JP2013541010A5 - - Google Patents
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- Publication number
- JP2013541010A5 JP2013541010A5 JP2013533913A JP2013533913A JP2013541010A5 JP 2013541010 A5 JP2013541010 A5 JP 2013541010A5 JP 2013533913 A JP2013533913 A JP 2013533913A JP 2013533913 A JP2013533913 A JP 2013533913A JP 2013541010 A5 JP2013541010 A5 JP 2013541010A5
- Authority
- JP
- Japan
- Prior art keywords
- concentration
- pbmcs
- pharmaceutical composition
- glatiramer acetate
- iii
- 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.)
- Withdrawn
Links
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 claims description 23
- 102000013691 Interleukin-17 Human genes 0.000 claims description 11
- 239000006228 supernatant Substances 0.000 claims description 10
- 210000004369 blood Anatomy 0.000 claims description 6
- 239000008280 blood Substances 0.000 claims description 6
- PGHMRUGBZOYCAA-ADZNBVRBSA-N ionomycin Chemical compound O1[C@H](C[C@H](O)[C@H](C)[C@H](O)[C@H](C)/C=C/C[C@@H](C)C[C@@H](C)C(/O)=C/C(=O)[C@@H](C)C[C@@H](C)C[C@@H](CCC(O)=O)C)CC[C@@]1(C)[C@@H]1O[C@](C)([C@@H](C)O)CC1 PGHMRUGBZOYCAA-ADZNBVRBSA-N 0.000 claims description 3
- PGHMRUGBZOYCAA-UHFFFAOYSA-N ionomycin Natural products O1C(CC(O)C(C)C(O)C(C)C=CCC(C)CC(C)C(O)=CC(=O)C(C)CC(C)CC(CCC(O)=O)C)CCC1(C)C1OC(C)(C(C)O)CC1 PGHMRUGBZOYCAA-UHFFFAOYSA-N 0.000 claims description 3
- 210000002966 serum Anatomy 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 17
- 108010072051 Glatiramer Acetate Proteins 0.000 claims 14
- FHEAIOHRHQGZPC-KIWGSFCNSA-N acetic acid;(2s)-2-amino-3-(4-hydroxyphenyl)propanoic acid;(2s)-2-aminopentanedioic acid;(2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound CC(O)=O.C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 FHEAIOHRHQGZPC-KIWGSFCNSA-N 0.000 claims 14
- 229960003776 glatiramer acetate Drugs 0.000 claims 14
- 238000000034 method Methods 0.000 claims 13
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 claims 8
- 102100037850 Interferon gamma Human genes 0.000 claims 8
- 108010074328 Interferon-gamma Proteins 0.000 claims 8
- 108010002350 Interleukin-2 Proteins 0.000 claims 8
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims 8
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims 8
- 201000006417 multiple sclerosis Diseases 0.000 claims 5
- 239000000090 biomarker Substances 0.000 claims 4
- 238000010254 subcutaneous injection Methods 0.000 claims 4
- 239000007929 subcutaneous injection Substances 0.000 claims 4
- 239000007864 aqueous solution Substances 0.000 claims 2
- 238000012258 culturing Methods 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 239000001963 growth medium Substances 0.000 claims 2
- 238000010257 thawing Methods 0.000 claims 2
- 229940079593 drug Drugs 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 238000009097 single-agent therapy Methods 0.000 claims 1
- 230000004936 stimulating effect Effects 0.000 claims 1
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 238000003556 assay Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US39196810P | 2010-10-11 | 2010-10-11 | |
| US61/391,968 | 2010-10-11 | ||
| PCT/US2011/055588 WO2012051106A1 (en) | 2010-10-11 | 2011-10-10 | Cytokine biomarkers as predictive biomarkers of clinical response for glatiramer acetate |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016093309A Division JP2016188214A (ja) | 2010-10-11 | 2016-05-06 | グラチラマーアセテートに対する臨床的な反応の予測可能なバイオマーカーとしてのサイトカインバイオマーカー |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2013541010A JP2013541010A (ja) | 2013-11-07 |
| JP2013541010A5 true JP2013541010A5 (OSRAM) | 2016-07-28 |
Family
ID=45938670
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2013533913A Withdrawn JP2013541010A (ja) | 2010-10-11 | 2011-10-10 | グラチラマーアセテートに対する臨床的な反応の予測可能なバイオマーカーとしてのサイトカインバイオマーカー |
| JP2016093309A Withdrawn JP2016188214A (ja) | 2010-10-11 | 2016-05-06 | グラチラマーアセテートに対する臨床的な反応の予測可能なバイオマーカーとしてのサイトカインバイオマーカー |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016093309A Withdrawn JP2016188214A (ja) | 2010-10-11 | 2016-05-06 | グラチラマーアセテートに対する臨床的な反応の予測可能なバイオマーカーとしてのサイトカインバイオマーカー |
Country Status (15)
| Country | Link |
|---|---|
| US (3) | US8709433B2 (OSRAM) |
| EP (1) | EP2627669B1 (OSRAM) |
| JP (2) | JP2013541010A (OSRAM) |
| KR (1) | KR20140019296A (OSRAM) |
| AU (1) | AU2011313842B2 (OSRAM) |
| BR (1) | BR112013008573A2 (OSRAM) |
| CA (1) | CA2814500A1 (OSRAM) |
| EA (1) | EA025780B1 (OSRAM) |
| ES (1) | ES2602977T3 (OSRAM) |
| IL (1) | IL225118A (OSRAM) |
| MX (1) | MX347871B (OSRAM) |
| NZ (2) | NZ609938A (OSRAM) |
| PL (1) | PL2627669T3 (OSRAM) |
| PT (1) | PT2627669T (OSRAM) |
| WO (1) | WO2012051106A1 (OSRAM) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA103699C2 (ru) | 2009-08-20 | 2013-11-11 | Еда Рисёрч Энд Девелопмент Ко., Лтд. | Терапия глатирамера ацетатом с низкой частотой |
| USRE49251E1 (en) | 2010-01-04 | 2022-10-18 | Mapi Pharma Ltd. | Depot systems comprising glatiramer or pharmacologically acceptable salt thereof |
| EA025780B1 (ru) | 2010-10-11 | 2017-01-30 | Тева Фармасьютикал Индастриз Лтд. | Цитокиновые биомаркеры в качестве биомаркеров, прогнозирующих клинический ответ на глатирамер ацетат |
| CA2851510A1 (en) | 2011-10-10 | 2013-04-18 | Teva Pharmaceutical Industries Ltd. | Single nucleotide polymorphisms useful to predict clinical response for glatiramer acetate |
| TW201420111A (zh) | 2012-10-10 | 2014-06-01 | Teva Pharma | 對格拉默醋酸鹽（ｇｌａｔｉｒａｍｅｒ ａｃｅｔａｔｅ）之臨床反應具預測性之生物標記 |
| US10344330B2 (en) | 2013-03-14 | 2019-07-09 | Mylan Inc. | Glatiramer acetate response biomarker mRNA potency assay |
| UY35790A (es) | 2013-10-21 | 2015-05-29 | Teva Pharma | Marcadores genéticos que predicen la respuesta al acetato de glatiramer |
| TWI717314B (zh) | 2013-10-24 | 2021-02-01 | 美商麥蘭股份有限公司 | 供評估格拉默醋酸鹽製備物之免疫同一性用的人類ｔ細胞株分析方法 |
| US9155775B1 (en) | 2015-01-28 | 2015-10-13 | Teva Pharmaceutical Industries, Ltd. | Process for manufacturing glatiramer acetate product |
| US20160213633A1 (en) * | 2015-01-28 | 2016-07-28 | Teva Pharmaceutical Industries, Ltd. | Method of inducing anti-glatiramer acetate antibody response |
| US12097292B2 (en) | 2016-08-28 | 2024-09-24 | Mapi Pharma Ltd. | Process for preparing microparticles containing glatiramer acetate |
| US12370233B2 (en) | 2016-08-31 | 2025-07-29 | Mapi Pharma Ltd. | Depot systems comprising glatiramer acetate |
| WO2018178973A1 (en) | 2017-03-26 | 2018-10-04 | Mapi Pharma Ltd. | Glatiramer depot systems for treating progressive forms of multiple sclerosis |
| KR102734078B1 (ko) * | 2018-08-30 | 2024-11-25 | 싸토리우스 바이오애널리티컬 인스트루먼츠, 아이엔씨 | 단일 샘플 중 저농도 및 고농도 단백질의 농도 결정 방법 |
| WO2025181335A1 (en) * | 2024-02-29 | 2025-09-04 | Grifols Worldwide Operations Limited | Methods of treating a cognitive impairment |
Family Cites Families (61)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL36670A (en) | 1971-04-21 | 1974-09-10 | Sela M | Therapeutic basic copolymers of amino acids |
| IL113812A (en) | 1994-05-24 | 2000-06-29 | Yeda Res & Dev | Copolymer-1 pharmaceutical compositions containing it and its use |
| US6214791B1 (en) | 1997-01-10 | 2001-04-10 | Yeda Research And Development Co. Ltd. | Treatment of multiple sclerosis through ingestion or inhalation of copolymer-1 |
| IL119989A0 (en) | 1997-01-10 | 1997-04-15 | Yeda Res & Dev | Pharmaceutical compositions for oral treatment of multiple sclerosis |
| ES2527760T3 (es) | 1998-07-23 | 2015-01-29 | Yeda Research And Development Co., Ltd. | Tratamiento de enfermedad de Crohn con copolímero 1 y polipéptidos |
| CA2337688C (en) | 1998-07-23 | 2016-04-05 | Yeda Research And Development Co., Ltd. | Treatment of autoimmune conditions with copolymer 1 and related copolymers |
| AU766498B2 (en) | 1998-07-23 | 2003-10-16 | President And Fellows Of Harvard College, The | Synthetic peptides and methods of use for autoimmune disease therapies |
| US6800287B2 (en) | 1998-09-25 | 2004-10-05 | Yeda Research And Development Co., Ltd. | Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use |
| US6514938B1 (en) | 1998-09-25 | 2003-02-04 | Yeda Research And Development Co. Ltd. At The Weizmann Institute Of Science | Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use |
| WO2000018794A1 (en) | 1998-09-25 | 2000-04-06 | Yeda Research And Development Co., Ltd. | Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use |
| WO2000020010A1 (en) | 1998-10-02 | 2000-04-13 | Yeda Research And Development Co., Ltd. | Alternate day administration of copolymer 1 for treating autoimmune diseases |
| EP1128839A4 (en) | 1998-11-12 | 2002-10-09 | Yeda Res & Dev | PHARMACEUTICAL COMPOSITIONS CONTAINING COPOLYMERS OF SYNTHETIC PEPTIDES AND METHODS FOR PREVENTING AND TREATING GVHD AND HVGD |
| PT1248643E (pt) | 2000-01-20 | 2005-10-31 | Yeda Res & Dev | Utilizacao de copolimero 1 e peptidos e polipeptidos congeneres e de celulas t tratadas co estes compostos para terapia neuroprotectora |
| ZA200206457B (en) | 2000-02-18 | 2003-08-13 | Yeda Res & Dev | Oral, nasal and pulmonary dosage formulations of copolymer 1. |
| MXPA02008023A (es) | 2000-02-18 | 2005-06-30 | Yeda Res & Dev | Formulaciones de copolimero 1 para dosificacion oral, nasal y pulmonar. |
| US20020077278A1 (en) | 2000-06-05 | 2002-06-20 | Yong V. Wee | Use of glatiramer acetate (copolymer 1) in the treatment of central nervous system disorders |
| CA2411536A1 (en) | 2000-06-05 | 2001-12-13 | V. Wee Yong | The use of glatiramer acetate (copolymer 1) in the treatment of central nervous system disorders |
| EP1294390B1 (en) | 2000-06-07 | 2006-01-04 | YEDA RESEARCH AND DEVELOPMENT CO., Ltd. | The use of copolymer 1 and related peptides and polypeptides and t cells treated therewith for neuroprotection from glutamate toxicity |
| WO2002076503A1 (en) | 2000-06-20 | 2002-10-03 | Mayo Foundation For Medical Education And Research | Treatment of central nervous system diseases by antibodies against glatiramer acetate |
| DE60237170D1 (de) | 2001-12-04 | 2010-09-09 | Teva Pharma | Verfahren zur messung der wirkstärke von glatirameracetat |
| KR20040081431A (ko) | 2001-12-06 | 2004-09-21 | 예다 리서치 앤드 디벨럽먼트 캄파니 리미티드 | 운동신경 질환의 치료용 백신 및 치료 방법 |
| AU2003283152A1 (en) | 2002-11-13 | 2004-06-03 | Apotex Pharmachem Inc. | Process for the preparation of glatiramer acetate by polymerisation of n-carboxy anhydrides of l-alanine, l-tyrosine, benzyl l-glutamate and benzyloxycarbonyl l-lysine |
| CA2512735C (en) | 2003-01-07 | 2016-03-08 | Yeda Research And Development Co. Ltd. | Eye-drop vaccine containing copolymer 1 for therapeutic immunization |
| ES2397836T3 (es) | 2003-01-21 | 2013-03-11 | Yeda Research And Development Co., Ltd. | Copolímero 1 para el tratamiento de enfermedades inflamatorias del intestino |
| EP1603530A1 (en) | 2003-03-04 | 2005-12-14 | Teva Pharmaceutical Industries Limited | Combination therapy with glatiramer acetate and alphacalcidol for the treatment of multiple sclerosis |
| SI1638589T1 (sl) | 2003-05-14 | 2014-07-31 | Teva Pharmaceutical Industries Ltd. | Kombinirana terapija z glatiramer acetatom in mitoksantronom za zdravljenje multiple skleroze |
| US7812116B2 (en) * | 2003-07-03 | 2010-10-12 | Rush University Medical Center | Immunogenic peptides |
| KR20060090715A (ko) | 2003-09-29 | 2006-08-14 | 추가이 세이야쿠 가부시키가이샤 | Ｎｋ 세포에 발현하는 단백질 |
| EA200600877A1 (ru) | 2003-10-31 | 2006-12-29 | Тева Фармасьютикал Индастриз, Лтд. | Наночастицы для доставки лекарств |
| US20080085269A1 (en) | 2003-11-12 | 2008-04-10 | Michal Eisenbach-Schwartz | Vaccine And Method For Treatment Of Neurodegenerative Diseases |
| EP1778286A4 (en) | 2004-03-03 | 2009-04-08 | Teva Pharma | COMBINATION THERAPY WITH ACETATE OF GLATIRAMER AND RILUZOLE |
| CA2579038A1 (en) | 2004-09-02 | 2006-03-16 | Teva Pharmaceutical Industries, Ltd. | Combination therapy with glatiramer acetate and n-acetylcysteine for the treatment of multiple sclerosis |
| WO2006029411A2 (en) | 2004-09-09 | 2006-03-16 | Yeda Research And Development Co. Ltd. | Mixtures of polypeptides, compositions containing and processes for preparing same, and uses thereof |
| MX2007002760A (es) | 2004-09-09 | 2007-05-18 | Teva Pharma | Procedimiento para la preparacion de mezclas de polipeptidos y utilizando acido bromhidrico purificado. |
| ES2331015T3 (es) | 2004-10-29 | 2009-12-18 | Sandoz Ag | Proceso para la preparacion de un glatiramero. |
| NZ556156A (en) | 2005-02-02 | 2010-03-26 | Teva Pharma | Process for producing acetate salts of polypeptides using hydrogenolysis |
| PT1848415E (pt) | 2005-02-17 | 2013-06-27 | Teva Pharma | Terapia de combinação com acetato de glatirâmero e rasagilina para o tratamento da esclerose múltipla |
| US20100167983A1 (en) | 2007-10-22 | 2010-07-01 | Teva Pharmaceutical Industries, Ltd. | Combination therapy with glatiramer acetate and rasagiline for the treatment of multiple sclerosis |
| EP1891233A4 (en) | 2005-04-25 | 2010-03-24 | Yeda Res & Dev | MARKERS ASSOCIATED WITH THERAPY EFFECTIVENESS OF GLATIRAMERATE ACETATE |
| WO2007030573A2 (en) | 2005-09-09 | 2007-03-15 | Yeda Research And Development Co. Ltd. | Polypeptides useful for molecular weight determinations |
| EP2517727A3 (en) * | 2005-09-29 | 2013-10-30 | Caprion Proteomics USA, LLC | Biomarkers for multiple sclerosis and methods of use thereof |
| WO2007081975A2 (en) * | 2006-01-11 | 2007-07-19 | Teva Pharmaceutical Industries, Ltd. | Method of treating multiple sclerosis |
| WO2007146331A1 (en) | 2006-06-12 | 2007-12-21 | Teva Pharmaceutical Industries, Ltd. | Tannate salt form of polypeptide mixtures, their preparation and use |
| WO2008006026A1 (en) | 2006-07-05 | 2008-01-10 | Momenta Pharmaceuticals, Inc. | Improved process for the preparation of copolymer-1 |
| US20100256038A1 (en) * | 2007-06-25 | 2010-10-07 | Vertex Pharmaceuticals Incorporated | Th-17 cells |
| AU2008330093A1 (en) | 2007-11-28 | 2009-06-04 | Yeda Research And Development Co., Ltd. | Method of delaying the onset of clinically definite multiple sclerosis |
| EP2113560A1 (en) * | 2008-04-28 | 2009-11-04 | TXCell | Compositions for treating an arthritic condition |
| EP2335066B1 (en) * | 2008-09-19 | 2016-12-28 | University of Utah Research Foundation | Methods for prediction of multiple sclerosis disease and therapy response |
| ATE549013T1 (de) | 2009-07-15 | 2012-03-15 | Teva Pharma | Formulierung von glatirameracetat mit verringertem volumen und verabreichungsverfahren |
| US8920373B2 (en) | 2009-07-15 | 2014-12-30 | Teva Pharmaceutical Industries, Ltd. | Reduced volume formulation of glatiramer acetate and methods of administration |
| UA103699C2 (ru) | 2009-08-20 | 2013-11-11 | Еда Рисёрч Энд Девелопмент Ко., Лтд. | Терапия глатирамера ацетатом с низкой частотой |
| US8759302B2 (en) | 2010-03-16 | 2014-06-24 | Teva Pharmaceutical Industries, Ltd. | Methods of treating a subject afflicted with an autoimmune disease using predictive biomarkers of clinical response to glatiramer acetate therapy in multiple sclerosis |
| EA025780B1 (ru) | 2010-10-11 | 2017-01-30 | Тева Фармасьютикал Индастриз Лтд. | Цитокиновые биомаркеры в качестве биомаркеров, прогнозирующих клинический ответ на глатирамер ацетат |
| CA2851510A1 (en) | 2011-10-10 | 2013-04-18 | Teva Pharmaceutical Industries Ltd. | Single nucleotide polymorphisms useful to predict clinical response for glatiramer acetate |
| TW201420111A (zh) | 2012-10-10 | 2014-06-01 | Teva Pharma | 對格拉默醋酸鹽（ｇｌａｔｉｒａｍｅｒ ａｃｅｔａｔｅ）之臨床反應具預測性之生物標記 |
| KR20150111918A (ko) | 2012-12-21 | 2015-10-06 | 테바 파마슈티컬 인더스트리즈 리미티드 | 글라티라머 아세테이트의 경점막 전달 |
| EA201591187A1 (ru) | 2012-12-21 | 2016-03-31 | Тева Фармасьютикал Индастриз Лтд. | Пероральная трансмукозальная доставка ацетата глатирамера |
| BR112015016169A2 (pt) | 2013-01-04 | 2017-07-11 | Teva Pharma | caracterizando produtos de drogas relacionados a acetato de glatirâmero |
| BR112015022538A2 (pt) | 2013-03-12 | 2017-07-18 | Teva Pharma | terapia de indução de rituximab seguida por terapia de acetato de glatirâmero |
| UY35790A (es) | 2013-10-21 | 2015-05-29 | Teva Pharma | Marcadores genéticos que predicen la respuesta al acetato de glatiramer |
| US9155775B1 (en) | 2015-01-28 | 2015-10-13 | Teva Pharmaceutical Industries, Ltd. | Process for manufacturing glatiramer acetate product |
-
2011
- 2011-10-10 EA EA201390543A patent/EA025780B1/ru not_active IP Right Cessation
- 2011-10-10 AU AU2011313842A patent/AU2011313842B2/en not_active Ceased
- 2011-10-10 PT PT118331990T patent/PT2627669T/pt unknown
- 2011-10-10 NZ NZ609938A patent/NZ609938A/en not_active IP Right Cessation
- 2011-10-10 NZ NZ703122A patent/NZ703122A/en not_active IP Right Cessation
- 2011-10-10 PL PL11833199T patent/PL2627669T3/pl unknown
- 2011-10-10 JP JP2013533913A patent/JP2013541010A/ja not_active Withdrawn
- 2011-10-10 EP EP11833199.0A patent/EP2627669B1/en active Active
- 2011-10-10 MX MX2013003929A patent/MX347871B/es active IP Right Grant
- 2011-10-10 US US13/269,913 patent/US8709433B2/en not_active Expired - Fee Related
- 2011-10-10 CA CA2814500A patent/CA2814500A1/en not_active Abandoned
- 2011-10-10 KR KR1020137012245A patent/KR20140019296A/ko not_active Ceased
- 2011-10-10 ES ES11833199.0T patent/ES2602977T3/es active Active
- 2011-10-10 BR BR112013008573A patent/BR112013008573A2/pt not_active IP Right Cessation
- 2011-10-10 WO PCT/US2011/055588 patent/WO2012051106A1/en not_active Ceased
-
2013
- 2013-03-07 IL IL225118A patent/IL225118A/en not_active IP Right Cessation
-
2014
- 2014-04-11 US US14/250,955 patent/US9063153B2/en not_active Expired - Fee Related
-
2015
- 2015-05-07 US US14/706,843 patent/US9625473B2/en not_active Expired - Fee Related
-
2016
- 2016-05-06 JP JP2016093309A patent/JP2016188214A/ja not_active Withdrawn
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