DE69306969T2 - Therapeutisches anti-hiv oligonukleotid und arzneimittel - Google Patents
Therapeutisches anti-hiv oligonukleotid und arzneimittelInfo
- Publication number
- DE69306969T2 DE69306969T2 DE69306969T DE69306969T DE69306969T2 DE 69306969 T2 DE69306969 T2 DE 69306969T2 DE 69306969 T DE69306969 T DE 69306969T DE 69306969 T DE69306969 T DE 69306969T DE 69306969 T2 DE69306969 T2 DE 69306969T2
- Authority
- DE
- Germany
- Prior art keywords
- hiv
- oligonucleotides
- medicinal product
- therapeutic anti
- disclosed
- 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
- 108091034117 Oligonucleotide Proteins 0.000 title abstract 4
- 230000001225 therapeutic effect Effects 0.000 title abstract 2
- 230000036436 anti-hiv Effects 0.000 title 1
- 229940126601 medicinal product Drugs 0.000 title 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 abstract 3
- 241000713772 Human immunodeficiency virus 1 Species 0.000 abstract 2
- 239000002773 nucleotide Substances 0.000 abstract 2
- 125000003729 nucleotide group Chemical group 0.000 abstract 2
- 208000031886 HIV Infections Diseases 0.000 abstract 1
- 241000124008 Mammalia Species 0.000 abstract 1
- 101710163270 Nuclease Proteins 0.000 abstract 1
- 108091028043 Nucleic acid sequence Proteins 0.000 abstract 1
- 230000029087 digestion Effects 0.000 abstract 1
- 238000009472 formulation Methods 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 abstract 1
- 238000000034 method Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 150000004713 phosphodiesters Chemical class 0.000 abstract 1
- 230000035755 proliferation Effects 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
- 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
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1131—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against viruses
- C12N15/1132—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against viruses against retroviridae, e.g. HIV
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/31—Chemical structure of the backbone
- C12N2310/315—Phosphorothioates
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US95813592A | 1992-10-05 | 1992-10-05 | |
| PCT/US1993/009392 WO1994008004A1 (en) | 1992-10-05 | 1993-10-04 | Therapeutic anti-hiv oligonucleotide and pharmaceutical |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69306969D1 DE69306969D1 (de) | 1997-02-06 |
| DE69306969T2 true DE69306969T2 (de) | 1997-05-07 |
Family
ID=25500631
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69306969T Expired - Fee Related DE69306969T2 (de) | 1992-10-05 | 1993-10-04 | Therapeutisches anti-hiv oligonukleotid und arzneimittel |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US5684147A (de) |
| EP (1) | EP0664833B1 (de) |
| JP (1) | JPH08504570A (de) |
| KR (1) | KR950704482A (de) |
| AT (1) | ATE146819T1 (de) |
| AU (1) | AU678415B2 (de) |
| BR (1) | BR9307191A (de) |
| CA (1) | CA2146364A1 (de) |
| CZ (1) | CZ85495A3 (de) |
| DE (1) | DE69306969T2 (de) |
| DK (1) | DK0664833T3 (de) |
| ES (1) | ES2096343T3 (de) |
| FI (1) | FI951600A (de) |
| GR (1) | GR3022315T3 (de) |
| HU (1) | HUT72400A (de) |
| NO (1) | NO951307L (de) |
| NZ (1) | NZ257434A (de) |
| PL (1) | PL308261A1 (de) |
| WO (1) | WO1994008004A1 (de) |
Families Citing this family (44)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030026782A1 (en) | 1995-02-07 | 2003-02-06 | Arthur M. Krieg | Immunomodulatory oligonucleotides |
| US6239116B1 (en) | 1994-07-15 | 2001-05-29 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
| US6207646B1 (en) | 1994-07-15 | 2001-03-27 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
| US5733781A (en) * | 1994-07-19 | 1998-03-31 | Gen-Probe Incorporated | Oligonucleotides and methods for inhibiting propagation of human immunodeficiency virus |
| US6776986B1 (en) | 1996-06-06 | 2004-08-17 | Novartis Ag | Inhibition of HIV-1 replication by antisense RNA expression |
| US6610539B1 (en) * | 1997-07-10 | 2003-08-26 | Genesense Technologies, Inc. | Antisense oligonucleotide sequences as inhibitors of microorganisms |
| EP1584681A3 (de) * | 1997-07-10 | 2005-11-09 | GeneSense Technologies Inc. | Antisense oligonukleotid-sequenzen als inhibitoren für mikroorganismen |
| JP2001514884A (ja) | 1997-08-19 | 2001-09-18 | ハイブリドン・インク | 新規なｈｉｖ特異的合成オリゴヌクレオチド及びその使用方法 |
| SI1077722T1 (sl) | 1998-05-22 | 2007-02-28 | Ottawa Health Research Inst | Metode in produkti za induciranje sluznicne imunosti |
| EP1829856A3 (de) | 1998-11-12 | 2009-02-25 | Invitrogen Corporation | Transfektionsreagenzien |
| US6977245B2 (en) | 1999-04-12 | 2005-12-20 | The United States Of America As Represented By The Department Of Health And Human Services | Oligodeoxynucleotide and its use to induce an immune response |
| ATE456677T1 (de) * | 1999-07-09 | 2010-02-15 | Gen Probe Inc | Hiv-1 detektion mittels nukleinsäureamplifizierung |
| CA2396677A1 (en) * | 1999-12-23 | 2001-06-28 | The Board Of Regents Of The University Of Texas System | Inhibition of cellular proteases |
| AU2001227889A1 (en) * | 2000-01-14 | 2001-07-24 | The United States of America, represented by The Secretary, Department of Health & Human Services | Oligodeoxynucleotide and its use to induce an immune response |
| US6582920B2 (en) | 2000-09-01 | 2003-06-24 | Gen-Probe Incorporated | Amplification of HIV-1 RT sequences for detection of sequences associated with drug-resistance mutations |
| JP2002125687A (ja) * | 2000-10-30 | 2002-05-08 | Tosoh Corp | Ｈｉｖ−１検出のためのオリゴヌクレオチドおよび検出法 |
| US7666674B2 (en) | 2001-07-27 | 2010-02-23 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Use of sterically stabilized cationic liposomes to efficiently deliver CPG oligonucleotides in vivo |
| US7354909B2 (en) | 2001-08-14 | 2008-04-08 | The United States Of America As Represented By Secretary Of The Department Of Health And Human Services | Method for rapid generation of mature dendritic cells |
| WO2003015711A2 (en) | 2001-08-17 | 2003-02-27 | Coley Pharmaceutical Group, Inc. | Combination motif immune stimulatory oligonucleotides with improved activity |
| AU2002366710A1 (en) | 2001-12-20 | 2003-07-09 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of | USE OF CpG OLIGODEOXYNUCLEOTIDES TO INDUCE ANGIOGENESIS |
| US8466116B2 (en) | 2001-12-20 | 2013-06-18 | The Unites States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Use of CpG oligodeoxynucleotides to induce epithelial cell growth |
| US8263091B2 (en) | 2002-09-18 | 2012-09-11 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Method of treating and preventing infections in immunocompromised subjects with immunostimulatory CpG oligonucleotides |
| JP2006515277A (ja) | 2002-10-29 | 2006-05-25 | コーリー ファーマシューティカル グループ， リミテッド | Ｃ型肝炎ウィルス感染の処置および予防に関する方法および製品 |
| JP2006512927A (ja) | 2002-12-11 | 2006-04-20 | コーリー ファーマシューティカル グループ，インコーポレイテッド | ５’ｃｐｇ核酸およびその使用方法 |
| EP1627563A1 (de) | 2004-08-10 | 2006-02-22 | Academisch Medisch Centrum bij de Universiteit van Amsterdam | Verfahren und Mittel zur Herstellung einer stabilisierten Zelle |
| EP1647595A1 (de) * | 2004-10-15 | 2006-04-19 | Academisch Medisch Centrum bij de Universiteit van Amsterdam | Nukleinsäuren gegen Viren, insbesondere gegen HIV |
| US8399423B2 (en) * | 2005-10-12 | 2013-03-19 | Idera Pharmaceuticals, Inc. | Immune regulatory oligonucleotide (IRO) compounds to modulate toll-like receptor based immune response |
| USRE49583E1 (en) | 2005-11-17 | 2023-07-18 | Tet Systems Gmbh & Co. Kg | Inducible expression systems |
| DK1954811T3 (da) | 2005-11-17 | 2011-07-04 | Tet Systems Gmbh & Co Kg | Inducerbare ekspressionssystemer |
| WO2007067032A1 (en) | 2005-12-09 | 2007-06-14 | Academisch Medisch Cemtrum Bij De Universiteit Van Amsterdam | Means and methods for influencing the stability of cells |
| AU2006323315B2 (en) | 2005-12-09 | 2014-02-20 | Academisch Medisch Centrum Bij De Universiteit Van Amsterdam | Means and methods for influencing the stability of antibody producing cells |
| DK2454283T3 (en) | 2009-07-15 | 2018-05-07 | Aimm Therapeutics Bv | METHODS AND PROCEDURES FOR MANUFACTURING HIGH EFFICIENCY ANTIBODIES |
| CA2793959C (en) | 2010-03-25 | 2019-06-04 | Oregon Health & Science University | Cmv glycoproteins and recombinant vectors |
| PL2646466T3 (pl) | 2010-12-02 | 2017-09-29 | Aimm Therapeutics B.V. | Środki i sposoby do wytwarzania przeciwciał o wysokim powinowactwie |
| RS57397B8 (sr) | 2011-06-10 | 2020-01-31 | Univ Oregon Health & Science | Cmv glikoproteini i rekombinantni vektori |
| AU2012216792A1 (en) | 2011-09-12 | 2013-03-28 | International Aids Vaccine Initiative | Immunoselection of recombinant vesicular stomatitis virus expressing HIV-1 proteins by broadly neutralizing antibodies |
| ES2631608T3 (es) | 2012-06-27 | 2017-09-01 | International Aids Vaccine Initiative | Variante de la glicoproteína Env del VIH-1 |
| US9932364B2 (en) | 2013-08-26 | 2018-04-03 | The Royal Institution For The Advancement Of Learning/Mcgill University | Antisense-based small RNA agents targeting the Gag open reading frame of HIV-1 RNA |
| EP2848937A1 (de) | 2013-09-05 | 2015-03-18 | International Aids Vaccine Initiative | Verfahren zur Identifizierung neuartiger HIV-1-Immunogene |
| EP2873423B1 (de) | 2013-10-07 | 2017-05-31 | International Aids Vaccine Initiative | Lösliche hiv-1-hüllglykoproteintrimere |
| US10611829B2 (en) | 2014-01-31 | 2020-04-07 | Aimm Therapeutics B.V. | Means and methods for producing stable antibodies |
| CN106572974B (zh) | 2014-07-15 | 2021-04-23 | 生命技术公司 | 用于将分子有效递送到细胞的具有脂质聚集体的组合物和方法 |
| EP3069730A3 (de) | 2015-03-20 | 2017-03-15 | International Aids Vaccine Initiative | Lösliche hiv-1-hüllglykoproteintrimere |
| EP3072901A1 (de) | 2015-03-23 | 2016-09-28 | International Aids Vaccine Initiative | Lösliche hiv-1-hüllglykoproteintrimere |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE68929343T2 (de) * | 1988-02-16 | 2002-09-12 | Greatbatch Gen Aid Ltd | Modifizierte Zellen mit Resistenz gegen Retroviralinfektionen |
| DE68925278T2 (de) * | 1988-02-26 | 1996-09-19 | Worcester Found Ex Biology | Hemmung von htlv-iii durch exogene oligonukleotide |
-
1993
- 1993-10-04 ES ES93924289T patent/ES2096343T3/es not_active Expired - Lifetime
- 1993-10-04 EP EP93924289A patent/EP0664833B1/de not_active Expired - Lifetime
- 1993-10-04 DE DE69306969T patent/DE69306969T2/de not_active Expired - Fee Related
- 1993-10-04 DK DK93924289.7T patent/DK0664833T3/da active
- 1993-10-04 NZ NZ257434A patent/NZ257434A/en unknown
- 1993-10-04 WO PCT/US1993/009392 patent/WO1994008004A1/en not_active Application Discontinuation
- 1993-10-04 KR KR1019950701317A patent/KR950704482A/ko not_active Application Discontinuation
- 1993-10-04 AT AT93924289T patent/ATE146819T1/de not_active IP Right Cessation
- 1993-10-04 JP JP6509354A patent/JPH08504570A/ja active Pending
- 1993-10-04 PL PL93308261A patent/PL308261A1/xx unknown
- 1993-10-04 AU AU54028/94A patent/AU678415B2/en not_active Ceased
- 1993-10-04 HU HU9500995A patent/HUT72400A/hu unknown
- 1993-10-04 BR BR9307191A patent/BR9307191A/pt not_active Application Discontinuation
- 1993-10-04 CZ CZ95854A patent/CZ85495A3/cs unknown
- 1993-10-04 CA CA002146364A patent/CA2146364A1/en not_active Abandoned
-
1994
- 1994-10-07 US US08/319,823 patent/US5684147A/en not_active Expired - Lifetime
-
1995
- 1995-04-04 NO NO951307A patent/NO951307L/no unknown
- 1995-04-04 FI FI951600A patent/FI951600A/fi not_active Application Discontinuation
-
1997
- 1997-01-17 GR GR960403507T patent/GR3022315T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK0664833T3 (da) | 1997-04-14 |
| BR9307191A (pt) | 1999-03-30 |
| US5684147A (en) | 1997-11-04 |
| KR950704482A (ko) | 1995-11-20 |
| HU9500995D0 (en) | 1995-06-28 |
| EP0664833B1 (de) | 1996-12-27 |
| CZ85495A3 (en) | 1996-03-13 |
| EP0664833A1 (de) | 1995-08-02 |
| CA2146364A1 (en) | 1994-04-14 |
| GR3022315T3 (en) | 1997-04-30 |
| JPH08504570A (ja) | 1996-05-21 |
| FI951600A0 (fi) | 1995-04-04 |
| HUT72400A (en) | 1996-04-29 |
| NO951307L (no) | 1995-06-01 |
| PL308261A1 (en) | 1995-07-24 |
| NO951307D0 (no) | 1995-04-04 |
| WO1994008004A1 (en) | 1994-04-14 |
| AU5402894A (en) | 1994-04-26 |
| AU678415B2 (en) | 1997-05-29 |
| DE69306969D1 (de) | 1997-02-06 |
| NZ257434A (en) | 1997-01-29 |
| ATE146819T1 (de) | 1997-01-15 |
| ES2096343T3 (es) | 1997-03-01 |
| FI951600A (fi) | 1995-05-10 |
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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 |