BR112016020368A2 - proteínas fc multiméricas - Google Patents
proteínas fc multiméricasInfo
- Publication number
- BR112016020368A2 BR112016020368A2 BR112016020368-2A BR112016020368A BR112016020368A2 BR 112016020368 A2 BR112016020368 A2 BR 112016020368A2 BR 112016020368 A BR112016020368 A BR 112016020368A BR 112016020368 A2 BR112016020368 A2 BR 112016020368A2
- Authority
- BR
- Brazil
- Prior art keywords
- proteins
- multimeric
- relates
- fusion proteins
- tailpiece
- Prior art date
Links
- 102000004169 proteins and genes Human genes 0.000 title abstract 2
- 108090000623 proteins and genes Proteins 0.000 title abstract 2
- 102000037865 fusion proteins Human genes 0.000 abstract 2
- 108020001507 fusion proteins Proteins 0.000 abstract 2
- 102000009109 Fc receptors Human genes 0.000 abstract 1
- 108010087819 Fc receptors Proteins 0.000 abstract 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 abstract 1
- 208000026278 immune system disease Diseases 0.000 abstract 1
- 239000000203 mixture Substances 0.000 abstract 1
- 235000018102 proteins Nutrition 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal 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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
-
- 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
- C12N15/62—DNA sequences coding for fusion proteins
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P21/00—Preparation of peptides or proteins
- C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
- C07K2317/41—Glycosylation, sialylation, or fucosylation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/524—CH2 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/526—CH3 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/528—CH4 domain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/53—Hinge
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Peptides Or Proteins (AREA)
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1403913.5 | 2014-03-05 | ||
| GB201403913A GB201403913D0 (en) | 2014-03-05 | 2014-03-05 | Proteins |
| GB1403912.7 | 2014-03-05 | ||
| GB201403912A GB201403912D0 (en) | 2014-03-05 | 2014-03-05 | Proteins |
| GB1405952.1 | 2014-04-02 | ||
| GB201405952A GB201405952D0 (en) | 2014-04-02 | 2014-04-02 | Proteins |
| GB1412646.0 | 2014-07-16 | ||
| GB201412646A GB201412646D0 (en) | 2014-07-16 | 2014-07-16 | Proteins |
| PCT/EP2015/054687 WO2015132364A1 (en) | 2014-03-05 | 2015-03-05 | Multimeric fc proteins |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BR112016020368A2 true BR112016020368A2 (pt) | 2018-01-23 |
Family
ID=52629578
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BR112016020368-2A BR112016020368A2 (pt) | 2014-03-05 | 2015-03-05 | proteínas fc multiméricas |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US11352414B2 (enExample) |
| EP (1) | EP3114143B1 (enExample) |
| JP (1) | JP6851200B2 (enExample) |
| KR (1) | KR20160130463A (enExample) |
| CN (1) | CN106068274A (enExample) |
| AU (1) | AU2015226100B2 (enExample) |
| BR (1) | BR112016020368A2 (enExample) |
| CA (1) | CA2939198A1 (enExample) |
| IL (1) | IL247096A0 (enExample) |
| MX (1) | MX2016010951A (enExample) |
| RU (1) | RU2016139006A (enExample) |
| SG (1) | SG11201606597QA (enExample) |
| TW (1) | TW201619188A (enExample) |
| UY (1) | UY36021A (enExample) |
| WO (1) | WO2015132364A1 (enExample) |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201619188A (zh) * | 2014-03-05 | 2016-06-01 | 優稀美生物醫藥公司 | 多聚體Fc蛋白質 |
| KR102546875B1 (ko) | 2014-05-02 | 2023-06-26 | 모멘타 파머슈티컬스 인코포레이티드 | 공학처리된 fc 작제물과 관련된 조성물 및 방법 |
| EP3303380B1 (en) | 2015-06-02 | 2020-01-15 | Novo Nordisk A/S | Insulins with polar recombinant extensions |
| GB201511787D0 (en) * | 2015-07-06 | 2015-08-19 | Ucb Biopharma Sprl | Proteins |
| GB201513033D0 (en) * | 2015-07-23 | 2015-09-09 | Ucb Biopharma Sprl | Proteins |
| ES2846024T7 (es) | 2015-07-24 | 2023-06-22 | Gliknik Inc | Proteínas de fusión de fragmentos de proteína humana para crear composiciones de Fc de inmunoglobulina multimerizada de forma ordenada con unión al complemento aumentada |
| MA43348A (fr) | 2015-10-01 | 2018-08-08 | Novo Nordisk As | Conjugués de protéines |
| JP2019511458A (ja) * | 2016-01-27 | 2019-04-25 | ツェー・エス・エル・ベーリング・レングナウ・アクチエンゲゼルシャフト | 組み換えIgG Fc多量体 |
| EP3423572B1 (en) | 2016-03-02 | 2023-11-29 | Momenta Pharmaceuticals, Inc. | Methods related to engineered fc constructs |
| GB201607979D0 (en) * | 2016-05-06 | 2016-06-22 | Liverpool School Tropical Medicine | Monomeric proteins and uses thereof |
| NZ749279A (en) | 2016-05-23 | 2025-08-29 | Momenta Pharmaceuticals Inc | Compositions and methods related to engineered fc constructs |
| CA3026420A1 (en) | 2016-06-07 | 2017-12-14 | Gliknik Inc. | Cysteine-optimized stradomers |
| EP3487534A4 (en) | 2016-07-22 | 2020-03-25 | Gliknik Inc. | FUSION PROTEINS FROM HUMAN PROTEIN FRAGMENTS USED TO CREATE ORDERED MULTIMERIZED IMMUNOGLOBULIN FC COMPOSITIONS WITH IMPROVED FC RECEPTOR BINDING |
| IL266988B2 (en) | 2016-12-09 | 2024-11-01 | Gliknik Inc | Methods of treating inflammatory disorders with multivalent fc compounds |
| JP2020503855A (ja) | 2016-12-09 | 2020-02-06 | グリックニック インコーポレイテッド | 多量体化ストラドマーgl−2045の製造最適化 |
| US11220531B2 (en) | 2017-01-06 | 2022-01-11 | Janssen Biotech, Inc. | Engineered Fc constructs |
| CN113480655B (zh) * | 2017-03-28 | 2022-05-31 | 礼进生物医药科技(上海)有限公司 | 用于增强肿瘤微环境中免疫应答的治疗剂和方法 |
| JP2020513019A (ja) | 2017-04-05 | 2020-04-30 | ノヴォ ノルディスク アー/エス | オリゴマー伸長インスリン−Fcコンジュゲート |
| KR101913743B1 (ko) | 2017-04-07 | 2018-11-01 | 국민대학교 산학협력단 | 혈중 반감기 연장을 위한 항체 Fc 변이체들 |
| US11149094B2 (en) * | 2017-06-05 | 2021-10-19 | Janssen Biotech, Inc. | Engineered multispecific antibodies and other multimeric proteins with asymmetrical CH2-CH3 region mutations |
| AU2018382586B2 (en) * | 2017-12-14 | 2025-01-16 | CSL Behring Lengnau AG | Recombinant IgG Fc multimers for the treatment of neuromyelitis optica |
| CN112236449A (zh) * | 2018-03-16 | 2021-01-15 | 利物浦热带医学院 | 嵌合fc受体结合蛋白及其用途 |
| KR102232659B1 (ko) * | 2018-07-16 | 2021-03-26 | 전북대학교 산학협력단 | 항원전달용 폴리펩타이드, 이를 포함하는 Fc-융합 단백질 및 이의 용도 |
| CA3115547A1 (en) * | 2018-11-14 | 2020-05-22 | Jn Biosciences Llc | Multimeric hybrid fc proteins for replacement of ivig |
| WO2021048330A1 (en) | 2019-09-13 | 2021-03-18 | CSL Behring Lengnau AG | Recombinant igg fc multimers for the treatment of immune complex-mediated kidney disorders |
| MX2022006703A (es) * | 2019-12-06 | 2022-07-12 | CSL Behring Lengnau AG | Composiciones estables de multimeros fc. |
| GB2595299B (en) * | 2020-05-21 | 2022-08-03 | Mabsolve Ltd | Modified immunoglobulin FC regions |
| CN115724985A (zh) * | 2021-08-27 | 2023-03-03 | 三生国健药业(上海)股份有限公司 | 一种cdc平台抗体 |
| AU2023283773A1 (en) * | 2022-06-10 | 2024-12-19 | Research Development Foundation | Engineered fcriib selective igg1 fc variants and uses thereof |
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| US5677425A (en) | 1987-09-04 | 1997-10-14 | Celltech Therapeutics Limited | Recombinant antibody |
| US20020147326A1 (en) | 1996-06-14 | 2002-10-10 | Smithkline Beecham Corporation | Hexameric fusion proteins and uses therefor |
| US5980898A (en) | 1996-11-14 | 1999-11-09 | The United States Of America As Represented By The U.S. Army Medical Research & Material Command | Adjuvant for transcutaneous immunization |
| GB9625640D0 (en) | 1996-12-10 | 1997-01-29 | Celltech Therapeutics Ltd | Biological products |
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| UA117901C2 (uk) | 2011-07-06 | 2018-10-25 | Ґенмаб Б.В. | Спосіб посилення ефекторної функції вихідного поліпептиду, його варіанти та їх застосування |
| EP2760891B1 (en) * | 2011-09-26 | 2018-11-07 | JN Biosciences LLC | Hybrid constant regions |
| BR112014015078A2 (pt) | 2011-12-21 | 2017-06-13 | Amgen Inc | polipeptídeos-fc variantes com ligação melhorada ao receptor fc neonatal |
| KR102041412B1 (ko) | 2011-12-30 | 2019-11-11 | 한미사이언스 주식회사 | 면역글로불린 Fc 단편 유도체 |
| SG11201408646VA (en) | 2012-07-06 | 2015-01-29 | Genmab Bv | Dimeric protein with triple mutations |
| BR112015002091A2 (pt) | 2012-08-02 | 2017-12-12 | Hoffmann La Roche | método para a produção de um polipeptídeo, polipeptídeo, uso de um polipeptídeo e composição |
| US9540442B2 (en) * | 2012-08-02 | 2017-01-10 | Jn Biosciences Llc | Antibodies or fusion proteins multimerized via cysteine mutation and a mu tailpiece |
| CN104718223A (zh) | 2012-08-20 | 2015-06-17 | 格利克尼克股份有限公司 | 具有抗原结合和多价FCγ受体结合活性的分子 |
| US20150218236A1 (en) | 2012-10-17 | 2015-08-06 | Liverpool School Of Tropical Medicine | Immunomodulatory proteins |
| TW201619188A (zh) * | 2014-03-05 | 2016-06-01 | 優稀美生物醫藥公司 | 多聚體Fc蛋白質 |
| EP3114137A1 (en) | 2014-03-05 | 2017-01-11 | UCB Biopharma SPRL | Multimeric fc proteins |
| BR112016023948A2 (pt) | 2014-04-16 | 2018-01-30 | Ucb Biopharma Sprl | proteínas fc multiméricas |
| KR102546875B1 (ko) | 2014-05-02 | 2023-06-26 | 모멘타 파머슈티컬스 인코포레이티드 | 공학처리된 fc 작제물과 관련된 조성물 및 방법 |
| CA2978501A1 (en) | 2015-03-05 | 2016-09-09 | Ucb Biopharma Sprl | Polymeric fc proteins and methods of screening to alter their functional characteristics |
| GB201511787D0 (en) | 2015-07-06 | 2015-08-19 | Ucb Biopharma Sprl | Proteins |
-
2015
- 2015-03-05 TW TW104107000A patent/TW201619188A/zh unknown
- 2015-03-05 UY UY0001036021A patent/UY36021A/es not_active Application Discontinuation
- 2015-03-05 CN CN201580011851.9A patent/CN106068274A/zh active Pending
- 2015-03-05 MX MX2016010951A patent/MX2016010951A/es unknown
- 2015-03-05 SG SG11201606597QA patent/SG11201606597QA/en unknown
- 2015-03-05 JP JP2016555527A patent/JP6851200B2/ja not_active Expired - Fee Related
- 2015-03-05 US US15/123,038 patent/US11352414B2/en active Active
- 2015-03-05 WO PCT/EP2015/054687 patent/WO2015132364A1/en not_active Ceased
- 2015-03-05 AU AU2015226100A patent/AU2015226100B2/en not_active Ceased
- 2015-03-05 CA CA2939198A patent/CA2939198A1/en not_active Abandoned
- 2015-03-05 BR BR112016020368-2A patent/BR112016020368A2/pt not_active Application Discontinuation
- 2015-03-05 RU RU2016139006A patent/RU2016139006A/ru not_active Application Discontinuation
- 2015-03-05 KR KR1020167027642A patent/KR20160130463A/ko not_active Withdrawn
- 2015-03-05 EP EP15708208.2A patent/EP3114143B1/en active Active
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2016
- 2016-08-03 IL IL247096A patent/IL247096A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| US20170088603A1 (en) | 2017-03-30 |
| AU2015226100A1 (en) | 2016-08-25 |
| WO2015132364A1 (en) | 2015-09-11 |
| CN106068274A (zh) | 2016-11-02 |
| JP2017512063A (ja) | 2017-05-18 |
| UY36021A (es) | 2015-09-30 |
| EP3114143B1 (en) | 2020-07-08 |
| RU2016139006A (ru) | 2018-04-05 |
| US11352414B2 (en) | 2022-06-07 |
| SG11201606597QA (en) | 2016-09-29 |
| MX2016010951A (es) | 2016-11-29 |
| KR20160130463A (ko) | 2016-11-11 |
| EP3114143A1 (en) | 2017-01-11 |
| JP6851200B2 (ja) | 2021-03-31 |
| AU2015226100B2 (en) | 2020-05-07 |
| CA2939198A1 (en) | 2015-09-11 |
| IL247096A0 (en) | 2016-09-29 |
| TW201619188A (zh) | 2016-06-01 |
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