MX351012B - Neurotoxinas que exhiben actividad biologica acortada. - Google Patents
Neurotoxinas que exhiben actividad biologica acortada.Info
- Publication number
- MX351012B MX351012B MX2014005544A MX2014005544A MX351012B MX 351012 B MX351012 B MX 351012B MX 2014005544 A MX2014005544 A MX 2014005544A MX 2014005544 A MX2014005544 A MX 2014005544A MX 351012 B MX351012 B MX 351012B
- Authority
- MX
- Mexico
- Prior art keywords
- polypeptides
- present
- polynucleotide
- medicaments
- ligase
- Prior art date
Links
- 230000004071 biological effect Effects 0.000 title abstract 2
- 230000001747 exhibiting effect Effects 0.000 title abstract 2
- 239000002581 neurotoxin Substances 0.000 title abstract 2
- 231100000618 neurotoxin Toxicity 0.000 title abstract 2
- 229920001184 polypeptide Polymers 0.000 abstract 8
- 102000004196 processed proteins & peptides Human genes 0.000 abstract 8
- 108090000765 processed proteins & peptides Proteins 0.000 abstract 8
- 102000040430 polynucleotide Human genes 0.000 abstract 4
- 108091033319 polynucleotide Proteins 0.000 abstract 4
- 239000002157 polynucleotide Substances 0.000 abstract 4
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 abstract 2
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 abstract 2
- 239000003814 drug Substances 0.000 abstract 2
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 abstract 1
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 abstract 1
- 101710138657 Neurotoxin Proteins 0.000 abstract 1
- 125000003275 alpha amino acid group Chemical group 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000000034 method Methods 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- 239000013598 vector Substances 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
- A61K38/4893—Botulinum neurotoxin (3.4.24.69)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- 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
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
-
- 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
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
- A61P17/10—Anti-acne agents
-
- 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
-
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4746—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used p53
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/24—Metalloendopeptidases (3.4.24)
- C12Y304/24069—Bontoxilysin (3.4.24.69), i.e. botulinum neurotoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Wood Science & Technology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- General Engineering & Computer Science (AREA)
- Immunology (AREA)
- Toxicology (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Biophysics (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Gynecology & Obstetrics (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Reproductive Health (AREA)
- Ophthalmology & Optometry (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Rheumatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
La presente invención se refiere al campo farmacéutico. Específicamente, contempla un polinucleótido que codifica para un polipéptido de neurotoxina que exhibe una duración reducida del efecto biológico en un sujeto, en donde el polipéptido comprende al menos un motivo de reconocimiento de ligasa E3 de la cadena ligera, en donde el motivo de reconocimiento de ligasa E3 es de preferencia un motivo de unión para la ligasa E3 MDM2. La invención se refiere además a polipéptidos codificados por el polinucleátido de la invención así como a polipéptidos que comprenden una o más sustituciones de aminoácido. La presente invención también abarca vectores y células hospederas que comprenden el polinucleótido, polipéptidos codificados por el mismo y anticuerpos que se unen específicamente a los polipéptidos. Más aún, la invención se refiere a medicamentos que comprenden los polinucleátidos y polipéptidos, así como a aplicaciones terapéuticas específicas de los mismos. Además, la presente invención contempla métodos para la elaboración de los polipéptidos y medicamentos.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161628911P | 2011-11-09 | 2011-11-09 | |
EP11188440 | 2011-11-09 | ||
US201261659137P | 2012-06-13 | 2012-06-13 | |
EP12171801 | 2012-06-13 | ||
PCT/EP2012/072158 WO2013068476A1 (en) | 2011-11-09 | 2012-11-08 | Neurotoxins exhibiting shortened biological activity |
Publications (2)
Publication Number | Publication Date |
---|---|
MX2014005544A MX2014005544A (es) | 2014-05-30 |
MX351012B true MX351012B (es) | 2017-09-28 |
Family
ID=48288558
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
MX2014005544A MX351012B (es) | 2011-11-09 | 2012-11-08 | Neurotoxinas que exhiben actividad biologica acortada. |
Country Status (18)
Country | Link |
---|---|
US (1) | US9809809B2 (es) |
EP (1) | EP2776457B1 (es) |
JP (1) | JP6162135B2 (es) |
KR (1) | KR20150000468A (es) |
CN (1) | CN103974973A (es) |
AR (1) | AR089655A1 (es) |
AU (1) | AU2012334080B2 (es) |
BR (1) | BR112014011137A2 (es) |
CA (1) | CA2855173A1 (es) |
CL (1) | CL2014001217A1 (es) |
ES (1) | ES2638333T3 (es) |
HK (1) | HK1199890A1 (es) |
IL (1) | IL232508B (es) |
MX (1) | MX351012B (es) |
RU (1) | RU2646110C2 (es) |
SG (1) | SG11201402131TA (es) |
TW (1) | TWI583792B (es) |
WO (1) | WO2013068476A1 (es) |
Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20140377248A1 (en) * | 2011-12-23 | 2014-12-25 | Merz Pharma Gmbh & Co. Kgaa | Method for the manufacturing of di-chain proteins for use in humans |
BR112015003591B1 (pt) * | 2012-11-21 | 2022-02-01 | Ipsen Bioinnovation Limited | Usos de lys-c e métodos para fabricação de um polipeptídeo proteoliticamente processado |
GB201312317D0 (en) * | 2013-07-09 | 2013-08-21 | Syntaxin Ltd | Cationic neurotoxins |
ES2642916T3 (es) | 2014-06-06 | 2017-11-20 | Galit KLEINER-FISMAN | Toxina botulínica para su uso en el tratamiento de la paratonia |
EP3154571A1 (en) | 2014-06-13 | 2017-04-19 | Merz Pharma GmbH & Co. KGaA | Use of recombinant clostridial neurotoxins for the treatment of patients having certain muscle-related disorders |
US20170128551A1 (en) * | 2014-06-13 | 2017-05-11 | Klaus Fink | Novel uses of recombinant clostridial neurotoxins with decreased duration of effect |
WO2015188945A1 (en) | 2014-06-13 | 2015-12-17 | Merz Pharma Gmbh & Co. Kgaa | Novel uses of recombinant clostridial neurotoxins with decreased duration of effect |
EP3154562A1 (en) * | 2014-06-13 | 2017-04-19 | Merz Pharma GmbH & Co. KGaA | Novel uses of recombinant clostridial neurotoxins with decreased duration of effect |
WO2016097243A1 (en) | 2014-12-19 | 2016-06-23 | Merz Pharma Gmbh & Co. Kgaa | Means and methods for the determination of the biological activity of bont/e in cells |
US10549042B2 (en) | 2014-12-23 | 2020-02-04 | Merz Pharma Gmbh & Co. Kgaa | Botulinum toxin prefilled glass syringe |
US10647750B2 (en) * | 2015-01-09 | 2020-05-12 | Ipsen Bioinnovation Limited | Cationic neurotoxins |
US9765117B2 (en) | 2015-08-24 | 2017-09-19 | Romek Figa | Peptides for treating cancer |
WO2017063743A1 (en) | 2015-10-14 | 2017-04-20 | Merz Pharma Gmbh & Co. Kgaa | Improvements to ultrasound-based therapy of photoaged tissue |
KR20180114891A (ko) | 2016-03-02 | 2018-10-19 | 메르츠 파마 게엠베하 운트 코. 카가아 | 보툴리눔 독소를 포함하는 조성물 |
TWI737742B (zh) | 2016-06-22 | 2021-09-01 | 德商梅茲製藥有限兩合公司 | 肉毒桿菌毒素的預填充式注射器系統、具有其之套組以及其之使用 |
EP3290437A1 (en) | 2016-08-31 | 2018-03-07 | Merz Pharma GmbH & Co. KGaA | Novel recombinant clostridial neurotoxins with decreased duration of effect |
CN106432423B (zh) * | 2016-09-21 | 2019-05-10 | 北京大学深圳研究生院 | 一种α-螺旋多肽及其用途 |
EP3312193A1 (en) | 2016-10-19 | 2018-04-25 | Merz Pharma GmbH & Co. KGaA | Novel recombinant botulinum neurotoxins with accelerated onset of effect |
WO2018175688A1 (en) | 2017-03-22 | 2018-09-27 | Bonti, Inc. | Botulinum neurotoxins for use in therapy |
US11952601B2 (en) | 2017-06-20 | 2024-04-09 | Merz Pharma Gmbh & Co. Kgaa | Recombinant botulinum toxin with increased duration of effect |
ES2930237T3 (es) * | 2017-07-06 | 2022-12-09 | Merz Pharma Gmbh & Co Kgaa | Neurotoxinas botulínicas recombinantes nuevas con mayor duración de efectos |
WO2019133179A2 (en) * | 2017-12-01 | 2019-07-04 | Massachusetts Institute Of Technology | Solution-phase affinity selection of inhibitors from combinatorial peptide libraries |
US11707510B2 (en) * | 2018-02-16 | 2023-07-25 | Preclinics Discovery Gmbh | Nucleic acid-based botulinum neurotoxin for therapeutic use |
US12054540B2 (en) * | 2018-03-13 | 2024-08-06 | Smivet B.V. | Single domain antibodies binding to tetanus neurotoxin |
GB201815844D0 (en) * | 2018-09-28 | 2018-11-14 | Ipsen Biopharm Ltd | Therapeutic & comestic uses of botulinum neurotoxin serotype e |
CN109666683B (zh) * | 2019-02-27 | 2021-10-29 | 昆明理工大学 | 乙酰辅酶A乙酰转移酶基因RKAcaT2及其应用 |
CN110721314B (zh) * | 2019-10-11 | 2022-11-29 | 江苏恒泰生物科技有限公司 | 一种抗肿瘤纳米药物及其制备方法 |
SE2050326A1 (en) * | 2020-03-25 | 2021-06-29 | Jonathan Davies | Engineered botulinum neurotoxin serotype E |
CN111763663B (zh) * | 2020-07-09 | 2022-04-15 | 昆明理工大学 | 一种天麻葡糖基转移酶基因及应用 |
CN112410321B (zh) * | 2020-11-26 | 2022-01-28 | 昆明理工大学 | 一种β-葡萄糖苷酶Ttbgl3及其应用 |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2259149A1 (en) * | 1996-07-05 | 1998-01-15 | Novartis Ag | Inhibitors of the interaction between p53 and mdm2 |
GB9708092D0 (en) * | 1997-04-22 | 1997-06-11 | Univ Dundee | Materials and methods relating to inhibiting the interaction of p53 and mdm2 |
GB9708089D0 (en) * | 1997-04-22 | 1997-06-11 | Univ Dundee | Materials and methods relating to stabilising substances in cells |
TW574036B (en) | 1998-09-11 | 2004-02-01 | Elan Pharm Inc | Stable liquid compositions of botulinum toxin |
US6903187B1 (en) * | 2000-07-21 | 2005-06-07 | Allergan, Inc. | Leucine-based motif and clostridial neurotoxins |
US6678651B2 (en) * | 2000-09-15 | 2004-01-13 | Mindspeed Technologies, Inc. | Short-term enhancement in CELP speech coding |
DE10333317A1 (de) | 2003-07-22 | 2005-02-17 | Biotecon Therapeutics Gmbh | Formulierung für Proteinarzneimittel ohne Zusatz von humanem Serumalbumin (HSA) |
EP2266600B1 (en) | 2004-07-26 | 2014-09-10 | Merz Pharma GmbH & Co. KGaA | Therapeutic composition with a botulinum neurotoxin |
WO2008106507A2 (en) * | 2007-02-27 | 2008-09-04 | University Of South Florida | Mdm2/mdmx inhibitor peptide |
US8598321B2 (en) * | 2007-03-22 | 2013-12-03 | The Regents Of The University Of California | Therapeutic monoclonal antibodies that neutralize botulinum neurotoxins |
US7732579B2 (en) * | 2007-06-13 | 2010-06-08 | The United States Of America As Represented By The Secretary Of Agriculture | High-affinity monoclonal antibodies for botulinum toxin type A |
EP2178905B1 (en) * | 2007-07-26 | 2013-11-06 | Allergan, Inc. | Methods of activiting clostridial toxins |
FR2924721B1 (fr) * | 2007-12-10 | 2010-02-26 | Cytomics Systems | Procede de criblage d'agents modulant l'activite de l'ubiquitine ligase mdm2 et moyens destines a la mise en oeuvre dudit procede |
US8343743B2 (en) * | 2008-06-10 | 2013-01-01 | Synaptic Research, Llc | Designer ubiquitin ligases having a non-cleavable SNAP25 domain and E3-ligase domain |
US20100278826A1 (en) * | 2008-06-10 | 2010-11-04 | Shoemaker Charles B | Designer Ubiquitin Ligases For Regulation Of Intracellular Pathogenic Proteins |
WO2011000929A1 (en) * | 2009-07-02 | 2011-01-06 | Merz Pharma Gmbh & Co. Kgaa | Neurotoxins exhibiting shortened biological activity |
-
2012
- 2012-11-08 RU RU2014123060A patent/RU2646110C2/ru not_active IP Right Cessation
- 2012-11-08 CN CN201280055116.4A patent/CN103974973A/zh active Pending
- 2012-11-08 KR KR1020147015371A patent/KR20150000468A/ko not_active Application Discontinuation
- 2012-11-08 WO PCT/EP2012/072158 patent/WO2013068476A1/en active Application Filing
- 2012-11-08 AU AU2012334080A patent/AU2012334080B2/en not_active Ceased
- 2012-11-08 BR BR112014011137A patent/BR112014011137A2/pt not_active IP Right Cessation
- 2012-11-08 SG SG11201402131TA patent/SG11201402131TA/en unknown
- 2012-11-08 JP JP2014540464A patent/JP6162135B2/ja not_active Expired - Fee Related
- 2012-11-08 TW TW101141558A patent/TWI583792B/zh not_active IP Right Cessation
- 2012-11-08 US US14/356,449 patent/US9809809B2/en active Active
- 2012-11-08 CA CA2855173A patent/CA2855173A1/en not_active Abandoned
- 2012-11-08 MX MX2014005544A patent/MX351012B/es active IP Right Grant
- 2012-11-08 ES ES12783603.9T patent/ES2638333T3/es active Active
- 2012-11-08 EP EP12783603.9A patent/EP2776457B1/en active Active
- 2012-11-09 AR ARP120104249A patent/AR089655A1/es unknown
-
2014
- 2014-05-08 IL IL232508A patent/IL232508B/en not_active IP Right Cessation
- 2014-05-09 CL CL2014001217A patent/CL2014001217A1/es unknown
-
2015
- 2015-01-14 HK HK15100392.7A patent/HK1199890A1/xx unknown
Also Published As
Publication number | Publication date |
---|---|
AU2012334080A1 (en) | 2014-05-15 |
AR089655A1 (es) | 2014-09-10 |
EP2776457A1 (en) | 2014-09-17 |
TW201326390A (zh) | 2013-07-01 |
CN103974973A (zh) | 2014-08-06 |
CA2855173A1 (en) | 2013-05-16 |
TWI583792B (zh) | 2017-05-21 |
US20140308267A1 (en) | 2014-10-16 |
IL232508B (en) | 2018-06-28 |
JP2014533945A (ja) | 2014-12-18 |
ES2638333T3 (es) | 2017-10-19 |
SG11201402131TA (en) | 2014-08-28 |
RU2646110C2 (ru) | 2018-03-01 |
US9809809B2 (en) | 2017-11-07 |
RU2014123060A (ru) | 2015-12-20 |
AU2012334080B2 (en) | 2016-12-15 |
EP2776457B1 (en) | 2017-08-02 |
MX2014005544A (es) | 2014-05-30 |
CL2014001217A1 (es) | 2014-10-10 |
HK1199890A1 (en) | 2015-07-24 |
JP6162135B2 (ja) | 2017-07-12 |
WO2013068476A1 (en) | 2013-05-16 |
IL232508A0 (en) | 2014-06-30 |
BR112014011137A2 (pt) | 2018-06-12 |
KR20150000468A (ko) | 2015-01-02 |
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