NO20072882L - Defekte influensaviruspartikler. - Google Patents
Defekte influensaviruspartikler.Info
- Publication number
- NO20072882L NO20072882L NO20072882A NO20072882A NO20072882L NO 20072882 L NO20072882 L NO 20072882L NO 20072882 A NO20072882 A NO 20072882A NO 20072882 A NO20072882 A NO 20072882A NO 20072882 L NO20072882 L NO 20072882L
- Authority
- NO
- Norway
- Prior art keywords
- influenza virus
- influenza
- defective
- nucleic acid
- provides
- Prior art date
Links
- 241000712461 unidentified influenza virus Species 0.000 title abstract 9
- 230000002950 deficient Effects 0.000 title abstract 6
- 239000002245 particle Substances 0.000 title abstract 6
- 206010022000 influenza Diseases 0.000 abstract 5
- 150000007523 nucleic acids Chemical class 0.000 abstract 4
- 102000039446 nucleic acids Human genes 0.000 abstract 4
- 108020004707 nucleic acids Proteins 0.000 abstract 4
- 230000002378 acidificating effect Effects 0.000 abstract 2
- 230000001900 immune effect Effects 0.000 abstract 2
- 208000015181 infectious disease Diseases 0.000 abstract 2
- 239000000203 mixture Substances 0.000 abstract 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 229960005486 vaccine Drugs 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
- C12N7/04—Inactivation or attenuation; Producing viral sub-units
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/145—Orthomyxoviridae, e.g. influenza virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
- A61K2039/5254—Virus avirulent or attenuated
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
- A61K2039/5256—Virus expressing foreign proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
- A61K2039/5258—Virus-like particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/16011—Orthomyxoviridae
- C12N2760/16111—Influenzavirus A, i.e. influenza A virus
- C12N2760/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/16011—Orthomyxoviridae
- C12N2760/16111—Influenzavirus A, i.e. influenza A virus
- C12N2760/16141—Use of virus, viral particle or viral elements as a vector
- C12N2760/16143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/16011—Orthomyxoviridae
- C12N2760/16111—Influenzavirus A, i.e. influenza A virus
- C12N2760/16151—Methods of production or purification of viral material
- C12N2760/16152—Methods of production or purification of viral material relating to complementing cells and packaging systems for producing virus or viral particles
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/16011—Orthomyxoviridae
- C12N2760/16111—Influenzavirus A, i.e. influenza A virus
- C12N2760/16161—Methods of inactivation or attenuation
- C12N2760/16162—Methods of inactivation or attenuation by genetic engineering
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- General Health & Medical Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Molecular Biology (AREA)
- Public Health (AREA)
- Biophysics (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pulmonology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Plant Pathology (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Physics & Mathematics (AREA)
- Epidemiology (AREA)
- Cell Biology (AREA)
- Mycology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP04105696 | 2004-11-11 | ||
| US62687804P | 2004-11-12 | 2004-11-12 | |
| EP05105708 | 2005-06-27 | ||
| US69443105P | 2005-06-28 | 2005-06-28 | |
| PCT/EP2005/055808 WO2006051069A2 (en) | 2004-11-11 | 2005-11-08 | Defective influenza virus particles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO20072882L true NO20072882L (no) | 2007-08-03 |
Family
ID=36228630
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20072882A NO20072882L (no) | 2004-11-11 | 2007-06-06 | Defekte influensaviruspartikler. |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20080292658A1 (de) |
| EP (2) | EP1812564A2 (de) |
| JP (2) | JP4986859B2 (de) |
| KR (1) | KR20070100882A (de) |
| AU (1) | AU2005303817B8 (de) |
| CA (1) | CA2587451A1 (de) |
| IL (2) | IL182817A (de) |
| MX (1) | MX2007005719A (de) |
| NO (1) | NO20072882L (de) |
| NZ (1) | NZ555118A (de) |
| WO (1) | WO2006051069A2 (de) |
Families Citing this family (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20040002853A (ko) | 2001-01-19 | 2004-01-07 | 비로노바티브 비.브이. | 감응성 포유류에서 호흡계 질환을 유발하는 바이러스 |
| US7176021B2 (en) | 2001-02-23 | 2007-02-13 | Wisconsin Alumni Research Foundation | Mutant cells with altered sialic acid |
| KR101113432B1 (ko) | 2002-02-13 | 2012-02-29 | 위스콘신 얼럼나이 리서어치 화운데이션 | 인플루엔자 바이러스 벡터의 패키징을 위한 신호 |
| EP1485468A4 (de) | 2002-02-21 | 2007-01-03 | Medimmune Vaccines Inc | Rekombinante parainfluenzavirus-expressionssysteme und impfstoffe mit aus metapneumovirus stammenden heterologen antigenen |
| US7682619B2 (en) | 2006-04-06 | 2010-03-23 | Cornell Research Foundation, Inc. | Canine influenza virus |
| GB2437799B (en) * | 2006-05-24 | 2008-08-13 | Univ Warwick | Defective interfering virus |
| AU2007253033B2 (en) * | 2006-05-24 | 2013-01-24 | The University Of Warwick | Defective interfering virus |
| WO2008073161A2 (en) * | 2006-08-14 | 2008-06-19 | Massachusetts Institute Of Technology | Hemagglutinin polypeptides, and reagents and methods relating thereto |
| WO2008147496A2 (en) * | 2007-05-04 | 2008-12-04 | Warf - Wisconsin Alumni Research Foundation | Neuraminidase-deficient live influenza vaccines |
| GB0822672D0 (en) | 2008-12-12 | 2009-01-21 | Univ Warwick | Anti-viral protection with viruses containing a defective genome |
| US10130697B2 (en) | 2010-03-23 | 2018-11-20 | Wisconsin Alumni Research Foundation (Warf) | Vaccines comprising mutant attenuated influenza viruses |
| JP2014527799A (ja) | 2011-08-26 | 2014-10-23 | ダブリュエーアールエフ−ウィスコンシン アラムナイ リサーチ ファウンデーション | 変異型ｐｂ２遺伝子セグメントを有する弱毒化生ワクチンとしてのインフルエンザウイルス |
| SG11201406769RA (en) | 2012-05-10 | 2014-11-27 | Massachusetts Inst Technology | Agents for influenza neutralization |
| CN105518129B (zh) * | 2013-07-19 | 2020-04-28 | 罗切斯特大学 | 减毒流感疫苗和其用途 |
| GB2522615A (en) * | 2014-01-16 | 2015-08-05 | Univ Warwick | Assay and medicament |
| US10053671B2 (en) | 2014-06-20 | 2018-08-21 | Wisconsin Alumni Research Foundation (Warf) | Mutations that confer genetic stability to additional genes in influenza viruses |
| WO2016172588A1 (en) | 2015-04-24 | 2016-10-27 | Andrew Cox | Attenuated influenza vaccines and uses thereof |
| US10494613B2 (en) | 2015-08-28 | 2019-12-03 | Wisconsin Alumni Research Foundation (Warf) | Generation of infectious influenza viruses from virus-like particles |
| US11197925B2 (en) | 2016-02-19 | 2021-12-14 | Wisconsin Alumni Research Foundation (Warf) | Influenza B virus replication for vaccine development |
| WO2019084310A1 (en) | 2017-10-25 | 2019-05-02 | Yoshihiro Kawaoka | HAS RECOMBINANT INFLUENZA VIRUSES STABILIZED FOR EGG REPLICATION |
| US12343390B2 (en) | 2018-08-07 | 2025-07-01 | Wisconsin Alumni Research Foundation (Warf) | Recombinant biologically contained filovirus vaccine |
| JP7655849B2 (ja) | 2018-08-20 | 2025-04-02 | ウィスコンシン アルムニ リサーチ ファンデイション | ヘマグルチニン（ｈａ）タンパク質内の非ドミナントエピトープに対する免疫応答を誘起するためのベクター |
| CL2018003871A1 (es) * | 2018-12-28 | 2021-01-15 | Univ Pontificia Catolica Chile | Anticuerpos monoclonales específicos para el antígeno pb2 del virus de la influenza humana (flu), secuencias nucleotídicas; método y kit de diagnóstico de infección producida por flu |
| EP3921413A1 (de) | 2019-02-08 | 2021-12-15 | Wisconsin Alumni Research Foundation (WARF) | Humanisierte zelllinie |
| CN114929269A (zh) | 2019-05-01 | 2022-08-19 | 威斯康星校友研究基金会(Warf) | 用于疫苗开发的改进的流感病毒复制 |
| US11807872B2 (en) | 2019-08-27 | 2023-11-07 | Wisconsin Alumni Research Foundation (Warf) | Recombinant influenza viruses with stabilized HA for replication in eggs |
| JP2023511444A (ja) | 2020-01-24 | 2023-03-17 | ウィスコンシン アルムニ リサーチ ファンデイション | 安定化されたｎａを有する組換えインフルエンザウイルス |
| WO2021195410A1 (en) | 2020-03-25 | 2021-09-30 | Wisconsin Alumni Research Foundation (Warf) | Recombinant multivalent influenza viruses |
| WO2022006491A1 (en) * | 2020-07-02 | 2022-01-06 | The Regents Of The University Of California | Recombinant enteroviruses and uses thereof |
| WO2023138651A1 (en) * | 2022-01-19 | 2023-07-27 | Versitech Limited | Rationally designed single-round infectious virus and methods of use thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5166057A (en) | 1989-08-28 | 1992-11-24 | The Mount Sinai School Of Medicine Of The City University Of New York | Recombinant negative strand rna virus expression-systems |
| CA2380514A1 (en) * | 1999-07-30 | 2001-02-08 | George Gow Brownlee | Attenuated influenza virus useful as vaccine |
| DK1499348T3 (en) | 2002-04-26 | 2015-01-05 | Medimmune Llc | PROCEDURE FOR PREPARING INFECTIOUS INFLUENZA B-VIRA IN CELL CULTURE |
| US7078218B2 (en) * | 2002-12-13 | 2006-07-18 | Alphavax, Inc. | Alphavirus particles and methods for preparation |
| AU2004232992A1 (en) | 2003-04-23 | 2004-11-04 | Wisconsin Alumni Research Foundation | Recombinant influenza viruses holding a mutation in a transmembrane protein gene |
-
2005
- 2005-11-08 EP EP05801665A patent/EP1812564A2/de not_active Ceased
- 2005-11-08 AU AU2005303817A patent/AU2005303817B8/en not_active Ceased
- 2005-11-08 KR KR1020077013149A patent/KR20070100882A/ko not_active Abandoned
- 2005-11-08 JP JP2007540638A patent/JP4986859B2/ja not_active Expired - Fee Related
- 2005-11-08 WO PCT/EP2005/055808 patent/WO2006051069A2/en not_active Ceased
- 2005-11-08 CA CA002587451A patent/CA2587451A1/en not_active Abandoned
- 2005-11-08 EP EP10182312A patent/EP2272950A3/de not_active Withdrawn
- 2005-11-08 MX MX2007005719A patent/MX2007005719A/es active IP Right Grant
- 2005-11-08 US US11/667,594 patent/US20080292658A1/en not_active Abandoned
- 2005-11-08 NZ NZ555118A patent/NZ555118A/en not_active IP Right Cessation
-
2007
- 2007-04-26 IL IL182817A patent/IL182817A/en not_active IP Right Cessation
- 2007-06-06 NO NO20072882A patent/NO20072882L/no not_active Application Discontinuation
-
2012
- 2012-01-27 JP JP2012015022A patent/JP2012110339A/ja not_active Withdrawn
- 2012-02-20 IL IL218203A patent/IL218203A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL182817A (en) | 2012-04-30 |
| EP2272950A3 (de) | 2011-07-20 |
| US20080292658A1 (en) | 2008-11-27 |
| IL218203A0 (en) | 2012-04-30 |
| AU2005303817A1 (en) | 2006-05-18 |
| EP1812564A2 (de) | 2007-08-01 |
| AU2005303817B2 (en) | 2010-06-10 |
| NZ555118A (en) | 2009-09-25 |
| KR20070100882A (ko) | 2007-10-12 |
| JP2008519591A (ja) | 2008-06-12 |
| CA2587451A1 (en) | 2006-05-18 |
| JP4986859B2 (ja) | 2012-07-25 |
| WO2006051069A3 (en) | 2006-07-20 |
| WO2006051069A2 (en) | 2006-05-18 |
| AU2005303817B8 (en) | 2010-09-30 |
| EP2272950A2 (de) | 2011-01-12 |
| IL182817A0 (en) | 2007-08-19 |
| MX2007005719A (es) | 2007-10-04 |
| JP2012110339A (ja) | 2012-06-14 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| CHAD | Change of the owner's name or address (par. 44 patent law, par. patentforskriften) |
Owner name: ABBOT BIOLOGICALS BV, NL Owner name: ERASMUS UNIVERSITY MEDICAL CENTER, NL |
|
| FC2A | Withdrawal, rejection or dismissal of laid open patent application |