CY1118222T1 - Συνθεσεις λυασης φαινυλαλανινης αμμωνιας προκαρυωτικων και μεθοδοι αγωγης καρκινου χρησιμοποιωντας συνθεσεις εξ' αυτης - Google Patents
Συνθεσεις λυασης φαινυλαλανινης αμμωνιας προκαρυωτικων και μεθοδοι αγωγης καρκινου χρησιμοποιωντας συνθεσεις εξ' αυτηςInfo
- Publication number
- CY1118222T1 CY1118222T1 CY20161101163T CY161101163T CY1118222T1 CY 1118222 T1 CY1118222 T1 CY 1118222T1 CY 20161101163 T CY20161101163 T CY 20161101163T CY 161101163 T CY161101163 T CY 161101163T CY 1118222 T1 CY1118222 T1 CY 1118222T1
- Authority
- CY
- Cyprus
- Prior art keywords
- compositions
- methods
- pal
- phynylanine
- lyses
- Prior art date
Links
Classifications
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- 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
- A61K38/164—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
- 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
- A61K38/51—Lyases (4)
-
- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- 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
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
- 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
- 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
- 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
- A61P3/00—Drugs for disorders of the metabolism
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Neurology (AREA)
- Oncology (AREA)
- Dermatology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Pulmonology (AREA)
- Obesity (AREA)
- Biomedical Technology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Enzymes And Modification Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6612507P | 2007-08-17 | 2007-08-17 | |
| PCT/US2008/009765 WO2009025760A2 (en) | 2007-08-17 | 2008-08-15 | Compositions of prokaryotic phenylalanine ammonia-lyase and methods of treating cancer using compositions thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CY1118222T1 true CY1118222T1 (el) | 2017-06-28 |
Family
ID=40363135
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CY20161101163T CY1118222T1 (el) | 2007-08-17 | 2016-11-10 | Συνθεσεις λυασης φαινυλαλανινης αμμωνιας προκαρυωτικων και μεθοδοι αγωγης καρκινου χρησιμοποιωντας συνθεσεις εξ' αυτης |
Country Status (23)
| Country | Link |
|---|---|
| US (4) | US7537923B2 (https=) |
| EP (1) | EP2175875B1 (https=) |
| JP (1) | JP5584120B2 (https=) |
| CN (1) | CN101803492B (https=) |
| AR (2) | AR067972A1 (https=) |
| AU (1) | AU2008289549B2 (https=) |
| BR (2) | BRPI0811589B8 (https=) |
| CA (1) | CA2687028C (https=) |
| CL (1) | CL2008002390A1 (https=) |
| CY (1) | CY1118222T1 (https=) |
| DK (1) | DK2175875T3 (https=) |
| ES (1) | ES2602618T3 (https=) |
| HR (1) | HRP20161474T1 (https=) |
| HU (1) | HUE029510T4 (https=) |
| LT (1) | LT2175875T (https=) |
| MX (1) | MX2009012261A (https=) |
| PE (1) | PE20090605A1 (https=) |
| PL (1) | PL2175875T3 (https=) |
| PT (1) | PT2175875T (https=) |
| RU (2) | RU2009141987A (https=) |
| SI (1) | SI2175875T1 (https=) |
| TW (1) | TWI418787B (https=) |
| WO (1) | WO2009025760A2 (https=) |
Families Citing this family (38)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7534595B2 (en) * | 2006-06-12 | 2009-05-19 | Biomarin Pharmaceutical Inc. | Compositions of prokaryotic phenylalanine ammonia-lyase and methods of using compositions thereof |
| US7537923B2 (en) | 2007-08-17 | 2009-05-26 | Biomarin Pharmaceutical Inc. | Compositions of prokaryotic phenylalanine ammonia-lyase and methods of treating cancer using compositions thereof |
| EP2219602A1 (en) * | 2007-11-15 | 2010-08-25 | Amgen, Inc | Aqueous formulation of erythropoiesis stimulating protein stablised by antioxidants for parenteral administration |
| WO2010014225A2 (en) | 2008-07-30 | 2010-02-04 | Biomarin Pharmaceutical Inc. | Assays for detection of phenylalanine ammonia-lyase and antibodies to phenylalanine ammonia-lyase |
| WO2011078667A2 (en) | 2009-12-22 | 2011-06-30 | Dsm Ip Assets B.V. | Method of finding a biocatalyst having ammonia lyase activity |
| ES2582459T3 (es) * | 2010-02-04 | 2016-09-13 | Biomarin Pharmaceutical Inc. | Composiciones de variantes de fenilalanina amoníaco-liasa de procariotas y métodos de uso de sus composiciones |
| WO2012075173A2 (en) | 2010-12-01 | 2012-06-07 | Board Of Regents The University Of Texas System | Compositions and method for deimmunization of proteins |
| CA2880620A1 (en) * | 2012-07-27 | 2014-01-30 | University Of North Texas | Genetically modified probiotic for the treatment of phenylketonuria (pku) disease |
| KR102218930B1 (ko) | 2013-04-18 | 2021-02-23 | 코덱시스, 인코포레이티드 | 조작된 페닐알라닌 암모니아 리아제 폴리펩티드 |
| AU2014348683B2 (en) | 2013-11-18 | 2020-11-05 | Rubius Therapeutics, Inc. | Synthetic membrane-receiver complexes |
| ES2865825T3 (es) | 2014-04-01 | 2021-10-18 | Rubius Therapeutics Inc | Procedimientos y composiciones para inmunomodulación |
| WO2015161019A1 (en) | 2014-04-16 | 2015-10-22 | Codexis, Inc. | Engineered tyrosine ammonia lyase |
| ES2897635T3 (es) | 2014-04-29 | 2022-03-02 | Bio Cancer Treat International Ltd | Métodos y composiciones para modular el sistema inmunológico con la arginasa I |
| US10752923B2 (en) | 2014-07-14 | 2020-08-25 | Cysbio Aps | Processes for the production of hydroxycinnamic acids using polypeptides having tyrosine ammonia lyase activity |
| FI3237621T3 (fi) | 2014-12-22 | 2023-06-01 | Codexis Inc | Ihmisen alfa-galaktosidaasivariantteja |
| PE20190401A1 (es) | 2016-07-26 | 2019-03-13 | Biomarin Pharm Inc | Novedosas proteinas de la capside del virus adenoasociado |
| IT201600086488A1 (it) * | 2016-08-22 | 2018-02-22 | St Microelectronics Srl | Dispositivo a semiconduttore e corrispondente procedimento |
| AU2018217495B2 (en) * | 2017-02-13 | 2021-03-04 | Codexis, Inc. | Engineered phenylalanine ammonia lyase polypeptides |
| BR112020022722A8 (pt) | 2018-05-09 | 2022-01-18 | Biomarin Pharm Inc | Genoma e seu uso, vetor, partícula, molécula de ácido nucleico isolada, ácido nucleico, composição, tratamento, método |
| TW202005978A (zh) | 2018-05-14 | 2020-02-01 | 美商拜奧馬林製藥公司 | 新穎肝靶向腺相關病毒載體 |
| US10900055B2 (en) | 2018-06-12 | 2021-01-26 | Codexis, Inc. | Engineered tyrosine ammonia lyase |
| SG11202105668PA (en) | 2018-12-14 | 2021-06-29 | Codexis Inc | Engineered tyrosine ammonia lyase |
| SG11202106348QA (en) | 2018-12-20 | 2021-07-29 | Codexis Inc | Human alpha-galactosidase variants |
| PT3923988T (pt) | 2019-02-14 | 2025-07-29 | Som Innovation Biotech S A | Triantereno ou nolatrexedo para uso no tratamento de fenilcetonúria |
| CN118806923A (zh) * | 2019-08-07 | 2024-10-22 | 乐天医药生技股份有限公司 | 西妥昔单抗-ir700偶联物组合物 |
| EP4501403A3 (en) | 2019-08-30 | 2025-05-14 | Société des Produits Nestlé S.A. | Engineered lipase variants |
| KR20220129547A (ko) | 2019-12-20 | 2022-09-23 | 코덱시스, 인코포레이티드 | 조작된 산성 알파-글루코시다제 변이체 |
| WO2021158686A1 (en) | 2020-02-04 | 2021-08-12 | Codexis, Inc. | Engineered leucine decarboxylases |
| AR122409A1 (es) | 2020-04-03 | 2022-09-07 | Biomarin Pharm Inc | Tratamiento de la fenilcetonuria con aav y formulaciones terapéuticas |
| MX2023002421A (es) | 2020-08-28 | 2023-05-18 | Codexis Inc | Variantes de amilasa modificadas geneticamente. |
| EP4204554A4 (en) | 2020-08-28 | 2024-08-21 | Codexis, Inc. | MODIFIED PROTEASE VARIANTS |
| JP2024519847A (ja) | 2021-05-19 | 2024-05-21 | ビオマリン プハルマセウトイカル インコーポレイテッド | 原核生物フェニルアラニンアンモニアリアーゼの組成物及び青年対象を治療する方法 |
| TW202313969A (zh) | 2021-05-21 | 2023-04-01 | 美商克迪科思股份有限公司 | 經工程化的甲硫胺酸γ解離酶變異體 |
| CN118475692A (zh) | 2021-11-01 | 2024-08-09 | 森蒂斯生物公司 | 工程化亮氨酸脱羧酶 |
| CN115873837A (zh) * | 2022-11-18 | 2023-03-31 | 安徽盈科生物科技有限公司 | 高表达的新型的苯丙氨酸解氨酶 |
| CN118931888A (zh) * | 2023-05-09 | 2024-11-12 | 重庆派金生物科技有限公司 | 苯丙氨酸裂解酶突变体及其偶联物或其药学上可接受的盐 |
| GB202307239D0 (en) | 2023-05-15 | 2023-06-28 | Evox Therapeutics Ltd | Gene therapies for Phenylketonuria |
| WO2025106759A1 (en) | 2023-11-17 | 2025-05-22 | Biomarin Pharmaceutical Inc. | Conjugates of phenylalanine ammonia-lyase and poegma and methods for their use |
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| US4252822A (en) | 1979-12-26 | 1981-02-24 | Children's Hospital Medical Center | Method for treating phenylketonuria |
| US4562151A (en) | 1983-09-06 | 1985-12-31 | Monsanto Company | Stabilization of L-phenylalanine ammonia-lyase enzyme |
| US5206344A (en) | 1985-06-26 | 1993-04-27 | Cetus Oncology Corporation | Interleukin-2 muteins and polymer conjugation thereof |
| US5166322A (en) * | 1989-04-21 | 1992-11-24 | Genetics Institute | Cysteine added variants of interleukin-3 and chemical modifications thereof |
| US5766897A (en) | 1990-06-21 | 1998-06-16 | Incyte Pharmaceuticals, Inc. | Cysteine-pegylated proteins |
| US5212939A (en) * | 1991-12-04 | 1993-05-25 | Pratt Jr John M | Marine mooring swivel fitting |
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| DE69233695T2 (de) | 1992-12-04 | 2008-01-24 | Me Medical Enzymes Ag | Gentechnologisch hergestellte glutaminase und ihre verwendung in therapie |
| DK75593D0 (https=) | 1993-06-25 | 1993-06-25 | Novo Nordisk As | |
| KR0164757B1 (ko) * | 1995-06-13 | 1999-01-15 | 김광호 | 공조장치의 살균집진장치와 그 방법 |
| CA2230492C (en) * | 1995-09-21 | 2009-05-26 | Genentech, Inc. | Human growth hormone variants |
| CU22585A1 (es) * | 1995-11-17 | 1999-11-03 | Centro Inmunologia Molecular | Anticuerpos monoclonales antiidiótipos (ab2) de tipo igg con alta conectividad idiotípica y composiciones farmacéuticas que los contienen. su uso como inmunoreguladores de la respuesta inmune. |
| US6548644B1 (en) | 1997-03-10 | 2003-04-15 | Immunex Corporation | Site protected protein modification |
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| US5981239A (en) * | 1997-09-24 | 1999-11-09 | Great Lakes Chemical Corp. | Synthesis of optically active phenylalanine analogs using Rhodotorula graminis |
| US6451986B1 (en) | 1998-06-22 | 2002-09-17 | Immunex Corporation | Site specific protein modification |
| US6461849B1 (en) * | 1998-10-13 | 2002-10-08 | Novozymes, A/S | Modified polypeptide |
| US6686164B1 (en) | 1998-10-30 | 2004-02-03 | Novozymes A/S | Low allergenic protein variants |
| IL138990A0 (en) * | 1999-02-12 | 2001-11-25 | Biostream Inc | Matrices for drug delivery and methods for making and using the same |
| US6586398B1 (en) | 2000-04-07 | 2003-07-01 | Amgen, Inc. | Chemically modified novel erythropoietin stimulating protein compositions and methods |
| AU2001257032A1 (en) * | 2000-04-14 | 2001-10-30 | University Of South Carolina Research Foundation | Cloning, overexpression and therapeutic uses of bioactive histidine ammonia lyase |
| US6967097B2 (en) | 2000-07-24 | 2005-11-22 | Pcbu Services, Inc. | Phenylalainine ammonia lyase polypeptide and polynucleotide sequences and methods of obtaining and using same |
| US6939941B2 (en) * | 2001-09-12 | 2005-09-06 | Toray Fine Chemicals Co., Ltd. | Preparation of polysulfide compositions |
| EP1476563B1 (en) | 2002-02-26 | 2008-09-17 | E.I. Du Pont De Nemours And Company | Method for the recombination of genetic elements |
| US20080124275A1 (en) | 2002-11-14 | 2008-05-29 | The Scripps Research Institute | Crystalline Form of Fatty Acid Amide Hydrolase (Faah) |
| US7553653B2 (en) | 2004-09-17 | 2009-06-30 | Biomarin Pharmaceutical Inc. | Variants and chemically-modified variants of phenylalanine ammonia-lyase |
| EP2886658A1 (en) * | 2005-03-10 | 2015-06-24 | BASF Enzymes LLC | Lyase enzymes, nucleic acids encoding them and methods for making and using them |
| US7534595B2 (en) | 2006-06-12 | 2009-05-19 | Biomarin Pharmaceutical Inc. | Compositions of prokaryotic phenylalanine ammonia-lyase and methods of using compositions thereof |
| US7531341B1 (en) | 2006-06-12 | 2009-05-12 | Biomarin Pharmaceutical Inc. | Compositions of prokaryotic phenylalanine ammonia-lyase and methods of using compositions thereof |
| DE102006032167B4 (de) | 2006-07-12 | 2014-11-27 | Evonik Degussa Gmbh | Verfahren zur Herstellung von Triallylisocyanurat (TAIC) |
| US20090011400A1 (en) | 2006-12-01 | 2009-01-08 | The Salk Institute for Biological Studies and The Regents of the University of California | Substrate switched ammonia lyases and mutases |
| US7537923B2 (en) | 2007-08-17 | 2009-05-26 | Biomarin Pharmaceutical Inc. | Compositions of prokaryotic phenylalanine ammonia-lyase and methods of treating cancer using compositions thereof |
| WO2010014225A2 (en) | 2008-07-30 | 2010-02-04 | Biomarin Pharmaceutical Inc. | Assays for detection of phenylalanine ammonia-lyase and antibodies to phenylalanine ammonia-lyase |
-
2008
- 2008-04-22 US US12/107,736 patent/US7537923B2/en active Active
- 2008-04-22 US US12/107,731 patent/US7560263B2/en active Active
- 2008-08-14 CL CL2008002390A patent/CL2008002390A1/es unknown
- 2008-08-15 RU RU2009141987/15A patent/RU2009141987A/ru not_active Application Discontinuation
- 2008-08-15 PE PE2008001395A patent/PE20090605A1/es active IP Right Grant
- 2008-08-15 MX MX2009012261A patent/MX2009012261A/es active IP Right Grant
- 2008-08-15 JP JP2010521043A patent/JP5584120B2/ja active Active
- 2008-08-15 RU RU2012134838/15A patent/RU2553343C2/ru active
- 2008-08-15 LT LTEP08795357.6T patent/LT2175875T/lt unknown
- 2008-08-15 HR HRP20161474TT patent/HRP20161474T1/hr unknown
- 2008-08-15 PL PL08795357T patent/PL2175875T3/pl unknown
- 2008-08-15 EP EP08795357.6A patent/EP2175875B1/en active Active
- 2008-08-15 HU HUE08795357A patent/HUE029510T4/en unknown
- 2008-08-15 SI SI200831703A patent/SI2175875T1/sl unknown
- 2008-08-15 WO PCT/US2008/009765 patent/WO2009025760A2/en not_active Ceased
- 2008-08-15 DK DK08795357.6T patent/DK2175875T3/en active
- 2008-08-15 AU AU2008289549A patent/AU2008289549B2/en active Active
- 2008-08-15 AR ARP080103596A patent/AR067972A1/es not_active Application Discontinuation
- 2008-08-15 ES ES08795357.6T patent/ES2602618T3/es active Active
- 2008-08-15 TW TW097131325A patent/TWI418787B/zh active
- 2008-08-15 BR BRPI0811589A patent/BRPI0811589B8/pt active IP Right Grant
- 2008-08-15 CN CN200880016488.XA patent/CN101803492B/zh active Active
- 2008-08-15 CA CA2687028A patent/CA2687028C/en active Active
- 2008-08-15 BR BR122018072594A patent/BR122018072594B8/pt active IP Right Grant
- 2008-08-15 PT PT87953576T patent/PT2175875T/pt unknown
-
2009
- 2009-04-09 US US12/421,557 patent/US7790433B2/en active Active
-
2010
- 2010-07-09 US US12/833,911 patent/US20100278802A1/en not_active Abandoned
-
2016
- 2016-11-10 CY CY20161101163T patent/CY1118222T1/el unknown
-
2019
- 2019-01-24 AR ARP190100158A patent/AR117389A2/es not_active Application Discontinuation
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