BR112016030968A2 - análogos de pridopidina, preparação e uso destes - Google Patents
análogos de pridopidina, preparação e uso destesInfo
- Publication number
- BR112016030968A2 BR112016030968A2 BR112016030968A BR112016030968A BR112016030968A2 BR 112016030968 A2 BR112016030968 A2 BR 112016030968A2 BR 112016030968 A BR112016030968 A BR 112016030968A BR 112016030968 A BR112016030968 A BR 112016030968A BR 112016030968 A2 BR112016030968 A2 BR 112016030968A2
- Authority
- BR
- Brazil
- Prior art keywords
- pridopidine
- analogues
- preparation
- pridopidine analogues
- Prior art date
Links
- YGKUEOZJFIXDGI-UHFFFAOYSA-N pridopidine Chemical class C1CN(CCC)CCC1C1=CC=CC(S(C)(=O)=O)=C1 YGKUEOZJFIXDGI-UHFFFAOYSA-N 0.000 title 1
Classifications
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physics & Mathematics (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pathology (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Physics & Mathematics (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462019337P | 2014-06-30 | 2014-06-30 | |
US62/019,337 | 2014-06-30 | ||
US201462076436P | 2014-11-06 | 2014-11-06 | |
US62/076,436 | 2014-11-06 | ||
PCT/US2015/038349 WO2016003919A1 (en) | 2014-06-30 | 2015-06-29 | Analogs of pridopidine, their preparation and use |
Publications (2)
Publication Number | Publication Date |
---|---|
BR112016030968A2 true BR112016030968A2 (pt) | 2018-07-17 |
BR112016030968B1 BR112016030968B1 (pt) | 2023-11-21 |
Family
ID=54929343
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
BR112016030968-5A BR112016030968B1 (pt) | 2014-06-30 | 2015-06-29 | Análogos de pridopidina, preparação e uso destes |
Country Status (18)
Country | Link |
---|---|
US (3) | US10130621B2 (pt) |
EP (2) | EP4049998A1 (pt) |
JP (2) | JP6800842B2 (pt) |
CN (2) | CN106456618A (pt) |
AU (1) | AU2015284385B2 (pt) |
BR (1) | BR112016030968B1 (pt) |
CA (1) | CA2951494C (pt) |
DK (1) | DK3160470T3 (pt) |
EA (1) | EA201790101A1 (pt) |
ES (1) | ES2927888T3 (pt) |
HK (1) | HK1231406A1 (pt) |
HU (1) | HUE060242T2 (pt) |
IL (2) | IL249601B (pt) |
MX (1) | MX2016017332A (pt) |
PL (1) | PL3160470T3 (pt) |
TW (1) | TW201613859A (pt) |
UY (1) | UY36192A (pt) |
WO (1) | WO2016003919A1 (pt) |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE46117E1 (en) | 1999-12-22 | 2016-08-23 | Teva Pharmaceuticals International Gmbh | Modulators of dopamine neurotransmission |
KR20140008297A (ko) | 2010-09-03 | 2014-01-21 | 아이백스 인터내셔널 게엠베하 | 도파민성 안정제로서 유용한 프리도피딘의 듀테륨화된 유사체 |
MX347209B (es) | 2011-12-08 | 2017-04-19 | Teva Pharmaceuticals Int Gmbh | La sal de bromhidrato de pridopidina. |
US11090297B2 (en) * | 2013-06-21 | 2021-08-17 | Prilenia Neurotherapeutics Ltd. | Pridopidine for treating huntington's disease |
PL3010506T3 (pl) | 2013-06-21 | 2021-11-02 | Prilenia Neurotherapeutics Ltd. | Pridopidyna w leczeniu choroby huntingtona |
TW201613859A (en) | 2014-06-30 | 2016-04-16 | Teva Pharma | Analogs of PRIDOPIDINE, their preparation and use |
CA2970799A1 (en) | 2014-12-22 | 2016-06-30 | Teva Pharmaceuticals International Gmbh | L-tartrate salt of pridopidine |
US11471449B2 (en) | 2015-02-25 | 2022-10-18 | Prilenia Neurotherapeutics Ltd. | Use of pridopidine to improve cognitive function and for treating Alzheimer's disease |
EP3261721B1 (en) | 2015-02-25 | 2022-09-14 | Prilenia Neurotherapeutics Ltd. | Use of pridopidine to improve memory |
WO2023062632A1 (en) * | 2021-10-11 | 2023-04-20 | Prilenia Neurotherapeutics Ltd. | Pridopidine and analogs thereof for the treatment of neurodegenerative eye disease |
AR105434A1 (es) | 2015-07-22 | 2017-10-04 | Teva Pharmaceuticals Int Gmbh | Proceso para preparar pridopidina |
EP3419622B1 (en) | 2016-02-24 | 2024-03-06 | Prilenia Neurotherapeutics Ltd. | Treatment of neurodegenerative eye disease using pridopidine |
JP6912574B2 (ja) | 2016-08-24 | 2021-08-04 | プリレニア ニューロセラピューティクス リミテッド | 機能低下を治療するためのプリドピジンの使用 |
CN110012661A (zh) | 2016-08-24 | 2019-07-12 | 普瑞尼亚医疗发展有限公司 | 普利多匹定用于治疗肌张力障碍的用途 |
WO2018136600A1 (en) | 2017-01-20 | 2018-07-26 | Teva Pharmaceuticals International Gmbh | Use of pridopidine for the treatment of fragile x syndrome |
EP4154882A1 (en) | 2017-08-14 | 2023-03-29 | Prilenia Neurotherapeutics Ltd. | Treating amyotrophic lateral sclerosis with pridopidine |
MX2020002310A (es) | 2017-08-30 | 2020-09-17 | Prilenia Neurotherapeutics Ltd | Formas de dosificacion de alta concentracion de pridopidina. |
BR112020004622A2 (pt) | 2017-09-08 | 2020-09-24 | Prilenia Neurotherapeutics Ltd. | pridopidina para tratamento de discinesias induzidas por droga |
EP3937937A4 (en) * | 2019-03-15 | 2022-11-23 | Prilenia Neurotherapeutics Ltd. | TREATMENT OF DISEASES AND DISORDERS ASSOCIATED WITH MITOCHONDRIA, INCLUDING THEIR SYMPTOMS USING PRIDOPIDINE |
CN113950328A (zh) * | 2019-06-12 | 2022-01-18 | 普瑞尼亚神经治疗有限公司 | 用于治疗亨廷顿病及其症状的包含普利多匹定及其类似物的组合物 |
WO2021224914A1 (en) * | 2020-05-04 | 2021-11-11 | Prilenia Neurotherapeutics Ltd. | Treatment of viral infection, disease or disorder using a selective s1r agonist |
AU2021366505A1 (en) * | 2020-10-20 | 2023-06-01 | Prilenia Neurotherapeutics Ltd. | Use of pridopidine and analogs for the treatment of anxiety and depression |
CN116472043A (zh) * | 2020-10-20 | 2023-07-21 | 普瑞尼亚神经治疗有限公司 | 普利多匹定和类似物用于治疗焦虑和抑郁的用途 |
EP4322946A1 (en) * | 2021-04-14 | 2024-02-21 | Prilenia Neurotherapeutics Ltd. | Treatment of prodromal huntington disease |
CN114716391B (zh) * | 2022-04-24 | 2023-12-12 | 杭州仟源保灵药业有限公司 | 一种醋甲唑胺杂质及其制备方法和应用 |
Family Cites Families (30)
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JPS6472736A (en) | 1987-09-14 | 1989-03-17 | Toshiba Corp | Mri apparatus |
USRE46117E1 (en) | 1999-12-22 | 2016-08-23 | Teva Pharmaceuticals International Gmbh | Modulators of dopamine neurotransmission |
SE9904724D0 (sv) | 1999-12-22 | 1999-12-22 | Carlsson A Research Ab | New modulators of dopamine neurotransmission I |
TW200536854A (en) * | 2004-01-21 | 2005-11-16 | Teva Pharma | Process for the preparation of valacyclovir hydrochloride |
NZ552410A (en) * | 2004-06-08 | 2010-04-30 | Nsab Af Neurosearch Sweden Ab | New 4-phenyl-piperidin-4-ol derivatives as modulators of dopamine neurotransmission |
SE0401465D0 (sv) * | 2004-06-08 | 2004-06-08 | Carlsson A Research Ab | New substituted piperdines as modulators of dopamine neurotransmission |
EP1692134A2 (en) * | 2004-09-04 | 2006-08-23 | Teva Pharmaceutical Industries, Inc. | A valacyclovir impurity, process for the preparation of valacyclovir impurity and use as a reference standard |
KR101319235B1 (ko) * | 2004-10-13 | 2013-10-16 | 아이백스 인터내셔널 게엠베하 | 4-(3-메탄설폰일페닐)-1-n-프로필-피페리딘의 합성 공정 |
CA2584833A1 (en) * | 2004-10-13 | 2006-04-20 | Neurosearch Sweden Ab | Process for the synthesis of 4-(3-sulfonylphenyl)-piperidines |
KR20090108739A (ko) * | 2005-01-03 | 2009-10-16 | 테바 파마슈티컬 인더스트리즈 리미티드 | 불순물의 양이 감소된 올메사탄 메독소밀 |
SE529246C2 (sv) * | 2005-10-13 | 2007-06-12 | Neurosearch Sweden Ab | Nya disubstituerade fenyl-piperidiner som modulatorer för dopaminneurotransmission |
EP1961742A1 (en) | 2007-02-22 | 2008-08-27 | Novartis AG | compounds of formula (I) as serine protease inhibitors |
NZ580856A (en) * | 2007-04-12 | 2011-11-25 | Nsab Af Neurosearch Sweden Ab | N-oxide and/or di-n-oxide derivatives of dopamine receptor stabilizers/modulators displaying improved cardiovascular side-effects profiles |
CN101765428A (zh) | 2007-06-18 | 2010-06-30 | A·卡尔森研究股份有限公司 | 多巴胺稳定剂的用途 |
US20110206782A1 (en) * | 2010-02-24 | 2011-08-25 | Auspex Pharmaceuticals, Inc. | Piperidine modulators of dopamine receptor |
JP2013532233A (ja) | 2010-07-02 | 2013-08-15 | アクティエボラゲット・エスコーエッフ | 機械構成要素、および表面硬化方法 |
KR20140008297A (ko) | 2010-09-03 | 2014-01-21 | 아이백스 인터내셔널 게엠베하 | 도파민성 안정제로서 유용한 프리도피딘의 듀테륨화된 유사체 |
AU2012306386B2 (en) | 2011-09-07 | 2017-06-15 | Teva Pharmaceuticals International Gmbh | Polymorphic form of pridopidine hydrochloride |
MX347209B (es) | 2011-12-08 | 2017-04-19 | Teva Pharmaceuticals Int Gmbh | La sal de bromhidrato de pridopidina. |
BR112014024672A8 (pt) | 2012-04-04 | 2018-04-03 | Ivax Int Gmbh | Composições farmacêuticas para terapia de combinação |
AU2013323131A1 (en) * | 2012-09-27 | 2015-05-07 | Teva Pharmaceutical Industries Ltd. | Laquinimod and pridopidine for treating neurodegenerative disorders |
MX2015003812A (es) | 2012-09-27 | 2015-07-17 | Teva Pharma | Combinacion de rasagilina y pridopidina para tratar trastornos neurodegenerativos, en particular enfermedad de huntington. |
PL3010506T3 (pl) | 2013-06-21 | 2021-11-02 | Prilenia Neurotherapeutics Ltd. | Pridopidyna w leczeniu choroby huntingtona |
MX2016009427A (es) | 2014-01-22 | 2016-12-08 | Teva Pharmaceuticals Int Gmbh | Formulaciones de pridopidina de liberacion modificada. |
TW201613859A (en) | 2014-06-30 | 2016-04-16 | Teva Pharma | Analogs of PRIDOPIDINE, their preparation and use |
CA2970799A1 (en) | 2014-12-22 | 2016-06-30 | Teva Pharmaceuticals International Gmbh | L-tartrate salt of pridopidine |
EP3261721B1 (en) | 2015-02-25 | 2022-09-14 | Prilenia Neurotherapeutics Ltd. | Use of pridopidine to improve memory |
WO2016138135A1 (en) | 2015-02-25 | 2016-09-01 | Teva Pharmaceuticals International Gmbh | Sigma-1 receptor modulators for treating huntington's disease |
WO2017015615A1 (en) | 2015-07-22 | 2017-01-26 | Teva Pharmaceuticals International Gmbh | Pridopidine base formulations and their use |
AR105434A1 (es) | 2015-07-22 | 2017-10-04 | Teva Pharmaceuticals Int Gmbh | Proceso para preparar pridopidina |
-
2015
- 2015-06-23 TW TW104120197A patent/TW201613859A/zh unknown
- 2015-06-26 UY UY0001036192A patent/UY36192A/es not_active Application Discontinuation
- 2015-06-29 CN CN201580035520.9A patent/CN106456618A/zh active Pending
- 2015-06-29 DK DK15814023.6T patent/DK3160470T3/da active
- 2015-06-29 PL PL15814023.6T patent/PL3160470T3/pl unknown
- 2015-06-29 WO PCT/US2015/038349 patent/WO2016003919A1/en active Application Filing
- 2015-06-29 BR BR112016030968-5A patent/BR112016030968B1/pt active IP Right Grant
- 2015-06-29 EP EP22165235.7A patent/EP4049998A1/en active Pending
- 2015-06-29 US US14/754,339 patent/US10130621B2/en active Active
- 2015-06-29 JP JP2017520772A patent/JP6800842B2/ja active Active
- 2015-06-29 AU AU2015284385A patent/AU2015284385B2/en active Active
- 2015-06-29 EA EA201790101A patent/EA201790101A1/ru unknown
- 2015-06-29 CA CA2951494A patent/CA2951494C/en active Active
- 2015-06-29 MX MX2016017332A patent/MX2016017332A/es unknown
- 2015-06-29 CN CN202110715595.9A patent/CN113511997A/zh active Pending
- 2015-06-29 ES ES15814023T patent/ES2927888T3/es active Active
- 2015-06-29 HU HUE15814023A patent/HUE060242T2/hu unknown
- 2015-06-29 EP EP15814023.6A patent/EP3160470B1/en active Active
-
2016
- 2016-12-15 IL IL249601A patent/IL249601B/en active IP Right Grant
-
2017
- 2017-05-23 HK HK17105207.9A patent/HK1231406A1/zh unknown
-
2018
- 2018-10-03 US US16/150,977 patent/US10406145B2/en active Active
-
2019
- 2019-08-08 US US16/535,107 patent/US11141412B2/en active Active
-
2020
- 2020-01-28 IL IL272306A patent/IL272306B/en active IP Right Grant
- 2020-04-24 JP JP2020077160A patent/JP7035108B2/ja active Active
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Legal Events
Date | Code | Title | Description |
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B06F | Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette] | ||
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