-06-30 | 1994-01-06 | The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Anorectic epinephrine derivatives |
US5513661A (en) * | 1993-10-14 | 1996-05-07 | Hubbard; David R. | Use of sympathetic blockade for treatment of chronic muscle pain |
US6009875A (en) * | 1993-10-14 | 2000-01-04 | Berlex Laboratories, Inc. | Use of sympathetic antagonists for treatment of chronic muscle pain |
US5507790A (en) * | 1994-03-21 | 1996-04-16 | Weiss; William V. | Method of non-invasive reduction of human site-specific subcutaneous fat tissue deposits by accelerated lipolysis metabolism |
JPH0826961A (ja) * | 1994-07-12 | 1996-01-30 | Kao Corp | 皮膚外用剤組成物 |
US6492332B1 (en) | 1995-12-12 | 2002-12-10 | Omeros Corporation | Irrigation solution and methods for inhibition of tumor cell adhesion, pain and inflammation |
US20020028798A1 (en) * | 1995-12-12 | 2002-03-07 | Omeros Medical Systems | Irrigation solution and method for inhibition of pain and inflammation |
JPH10510540A (ja) | 1994-12-12 | 1998-10-13 | オメロス メディカル システムズ,インコーポレーテッド | 灌注用溶液並びに疼痛、炎症及びけいれんの抑制法 |
US20040127884A1 (en) * | 1994-12-12 | 2004-07-01 | Omeros Corporation | Vascular irrigation solution and method for inhibition of pain, inflammation, spasm and restenosis |
US7091181B2 (en) | 1994-12-12 | 2006-08-15 | Omeros Corporation | Method of inhibition of pain and inflammation during surgery comprising administration of soluble TNF receptors |
FR2740040B1 (fr) | 1995-10-23 | 1997-12-05 | Oreal | Utilisation d'au moins un agoniste beta-adrenergique en tant qu'antagoniste de substance p |
US6413961B1 (en) | 1995-12-12 | 2002-07-02 | Omeros Medical Systems, Inc. | Irrigation solution and method for inhibition of pain and inflammation |
US5667793A (en) * | 1996-08-02 | 1997-09-16 | Chesebrough-Pond's Usa Co., Division Of Conopco, Inc. | Skin care compositions for treating cellulite |
FR2761263B1 (fr) * | 1997-03-25 | 1999-12-31 | Sederma Sa | Compositions cosmetiques ou dermopharmaceutiques amincissantes |
FR2761603B1 (fr) * | 1997-04-02 | 1999-11-26 | Sederma Sa | Compositions cosmetiques amincissantes |
US6110448A (en) * | 1997-09-25 | 2000-08-29 | The Board Of Regents Of The University Of Oklahoma | Method for causing skin lightening |
US5879665A (en) * | 1997-09-25 | 1999-03-09 | The Board Of Regents Of The University Of Oklahoma | Composition for causing skin lightening |
FR2774905B1 (fr) * | 1998-02-17 | 2000-06-09 | Codif International Sa | Utilisation d'une composition cosmetique comportant au moins une substance qui comprend un groupement pyrone |
CA2697598A1 (en) * | 1999-01-12 | 2000-07-20 | Cambridge Enterprise Limited | Compounds and methods to inhibit or augment an inflammatory response |
AU7066400A (en) * | 1999-08-23 | 2001-03-19 | The Administrators Of The Tulane Eductional Fund | Modulation of the blood-brain barrier transporter for leptin |
US20030022856A1 (en) * | 2001-01-30 | 2003-01-30 | The Regents Of The University Of Michigan | Method for sustained release local delivery of drugs for ablation of unwanted tissue |
WO2002087700A1 (en) * | 2001-04-26 | 2002-11-07 | The Procter & Gamble Company | Method, kit and device for the treatment of cosmetic skin conditions |
KR100428817B1 (ko) * | 2001-05-24 | 2004-04-28 | 김원규 | 자외선 차단 및 슬리밍 효과를 가지는 기능성 화장품 조성물 |
AU2003224507A1 (en) * | 2002-04-19 | 2003-11-03 | N.V. Nutricia | Multiphasic diet |
US20040018959A1 (en) * | 2002-05-02 | 2004-01-29 | Randall S. Hickle | System and methods of lipid removal from the body |
WO2004089357A2 (en) * | 2003-04-02 | 2004-10-21 | Regents Of The University Of Minnesota | Anti-fungal formulation of triterpene and essential oil |
US20060122261A1 (en) * | 2003-11-20 | 2006-06-08 | Muhammed Majeed | [method of preparing labdane diterpene composition, preferably isoforskolin and deacetylforskolin from forskolin extract and their use for promoting lean body mass and other applications] |
CN1960698A (zh) * | 2004-05-31 | 2007-05-09 | 昭和电工株式会社 | 含肉碱衍生物的局部减肥制剂和化妆品 |
US20110077292A1 (en) * | 2004-07-01 | 2011-03-31 | Biotest Laboratories, Llc. | Forskolin carbonates and uses thereof |
US7829554B2 (en) | 2005-07-14 | 2010-11-09 | Lithera, Inc. | Sustained release enhanced lipolytic formulation for regional adipose tissue treatment |
US20090233885A1 (en) * | 2006-07-14 | 2009-09-17 | Duncan Diane I | Compositions and Methods for Fat Reduction |
US7955281B2 (en) * | 2006-09-07 | 2011-06-07 | Nivasonix, Llc | External ultrasound lipoplasty |
US8262591B2 (en) * | 2006-09-07 | 2012-09-11 | Nivasonix, Llc | External ultrasound lipoplasty |
MX2009004198A (es) * | 2006-10-17 | 2009-10-19 | Lithera Inc | Metodos, composiciones y formulaciones para el tratamiento de enfermedad ocular tiroidea. |
WO2008066775A2 (en) * | 2006-11-22 | 2008-06-05 | Duncan Diane I | Compositions and methods to reduce fat and retract skin |
FR2917971B1 (fr) | 2007-06-28 | 2009-10-23 | Engelhard Lyon Soc Par Actions | Composition amincissante |
US8153611B2 (en) * | 2007-06-28 | 2012-04-10 | Basf Beauty Care Solutions France S.A.S. | Use of sulfated oligosaccharides as slimming cosmetic ingredients |
JP4925019B2 (ja) * | 2009-04-23 | 2012-04-25 | 株式会社エンドレスアドバンス | 車両用ブレーキのキャリパー |
US20100280419A1 (en) * | 2009-05-01 | 2010-11-04 | Dimitri Donskoy | Ultrasonically Assisted Fitness Method and Apparatus |
US9132084B2 (en) * | 2009-05-27 | 2015-09-15 | Neothetics, Inc. | Methods for administration and formulations for the treatment of regional adipose tissue |
EP2523667A4 (de) * | 2010-01-15 | 2014-04-02 | Lithera Inc | Lyophilisierte kuchenformulierungen |
KR20140025312A (ko) * | 2010-11-24 | 2014-03-04 | 리쎄라 인코오포레이티드 | 지방증 및 윤곽 팽창의 미용적 치료를 위한 선택적인, 친유성, 및 지속성 베타 작용제 단일치료 제형 및 방법 |
JP2016520561A (ja) | 2013-04-12 | 2016-07-14 | アラーガン、インコーポレイテッドAllergan,Incorporated | 脂肪減少のためのビマトプロスト、ビマトプロスト類似体、プロスタミド及びプロスタグランジンの持続放出 |
CA2938126A1 (en) * | 2014-02-07 | 2015-08-13 | The Regents Of The University Of Michigan | Combinations of ikke/tbk1 inhibitors with beta adrenergic agonists or sympathetic nervous system activators |
WO2016060564A1 (en) * | 2014-10-14 | 2016-04-21 | Brains Online Holding B.V. Et All | Body sculpting |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2493471A (en) * | 1945-06-04 | 1950-01-03 | Parke Davis & Co | Stabilized organic compounds and methods of obtaining the same |
DE1275069B (de) * | 1960-02-15 | 1968-08-14 | Boehringer Sohn Ingelheim | 1-(3', 5'-Dihydroxyphenyl)-1-hydroxy-2-isopropylaminoalkane und Verfahren zu ihrer Herstellung |
US3074847A (en) * | 1960-04-27 | 1963-01-22 | Frank L Bigsby | Appetite control composition |
DE1183201B (de) * | 1961-02-21 | 1964-12-10 | Dresden Arzneimittel | Verfahren zur Stabilisierung von Rauwolfia-Alkaloid-Loesungen |
GB1268068A (en) * | 1968-08-07 | 1972-03-22 | Boehringer Sohn Ingelheim | Pharmaceutical compositions |
US3808317A (en) * | 1969-10-29 | 1974-04-30 | Alcon Labor Inc | Stabilized aqueous borate complexes of biologically active catechol amines |
FR2139748B1 (de) * | 1971-06-03 | 1974-08-30 | Theranol Lab | |
FR2142675A1 (en) * | 1971-06-23 | 1973-02-02 | Egema Sa | Triiodothyroalkanoic acid derivs - for treating lipid overload and celluitis |
FR2160258A1 (en) * | 1971-11-16 | 1973-06-29 | Egema | Triiodothyroalkanoic acid derivs - for treating lipid overload and celluitis |
US3818101A (en) * | 1972-08-28 | 1974-06-18 | Smithkline Corp | Methods for improving the feed intake of meat producing animals |
GB1453034A (en) * | 1972-12-15 | 1976-10-20 | Boehringer Sohn Ingelheim | Pharmaceutical composition for treating spasticity |
BE810633A (fr) * | 1973-02-07 | 1974-05-29 | Produit amaigrissant a application cutanee | |
JPS5212779A (en) * | 1975-07-18 | 1977-01-31 | Sanyo Electric Co Ltd | Apparatus for cleaning the solvent of dry cleaner |
FR2320735A1 (fr) * | 1975-08-12 | 1977-03-11 | Dabis Georges | Composition anti-cellulite |
CH622703A5 (en) * | 1976-06-10 | 1981-04-30 | Berema Sa | Therapeutic compositions for treating deposits of excess fat and infiltrates causing cellulite |
LU76148A1 (de) * | 1976-11-08 | 1978-07-10 | ||
IT1157365B (it) * | 1977-10-24 | 1987-02-11 | Sandoz Ag | Medicamenti per trattare l'obesita' o ridurre il peso del corpo |
ZA82357B (en) * | 1981-01-30 | 1982-12-29 | Reckitt & Colmann Prod Ltd | Imidazoline derivatives |
EP0059057A1 (de) * | 1981-02-20 | 1982-09-01 | Beecham Group Plc | Behandlung der Diarrhee |
-
1982
- 1982-12-10 US US06/448,836 patent/US4525359A/en not_active Expired - Lifetime
-
1983
- 1983-12-06 CA CA000442630A patent/CA1228026A/en not_active Expired
- 1983-12-09 EP EP83307525A patent/EP0120165B1/de not_active Expired - Lifetime
- 1983-12-09 AT AT83307525T patent/ATE54823T1/de not_active IP Right Cessation
- 1983-12-09 DE DE8383307525T patent/DE3381767D1/de not_active Expired - Lifetime
- 1983-12-09 JP JP58232606A patent/JPH0653681B2/ja not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
JPS59155313A (ja) | 1984-09-04 |
EP0120165B1 (de) | 1990-07-25 |
ATE54823T1 (de) | 1990-08-15 |
CA1228026A (en) | 1987-10-13 |
JPH0653681B2 (ja) | 1994-07-20 |
US4525359A (en) | 1985-06-25 |
EP0120165A3 (en) | 1985-06-19 |
EP0120165A2 (de) | 1984-10-03 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
8363 | Opposition against the patent | ||
8339 | Ceased/non-payment of the annual fee |