BR9814611A - Polipeptìdeos modificados dependentes de vitamina k - Google Patents

Polipeptìdeos modificados dependentes de vitamina k

Info

Publication number
BR9814611A
BR9814611A BR9814611-4A BR9814611A BR9814611A BR 9814611 A BR9814611 A BR 9814611A BR 9814611 A BR9814611 A BR 9814611A BR 9814611 A BR9814611 A BR 9814611A
Authority
BR
Brazil
Prior art keywords
vitamin
dependent
modified polypeptides
polypeptides
mammals
Prior art date
Application number
BR9814611-4A
Other languages
English (en)
Inventor
Gary L Nelsestuen
Original Assignee
Univ Minnesota
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Univ Minnesota filed Critical Univ Minnesota
Publication of BR9814611A publication Critical patent/BR9814611A/pt

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    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/11DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/52Genes encoding for enzymes or proenzymes
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14Hydrolases (3)
    • C12N9/48Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424Serine endopeptidases (3.4.21)
    • C12N9/6437Coagulation factor VIIa (3.4.21.21)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14Hydrolases (3)
    • C12N9/48Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424Serine endopeptidases (3.4.21)
    • C12N9/644Coagulation factor IXa (3.4.21.22)
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14Hydrolases (3)
    • C12N9/48Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424Serine endopeptidases (3.4.21)
    • C12N9/6464Protein C (3.4.21.69)
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14Hydrolases (3)
    • C12N9/48Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424Serine endopeptidases (3.4.21)
    • C12N9/647Blood coagulation factors not provided for in a preceding group or according to more than one of the proceeding groups
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12YENZYMES
    • C12Y304/00Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21Serine endopeptidases (3.4.21)
    • C12Y304/21021Coagulation factor VIIa (3.4.21.21)
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12YENZYMES
    • C12Y304/00Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21Serine endopeptidases (3.4.21)
    • C12Y304/21022Coagulation factor IXa (3.4.21.22)
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12YENZYMES
    • C12Y304/00Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21Serine endopeptidases (3.4.21)
    • C12Y304/21069Protein C activated (3.4.21.69)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Hematology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Diabetes (AREA)
  • Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Plant Pathology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

Patente de Invenção: <B>"POLIPEPTìDEOS MODIFICADOS DEPENDENTES DE VITAMINA K"<D>. A invenção proporciona polipeptídeos dependentes de vitamina K com afinidade de ligação de membrana intensificada. Esses polipeptídeos podem ser usados para modular a formação de coágulos em mamíferos. Métodos de modulação da formação de coágulos em mamíferos também são descritos.
BR9814611-4A 1997-10-23 1998-10-20 Polipeptìdeos modificados dependentes de vitamina k BR9814611A (pt)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/955,636 US6017882A (en) 1997-10-23 1997-10-23 Modified vitamin K-dependent polypeptides
PCT/US1998/022152 WO1999020767A1 (en) 1997-10-23 1998-10-20 Modified vitamin k-dependent polypeptides

Publications (1)

Publication Number Publication Date
BR9814611A true BR9814611A (pt) 2000-10-03

Family

ID=25497114

Family Applications (1)

Application Number Title Priority Date Filing Date
BR9814611-4A BR9814611A (pt) 1997-10-23 1998-10-20 Polipeptìdeos modificados dependentes de vitamina k

Country Status (30)

Country Link
US (1) US6017882A (pt)
EP (2) EP1676919B1 (pt)
JP (1) JP4276379B2 (pt)
KR (1) KR20010031370A (pt)
CN (1) CN1246462C (pt)
AP (1) AP2000001811A0 (pt)
AR (2) AR020048A1 (pt)
AT (1) ATE390486T1 (pt)
AU (1) AU749279C (pt)
BR (1) BR9814611A (pt)
CA (1) CA2307175C (pt)
DE (1) DE69839313T2 (pt)
DK (1) DK1090128T3 (pt)
EA (1) EA200000449A1 (pt)
ES (2) ES2496104T3 (pt)
HR (1) HRP20000234A2 (pt)
HU (1) HU225993B1 (pt)
ID (1) ID26330A (pt)
IL (1) IL135603A0 (pt)
IS (1) IS5449A (pt)
MY (1) MY136336A (pt)
NO (1) NO20002025L (pt)
NZ (1) NZ504114A (pt)
PL (1) PL194194B1 (pt)
PT (1) PT1090128E (pt)
SG (1) SG105547A1 (pt)
TR (1) TR200001105T2 (pt)
TW (1) TW587081B (pt)
WO (1) WO1999020767A1 (pt)
ZA (1) ZA989597B (pt)

Families Citing this family (50)

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US7247708B2 (en) 1997-10-23 2007-07-24 Regents Of The University Of Minnesota Modified vitamin K-dependent polypeptides
US6747003B1 (en) * 1997-10-23 2004-06-08 Regents Of The University Of Minnesota Modified vitamin K-dependent polypeptides
US6693075B1 (en) * 1997-10-23 2004-02-17 Regents Of The University Of Minnesota Modified vitamin K-dependent polypeptides
US6998122B1 (en) 1999-04-30 2006-02-14 Eli Lilly And Company Protein C derivatives
WO2001036462A2 (en) * 1999-11-19 2001-05-25 Eli Lilly And Company Protein c derivatives
WO2001057193A2 (en) 2000-02-02 2001-08-09 Eli Lilly And Company Protein c derivatives
EP1263943A1 (en) 2000-02-11 2002-12-11 Eli Lilly &amp; Company Protein c derivatives
AU783512B2 (en) * 2000-02-11 2005-11-03 Bayer Healthcare Llc Factor VII or VIIa-like molecules
US7812132B2 (en) * 2000-04-28 2010-10-12 Regents Of The University Of Minnesota Modified vitamin K-dependent polypeptides
US7220837B1 (en) 2000-04-28 2007-05-22 Regents Of The University Of Minnesota Modified vitamin K-dependent polypeptides
US7160540B2 (en) * 2000-06-30 2007-01-09 Regents Of The University Of Minnesota Methods for detecting activity of clottings factors
US6423826B1 (en) 2000-06-30 2002-07-23 Regents Of The University Of Minnesota High molecular weight derivatives of vitamin K-dependent polypeptides
US20030211094A1 (en) 2001-06-26 2003-11-13 Nelsestuen Gary L. High molecular weight derivatives of vitamin k-dependent polypeptides
AU2001278336B2 (en) * 2000-07-31 2007-01-18 Ottawa Heart Institute Research Corporation Charged phospholipid compositions and methods for their use
US6933367B2 (en) 2000-10-18 2005-08-23 Maxygen Aps Protein C or activated protein C-like molecules
AU2002235073B2 (en) * 2001-03-02 2007-02-01 T.A.C. Thrombosis And Coagulation Ab Protein C variants
JP2005518801A (ja) * 2002-03-01 2005-06-30 テイ・エイ・シー・スロムボシス・アンド・コアグラシヨン・アクテイエボラーク 組換えプロテインcバリアント
US20030186862A1 (en) * 2002-04-02 2003-10-02 Nelsestuen Gary L. Factor VIIa compositions
ATE488581T1 (de) 2002-04-30 2010-12-15 Bayer Healthcare Llc Faktor vii oder faktor viia polypeptidvarianten
US20030232075A1 (en) * 2002-05-06 2003-12-18 University Of Minnesota, A Minnesota Corporation Compositions for producing factor Xa
BRPI0311959B8 (pt) 2002-06-21 2021-05-25 Novo Nordisk Healthcare Ag composição, métodos para preparar um polipeptídeo estável do fator vii, e para tratar uma síndrome responsiva do fator vii, e, uso do polipeptídeo do fator vii
US20040176704A1 (en) * 2003-03-04 2004-09-09 Stevens Timothy A Collection device adapted to accept cartridge for point of care system
EP3103869A1 (en) 2003-03-18 2016-12-14 Novo Nordisk Health Care AG Method for the production of factor vii polypeptides
WO2004083361A2 (en) * 2003-03-20 2004-09-30 Maxygen Holdings Ltd. FVII OR FVIIa VARIANTS
MXPA05013769A (es) 2003-06-19 2006-03-08 Maxygen Holdings Ltd Variantes del dominio gla del factor vii o viia.
ES2381110T3 (es) 2003-09-09 2012-05-23 Novo Nordisk Health Care Ag Polipéptidos de factor VII de coagulación
KR100755967B1 (ko) * 2003-10-23 2007-09-06 한국타이어 주식회사 타이어의 비드와 휠의 갭 측정장치
BRPI0416950B8 (pt) 2003-12-01 2021-05-25 Novo Nordisk Healthcare Ag métodos para remover vírus de uma composição do fator vii líquida, para inativar vírus em uma composição do fator vii líquida, e para eliminar em alto nível a presença de vírus ativos em uma composição do fator vii líquida.
KR20150138427A (ko) 2003-12-19 2015-12-09 노보 노르디스크 헬스 케어 악티엔게젤샤프트 인자 vii 폴리펩티드의 안정화된 조성물
CA2552043A1 (en) 2004-01-21 2005-08-04 Novo Nordisk A/S Transglutaminase mediated conjugation of peptides
EP1831242B1 (en) 2004-12-23 2012-09-26 Novo Nordisk Health Care AG Reduction of the content of protein contaminants in compositions comprising a vitamin k-dependent protein of interest
US8206750B2 (en) 2005-03-24 2012-06-26 Cerenis Therapeutics Holding S.A. Charged lipoprotein complexes and their uses
US20080188400A1 (en) * 2005-04-26 2008-08-07 Maxygen Holdings Ltd. Methods For Treating Bleeding
EP1893632B1 (en) 2005-06-17 2015-08-12 Novo Nordisk Health Care AG Selective reduction and derivatization of engineered factor vii proteins comprising at least one non-native cysteine
EP1904528B1 (en) 2005-07-13 2012-10-31 Novo Nordisk Health Care AG Host cell protein knock-out cells for production of therapeutic proteins
WO2007026021A1 (en) 2005-09-01 2007-03-08 Novo Nordisk Health Care Ag Hydrophobic interaction chromatography purification of factor vii polypeptides
EP1926817A2 (en) 2005-09-14 2008-06-04 Novo Nordisk Health Care AG Human coagulation factor vii polypeptides
EP2059527B1 (en) 2006-09-01 2014-12-03 Novo Nordisk Health Care AG Modified glycoproteins
CA2673260A1 (en) * 2006-12-20 2008-07-03 Bayer Healthcare Llc Factor vii and viia compositions
CN103451172A (zh) 2007-04-13 2013-12-18 催化剂生物科学公司 修饰的因子vii多肽及其应用
US20080305157A1 (en) * 2007-06-08 2008-12-11 University Of Maryland Office Of Technology Commercialization Encapsulation and separation of charged organic solutes inside catanionic vesicles
US9359629B2 (en) 2007-12-27 2016-06-07 Baxalta Incorporated Cell culture processes
TWI538916B (zh) 2008-04-11 2016-06-21 介控生化科技公司 經修飾的因子vii多肽和其用途
ES2966234T3 (es) 2009-06-09 2024-04-18 Prolong Pharmaceuticals Llc Composiciones de hemoglobina
EP2514760B1 (en) * 2009-12-14 2015-10-21 National University Corporation Hokkaido University Peptides imparting cell permeability to lipid membrane structure
TWI557135B (zh) 2010-11-03 2016-11-11 介控生化科技公司 經修飾之第九因子多胜肽及其用途
JP6363600B2 (ja) 2012-07-25 2018-07-25 カタリスト・バイオサイエンシーズ・インコーポレイテッドCatalyst Biosciences, Inc. 修飾第x因子ポリペプチドおよびその使用
US11491212B1 (en) 2017-09-27 2022-11-08 Catalyst Biosciences, Inc. Subcutaneous administration of modified factor IX polypeptides and treatment of hemophilia B
WO2021030787A1 (en) 2019-08-15 2021-02-18 Catalyst Biosciences, Inc. Modified factor vii polypeptides for subcutaneous administration and on-demand treatment
WO2021154414A2 (en) 2020-01-29 2021-08-05 Catalyst Biosciences, Inc. Gene therapy for hemophilia b with a chimeric aav capsid vector encoding modified factor ix polypeptides

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JP2799316B2 (ja) * 1987-06-12 1998-09-17 ヘキスト・マリオン・ルセル株式会社 雑種ヒトプロテインcおよびその遺伝子工学的製法
JPH0246296A (ja) * 1988-08-09 1990-02-15 Hoechst Japan Ltd 雑種プロテインc及びその製造方法
US5580560A (en) * 1989-11-13 1996-12-03 Novo Nordisk A/S Modified factor VII/VIIa
DE69131292T2 (de) * 1990-01-29 1999-09-30 Zymogenetics, Inc. Antikoagulierende proteine
US5504064A (en) * 1991-04-10 1996-04-02 Oklahoma Medical Research Foundation Treatment of bleeding with modified tissue factor in combination with an activator of FVII

Also Published As

Publication number Publication date
EP1090128B1 (en) 2008-03-26
IL135603A0 (en) 2001-05-20
AU749279C (en) 2004-09-16
CN1246462C (zh) 2006-03-22
PT1090128E (pt) 2008-04-17
NO20002025D0 (no) 2000-04-18
HUP0102257A3 (en) 2003-09-29
DE69839313D1 (de) 2008-05-08
US6017882A (en) 2000-01-25
ID26330A (id) 2000-12-14
EP1676919A1 (en) 2006-07-05
ZA989597B (en) 1999-04-23
ES2303362T3 (es) 2008-08-01
EP1676919B1 (en) 2014-07-23
PL340284A1 (en) 2001-01-29
AP2000001811A0 (en) 2000-06-30
AU2702499A (en) 1999-05-10
AR035786A2 (es) 2004-07-14
HU225993B1 (en) 2008-02-28
DK1090128T3 (da) 2008-06-23
WO1999020767A1 (en) 1999-04-29
HRP20000234A2 (en) 2001-08-31
HUP0102257A2 (hu) 2001-09-28
EP1090128A1 (en) 2001-04-11
MY136336A (en) 2008-09-30
ES2496104T3 (es) 2014-09-18
TW587081B (en) 2004-05-11
JP2001520042A (ja) 2001-10-30
PL194194B1 (pl) 2007-05-31
NZ504114A (en) 2002-10-25
IS5449A (is) 2000-04-14
CN1283231A (zh) 2001-02-07
KR20010031370A (ko) 2001-04-16
EA200000449A1 (ru) 2000-12-25
NO20002025L (no) 2000-06-19
AR020048A1 (es) 2002-04-10
AU749279B2 (en) 2002-06-20
JP4276379B2 (ja) 2009-06-10
DE69839313T2 (de) 2009-04-16
CA2307175C (en) 2009-04-14
TR200001105T2 (tr) 2000-09-21
SG105547A1 (en) 2004-08-27
ATE390486T1 (de) 2008-04-15
CA2307175A1 (en) 1999-04-29

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Legal Events

Date Code Title Description
B07A Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]
B07A Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]
B09B Patent application refused [chapter 9.2 patent gazette]

Free format text: DE ACORDO COM O ARTIGO 37, INDEFIRO O PRESENTE PEDIDO, TENDO POR BASE OS ARTIGOS 8O, 13 E 25 DA LEI 9.279 DE 14/05/1996.

B12B Appeal against refusal [chapter 12.2 patent gazette]
B07D Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]
B07E Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]

Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI

B11D Dismissal acc. art. 38, par 2 of ipl - failure to pay fee after grant in time