JP6333271B2 - IL−1βへの結合メンバー - Google Patents
IL−1βへの結合メンバー Download PDFInfo
- Publication number
- JP6333271B2 JP6333271B2 JP2015540154A JP2015540154A JP6333271B2 JP 6333271 B2 JP6333271 B2 JP 6333271B2 JP 2015540154 A JP2015540154 A JP 2015540154A JP 2015540154 A JP2015540154 A JP 2015540154A JP 6333271 B2 JP6333271 B2 JP 6333271B2
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- JP
- Japan
- Prior art keywords
- seq
- antibody
- cdr
- composition
- sequence
- 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.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
- C07K16/245—IL-1
-
- 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
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/04—Drugs for disorders of the respiratory system for throat disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
- G01N33/6869—Interleukin
-
- 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
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/35—Valency
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- 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
- C07K2317/622—Single chain antibody (scFv)
-
- 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
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/52—Assays involving cytokines
- G01N2333/54—Interleukins [IL]
- G01N2333/545—IL-1
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cell Biology (AREA)
- Endocrinology (AREA)
- Physical Education & Sports Medicine (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Pathology (AREA)
- General Physics & Mathematics (AREA)
- Mycology (AREA)
- Food Science & Technology (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Dermatology (AREA)
- Diabetes (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261722532P | 2012-11-05 | 2012-11-05 | |
| EP12007503.1 | 2012-11-05 | ||
| US61/722,532 | 2012-11-05 | ||
| EP12007503 | 2012-11-05 | ||
| PCT/EP2013/073009 WO2014068132A1 (en) | 2012-11-05 | 2013-11-05 | Binding members to il-1 beta |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2018083160A Division JP6779252B2 (ja) | 2012-11-05 | 2018-04-24 | IL−1βへの結合メンバー |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2016503293A JP2016503293A (ja) | 2016-02-04 |
| JP2016503293A5 JP2016503293A5 (enExample) | 2016-12-08 |
| JP6333271B2 true JP6333271B2 (ja) | 2018-06-06 |
Family
ID=47146146
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2015540154A Active JP6333271B2 (ja) | 2012-11-05 | 2013-11-05 | IL−1βへの結合メンバー |
| JP2018083160A Expired - Fee Related JP6779252B2 (ja) | 2012-11-05 | 2018-04-24 | IL−1βへの結合メンバー |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2018083160A Expired - Fee Related JP6779252B2 (ja) | 2012-11-05 | 2018-04-24 | IL−1βへの結合メンバー |
Country Status (11)
| Country | Link |
|---|---|
| US (5) | US9404930B2 (enExample) |
| EP (2) | EP2914287B1 (enExample) |
| JP (2) | JP6333271B2 (enExample) |
| KR (1) | KR102345999B1 (enExample) |
| CN (1) | CN104870015B (enExample) |
| BR (1) | BR112015009892B1 (enExample) |
| CA (1) | CA2888583C (enExample) |
| MX (1) | MX374817B (enExample) |
| PL (1) | PL2914287T3 (enExample) |
| RU (1) | RU2711118C2 (enExample) |
| WO (2) | WO2014068132A1 (enExample) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014068132A1 (en) * | 2012-11-05 | 2014-05-08 | Delenex Therapeutics Ag | Binding members to il-1 beta |
| EP3186390B1 (en) | 2014-08-29 | 2019-03-27 | Pioneer Hi-Bred International, Inc. | Methods and devices involving oil matrices |
| US9078427B1 (en) | 2014-08-29 | 2015-07-14 | Pioneer Hi Bred International Inc | Method of storing plant embryos |
| JP6202652B1 (ja) * | 2016-12-19 | 2017-09-27 | 株式会社ヘルスケアシステムズ | 抗エクオール抗体組成物及びその利用 |
| CN107362351B (zh) * | 2017-09-04 | 2020-11-10 | 上海市儿童医院 | Il-36r的拮抗剂在制备镇痛药物中的应用 |
| CN110818793A (zh) * | 2018-08-14 | 2020-02-21 | 中山康方生物医药有限公司 | 抗IL-1β的抗体、其药物组合物及其用途 |
| CN113453798A (zh) | 2019-02-28 | 2021-09-28 | 埃克森美孚化学专利公司 | 催化剂组合物及前体、其制备方法和合成气转化方法 |
| TWI793503B (zh) * | 2020-01-20 | 2023-02-21 | 美商美國禮來大藥廠 | 抗IL-1β抗體 |
| CA3201637A1 (en) | 2020-11-18 | 2022-05-27 | Novartis Ag | Bispecific antibodies for use in treatment of nlrc4-gof inflammasomapathy |
| JP2024501810A (ja) * | 2020-12-23 | 2024-01-16 | ヌマブ セラピューティクス アクチェンゲゼルシャフト | 減少した免疫原性を有する抗体可変ドメイン及び抗体 |
| WO2022136693A1 (en) * | 2020-12-23 | 2022-06-30 | Numab Therapeutics AG | Antibody variable domains and antibodies having decreased immunogenicity |
| CN113908589B (zh) * | 2021-10-08 | 2022-09-27 | 天津工业大学 | 一种表面印迹抗体的疏水电荷诱导模式膜层析介质及其制备方法 |
| CN116410331B (zh) * | 2021-12-31 | 2024-01-30 | 合源生物科技(天津)有限公司 | 靶向cs1的嵌合抗原受体、靶向bcma/cs1的双特异性嵌合抗原受体及其应用 |
| CN114113634A (zh) * | 2022-01-24 | 2022-03-01 | 中国农业大学 | 一种检测非洲猪瘟病毒抗体的ELISA检测试剂盒以及protein L的应用 |
| WO2024258943A1 (en) * | 2023-06-13 | 2024-12-19 | Merck Sharp & Dohme Llc | Methods of using cyclic peptides for trapping interleukin-1 beta |
| CN117964755B (zh) * | 2023-12-26 | 2025-01-21 | 华润生物医药有限公司 | 抗tslp抗体及其用途 |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0020685D0 (en) | 2000-08-22 | 2000-10-11 | Novartis Ag | Organic compounds |
| US20030026806A1 (en) * | 2000-10-27 | 2003-02-06 | Amgen Inc. | Antibodies and other selective IL-1 binding agents that allow binding to IL-1 receptor but not activation thereof |
| CN103739706B (zh) | 2002-05-22 | 2015-11-18 | 艾斯巴技术-诺华有限责任公司 | 在胞内环境中表现出增强的稳定性的免疫球蛋白构架及其鉴定方法 |
| WO2004067568A2 (en) * | 2003-01-24 | 2004-08-12 | Applied Molecular Evolution, Inc | Human il-1 beta antagonists |
| EP1851245B1 (en) * | 2005-01-26 | 2012-10-10 | Amgen Fremont Inc. | Antibodies against interleukin-1 beta |
| ES2424042T3 (es) | 2005-06-07 | 2013-09-26 | Esbatech - A Novartis Company Llc | Anticuerpos estables y solubles que inhiben TNF± |
| CN101228188A (zh) * | 2005-06-21 | 2008-07-23 | 佐马技术有限公司 | IL-1β结合抗体及其片段 |
| PL2293816T3 (pl) * | 2008-06-06 | 2013-04-30 | Xoma Us Llc | Sposoby leczenia reumatoidalnego zapalenia stawów |
| GB0811574D0 (en) | 2008-06-24 | 2008-07-30 | Trillion Genomics Ltd | Characterising planar samples by mass spectrometry |
| GB2461273A (en) | 2008-06-24 | 2009-12-30 | Seppo Haekkinen | Load monitoring system |
| CA2728829C (en) | 2008-06-25 | 2018-01-02 | Esbatech, An Alcon Biomedical Research Unit Llc | Solubility optimization of immunobinders |
| KR101834797B1 (ko) | 2008-06-25 | 2018-03-07 | 에스바테크 - 어 노바티스 컴파니 엘엘씨 | 보편적 항체 프레임워크를 사용한 래빗 항체의 인간화 |
| AU2009289547A1 (en) * | 2008-09-05 | 2010-03-11 | Xoma (Us) Llc | Methods for treating or preventing IL-1beta related diseases |
| NZ607510A (en) | 2010-09-10 | 2014-10-31 | Apexigen Inc | Anti-il-1 beta antibodies and methods of use |
| WO2014068132A1 (en) * | 2012-11-05 | 2014-05-08 | Delenex Therapeutics Ag | Binding members to il-1 beta |
-
2013
- 2013-11-05 WO PCT/EP2013/073009 patent/WO2014068132A1/en not_active Ceased
- 2013-11-05 EP EP13786473.2A patent/EP2914287B1/en active Active
- 2013-11-05 BR BR112015009892-4A patent/BR112015009892B1/pt not_active IP Right Cessation
- 2013-11-05 EP EP20163414.4A patent/EP3750917A1/en not_active Withdrawn
- 2013-11-05 KR KR1020157013550A patent/KR102345999B1/ko not_active Expired - Fee Related
- 2013-11-05 CN CN201380064089.1A patent/CN104870015B/zh not_active Expired - Fee Related
- 2013-11-05 MX MX2015005384A patent/MX374817B/es active IP Right Grant
- 2013-11-05 CA CA2888583A patent/CA2888583C/en active Active
- 2013-11-05 RU RU2015120450A patent/RU2711118C2/ru active
- 2013-11-05 PL PL13786473T patent/PL2914287T3/pl unknown
- 2013-11-05 JP JP2015540154A patent/JP6333271B2/ja active Active
- 2013-11-05 US US14/072,165 patent/US9404930B2/en active Active
-
2014
- 2014-11-05 WO PCT/EP2014/073772 patent/WO2015067636A1/en not_active Ceased
-
2016
- 2016-07-06 US US15/202,982 patent/US10077302B2/en active Active
-
2018
- 2018-04-24 JP JP2018083160A patent/JP6779252B2/ja not_active Expired - Fee Related
- 2018-08-30 US US16/118,124 patent/US10626171B2/en active Active
-
2020
- 2020-03-18 US US16/822,952 patent/US11267884B2/en active Active
-
2022
- 2022-01-28 US US17/587,751 patent/US20220220195A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| KR102345999B1 (ko) | 2021-12-30 |
| US10077302B2 (en) | 2018-09-18 |
| JP2018113988A (ja) | 2018-07-26 |
| CN104870015B (zh) | 2019-07-30 |
| US20220220195A1 (en) | 2022-07-14 |
| JP6779252B2 (ja) | 2020-11-04 |
| US11267884B2 (en) | 2022-03-08 |
| CN104870015A (zh) | 2015-08-26 |
| US20140134183A1 (en) | 2014-05-15 |
| US20200239565A1 (en) | 2020-07-30 |
| EP2914287B1 (en) | 2020-03-18 |
| WO2014068132A1 (en) | 2014-05-08 |
| HK1214150A1 (en) | 2016-07-22 |
| CA2888583C (en) | 2022-03-29 |
| RU2711118C2 (ru) | 2020-01-15 |
| KR20150079753A (ko) | 2015-07-08 |
| EP3750917A1 (en) | 2020-12-16 |
| US9404930B2 (en) | 2016-08-02 |
| JP2016503293A (ja) | 2016-02-04 |
| BR112015009892B1 (pt) | 2022-12-27 |
| BR112015009892A2 (pt) | 2017-08-22 |
| MX2015005384A (es) | 2015-10-09 |
| US20180362642A1 (en) | 2018-12-20 |
| US20170051054A1 (en) | 2017-02-23 |
| WO2015067636A1 (en) | 2015-05-14 |
| PL2914287T3 (pl) | 2020-09-07 |
| MX374817B (es) | 2025-03-06 |
| CA2888583A1 (en) | 2014-05-08 |
| RU2015120450A (ru) | 2016-12-27 |
| EP2914287A1 (en) | 2015-09-09 |
| US10626171B2 (en) | 2020-04-21 |
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