MA41218A - Combinaison de vaccin à base de listeria comportant des anticorps anti-ox40 ou anti-gitr - Google Patents

Combinaison de vaccin à base de listeria comportant des anticorps anti-ox40 ou anti-gitr

Info

Publication number
MA41218A
MA41218A MA041218A MA41218A MA41218A MA 41218 A MA41218 A MA 41218A MA 041218 A MA041218 A MA 041218A MA 41218 A MA41218 A MA 41218A MA 41218 A MA41218 A MA 41218A
Authority
MA
Morocco
Prior art keywords
vaccine combination
gitr antibodies
listeria vaccine
listeria
gitr
Prior art date
Application number
MA041218A
Other languages
English (en)
Inventor
Samir Khleif
Mikayel Mkrtichyan
Robert Petit
Anu Wallecha
Original Assignee
Advaxis Inc
Univ Res Inst Inc Augusta
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 Advaxis Inc, Univ Res Inst Inc Augusta filed Critical Advaxis Inc
Publication of MA41218A publication Critical patent/MA41218A/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • 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
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001103—Receptors for growth factors
    • A61K39/001106—Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ErbB4
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001193—Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR
    • A61K39/001194—Prostate specific antigen [PSA]
    • 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
    • A61K39/02—Bacterial antigens
    • 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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • C07K14/01—DNA viruses
    • C07K14/025—Papovaviridae, e.g. papillomavirus, polyomavirus, SV40, BK virus, JC virus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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
    • A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
    • A61K2039/522—Bacterial cells; Fungal cells; Protozoal cells 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/95—Fusion polypeptide containing a motif/fusion for degradation (ubiquitin fusions, PEST sequence)
    • 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
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/20011—Papillomaviridae
    • C12N2710/20034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Cell Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Developmental Biology & Embryology (AREA)
  • Zoology (AREA)
  • Urology & Nephrology (AREA)
  • Biotechnology (AREA)
  • Communicable Diseases (AREA)
  • Toxicology (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
MA041218A 2014-12-19 2015-12-17 Combinaison de vaccin à base de listeria comportant des anticorps anti-ox40 ou anti-gitr MA41218A (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201462094349P 2014-12-19 2014-12-19
US201462094472P 2014-12-19 2014-12-19
US201562147463P 2015-04-14 2015-04-14
US201562262896P 2015-12-03 2015-12-03

Publications (1)

Publication Number Publication Date
MA41218A true MA41218A (fr) 2017-10-24

Family

ID=56127737

Family Applications (2)

Application Number Title Priority Date Filing Date
MA041217A MA41217A (fr) 2014-12-19 2015-12-17 Polythérapies ayant des souches de listeria recombinées
MA041218A MA41218A (fr) 2014-12-19 2015-12-17 Combinaison de vaccin à base de listeria comportant des anticorps anti-ox40 ou anti-gitr

Family Applications Before (1)

Application Number Title Priority Date Filing Date
MA041217A MA41217A (fr) 2014-12-19 2015-12-17 Polythérapies ayant des souches de listeria recombinées

Country Status (14)

Country Link
US (2) US20170368157A1 (fr)
EP (2) EP3234148A4 (fr)
JP (2) JP2018501243A (fr)
KR (2) KR20170096012A (fr)
CN (2) CN107427565A (fr)
AU (2) AU2015364260A1 (fr)
CA (2) CA2971220A1 (fr)
HK (2) HK1245331A1 (fr)
IL (2) IL252680A0 (fr)
MA (2) MA41217A (fr)
MX (2) MX2017008187A (fr)
SG (2) SG11201704662SA (fr)
TW (2) TW201636360A (fr)
WO (2) WO2016100924A1 (fr)

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US9012141B2 (en) 2000-03-27 2015-04-21 Advaxis, Inc. Compositions and methods comprising KLK3 of FOLH1 antigen
WO2012125551A1 (fr) 2011-03-11 2012-09-20 Advaxis Adjuvants à base de listeria
SG10201700392UA (en) 2012-03-12 2017-03-30 Advaxis Inc Suppressor cell function inhibition following listeria vaccine treatment
KR102243062B1 (ko) 2013-05-02 2021-04-21 아납티스바이오, 아이엔씨. 예정된 사멸-1에 대한 항체
EP3107566A4 (fr) 2014-02-18 2017-10-11 Advaxis, Inc. Immunothérapie multi-cibles dirigée contre un biomarqueur
SG11201608820WA (en) 2014-04-24 2016-11-29 Advaxis Inc Recombinant listeria vaccine strains and methods of producing the same
MA41644A (fr) 2015-03-03 2018-01-09 Advaxis Inc Compositions à base de listeria comprenant un système d'expression de minigènes codant pour des peptides, et leurs procédés d'utilisation
US20180104284A1 (en) * 2015-05-13 2018-04-19 Advaxis, Inc. Immunogenic Listeria-Based Compositions Comprising Truncated Acta-Antigen Fusions And Methods Of Use Thereof
US20170199961A1 (en) 2015-12-16 2017-07-13 Gritstone Oncology, Inc. Neoantigen Identification, Manufacture, and Use
EP3666794A1 (fr) 2016-11-01 2020-06-17 AnaptysBio, Inc. Anticorps dirigés contre la mort programmée 1 (pd -1)
EP3534944A4 (fr) * 2016-11-07 2020-07-01 Advaxis, Inc. Combinaison d'un vaccin à base de listeria avec des anticorps anti-ctla-4 ou anti-cd137
CN110506107A (zh) 2016-11-30 2019-11-26 阿德瓦希斯公司 靶向复发性癌症突变的免疫原性组合物及其使用方法
BR112019014187A2 (pt) 2017-01-09 2020-02-11 Tesaro, Inc. Métodos de tratamento de câncer com anticorpos anti-pd-1
MX393780B (es) 2017-01-17 2025-03-24 Heparegenix Gmbh Inhibidores de proteina cinasa para promover la regeneracion hepatica o reducir o prevenir la muerte de hepatocitos
CN109136275B (zh) 2017-06-19 2021-03-16 百奥赛图(北京)医药科技股份有限公司 人源化gitr基因改造动物模型的制备方法及应用
US11179339B2 (en) 2017-09-19 2021-11-23 Advaxis, Inc. Compositions and methods for lyophilization of bacteria or listeria strains
ES3029080T3 (en) 2017-10-10 2025-06-23 Seattle Project Corp Neoantigen identification using hotspots
US11885815B2 (en) 2017-11-22 2024-01-30 Gritstone Bio, Inc. Reducing junction epitope presentation for neoantigens
EP3762719A1 (fr) * 2018-03-09 2021-01-13 Advaxis, Inc. Compositions et méthodes d'évaluation d'atténuation et d'infectivité de souches de listeria
KR102825164B1 (ko) 2018-03-27 2025-06-26 브리스톨-마이어스 스큅 컴퍼니 자외선 신호를 사용한 단백질 농도의 실시간 모니터링
CN110408634B (zh) 2018-04-27 2021-08-03 苏州若泰医药科技有限公司 一种非整合李斯特菌疫苗及抗肿瘤免疫应答方法
CN110579608B (zh) * 2018-06-11 2022-07-08 苏州若泰医药科技有限公司 一种筛选高表达外源蛋白的非整合减毒李斯特菌菌株的方法
US10925947B2 (en) * 2018-06-29 2021-02-23 Immatics Biotechnologies Gmbh A*03 restricted peptides for use in immunotherapy against cancers and related methods
WO2020172658A1 (fr) 2019-02-24 2020-08-27 Bristol-Myers Squibb Company Procédés d'isolement d'une protéine
CN111979162B (zh) * 2019-05-22 2024-02-13 上海市公共卫生临床中心 重组卡介苗菌株、其制备方法和用途
US20220220430A1 (en) 2019-05-23 2022-07-14 Bristol-Myers Squibb Company Methods of monitoring cell culture media
CN114502587A (zh) * 2019-07-30 2022-05-13 普瑞文森生物有限公司 通过非耗竭性b细胞抑制剂降低免疫原性的方法和组合物
WO2021098748A1 (fr) * 2019-11-21 2021-05-27 Beigene (Beijing) Co., Ltd. Procédés de traitement du cancer avec un anticorps anti-ox40 en combinaison avec des agents chimiothérapeutiques
JP2023532444A (ja) 2020-06-23 2023-07-28 ザ・リージェンツ・オブ・ザ・ユニバーシティ・オブ・コロラド・ア・ボディ・コーポレイト 呼吸器病原体を診断し、ｃｏｖｉｄ－１９に関連する転帰を予測する方法
US20230374064A1 (en) 2020-10-05 2023-11-23 Bristol-Myers Squibb Company Methods for concentrating proteins
JP2025509274A (ja) 2022-03-09 2025-04-11 ブリストル－マイヤーズ スクイブ カンパニー 治療用タンパク質の一過性発現
CN114736295B (zh) * 2022-06-14 2022-08-09 北京科跃中楷生物技术有限公司 一种辣根过氧化物酶标记抗体及其制备方法
KR20260026491A (ko) * 2023-06-16 2026-02-26 위스콘신 얼럼나이 리서어치 화운데이션 표적 방사성 핵종 치료 및 유전자 조작 면역 세포 치료의 용법에 의한 고형 종양의 치료

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US7635479B2 (en) * 2000-03-29 2009-12-22 The Trustees Of The University Of Pennsylvania Composition and methods for enhancing immunogenecity of antigens
US10106619B2 (en) * 2006-10-04 2018-10-23 La Jolla Institute For Allergy And Immunology Virus vaccination and treatment methods with OX40 agonist compositions
EP1921149A1 (fr) * 2006-11-13 2008-05-14 AEterna Zentaris GmbH Microorganimses portant des séquences nucléotidiques codant pour des antigènes et des toxines, procédé de fabrication, et leurs utilisations
CN101214372A (zh) * 2008-01-04 2008-07-09 中国人民解放军第四军医大学 一种体内诱导出针对TNF-α分子的自身抗体的蛋白疫苗的构建方法
US20120135033A1 (en) * 2008-05-19 2012-05-31 Anu Wallecha Multiple delivery system for heterologous antigens
US9017660B2 (en) * 2009-11-11 2015-04-28 Advaxis, Inc. Compositions and methods for prevention of escape mutation in the treatment of Her2/neu over-expressing tumors
US20110223187A1 (en) * 2010-02-15 2011-09-15 Vafa Shahabi Live listeria-based vaccines for central nervous system therapy
WO2014047350A1 (fr) * 2012-09-20 2014-03-27 Morningside Technology Ventures Ltd. Virus oncolytique codant pour des agents de liaison de pd-1 et ses utilisations
US20140356930A1 (en) * 2013-06-03 2014-12-04 Panacea Pharmaceuticals Immune system enhancing immunotherapy for the treatment of cancer

Also Published As

Publication number Publication date
JP2018501244A (ja) 2018-01-18
CA2971455A1 (fr) 2016-06-23
MA41217A (fr) 2017-10-24
EP3234148A4 (fr) 2018-10-17
TW201639594A (zh) 2016-11-16
MX2017008187A (es) 2017-09-13
JP2018501243A (ja) 2018-01-18
MX2017008173A (es) 2017-09-18
US20170368157A1 (en) 2017-12-28
AU2015364255A1 (en) 2017-07-20
US20180153974A1 (en) 2018-06-07
EP3234148A1 (fr) 2017-10-25
WO2016100924A1 (fr) 2016-06-23
HK1246341A1 (zh) 2018-09-07
HK1245331A1 (zh) 2018-08-24
SG11201704662SA (en) 2017-07-28
TW201636360A (zh) 2016-10-16
WO2016100929A1 (fr) 2016-06-23
IL252743A0 (en) 2017-08-31
IL252680A0 (en) 2017-08-31
CA2971220A1 (fr) 2016-06-23
SG11201704599PA (en) 2017-07-28
EP3234106A1 (fr) 2017-10-25
AU2015364260A1 (en) 2017-07-20
KR20170096012A (ko) 2017-08-23
CN107427565A (zh) 2017-12-01
KR20170092626A (ko) 2017-08-11
CN107206060A (zh) 2017-09-26
EP3234106A4 (fr) 2018-07-18

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