ES2717177T3 - Fabricación de proteínas inhibidoras inter-alfa (IaIp) a partir de plasma - Google Patents
Fabricación de proteínas inhibidoras inter-alfa (IaIp) a partir de plasma Download PDFInfo
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- ES2717177T3 ES2717177T3 ES11749976T ES11749976T ES2717177T3 ES 2717177 T3 ES2717177 T3 ES 2717177T3 ES 11749976 T ES11749976 T ES 11749976T ES 11749976 T ES11749976 T ES 11749976T ES 2717177 T3 ES2717177 T3 ES 2717177T3
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- iaip
- precipitate
- fraction
- composition
- iii
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229940021317 other blood product in atc Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 description 1
- SNGREZUHAYWORS-UHFFFAOYSA-N perfluorooctanoic acid Chemical compound OC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F SNGREZUHAYWORS-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001987 poloxamine Polymers 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 239000012465 retentate Substances 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 235000021391 short chain fatty acids Nutrition 0.000 description 1
- 150000004666 short chain fatty acids Chemical class 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940057950 sodium laureth sulfate Drugs 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- SXHLENDCVBIJFO-UHFFFAOYSA-M sodium;2-[2-(2-dodecoxyethoxy)ethoxy]ethyl sulfate Chemical compound [Na+].CCCCCCCCCCCCOCCOCCOCCOS([O-])(=O)=O SXHLENDCVBIJFO-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000012610 weak anion exchange resin Substances 0.000 description 1
- 239000002888 zwitterionic surfactant Substances 0.000 description 1
Classifications
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
-
- 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
- A61P13/12—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
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/30—Extraction; Separation; Purification by precipitation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
- C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Diabetes (AREA)
- Gastroenterology & Hepatology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- Pulmonology (AREA)
- Analytical Chemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Communicable Diseases (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US36733110P | 2010-07-23 | 2010-07-23 | |
| PCT/US2011/045099 WO2012012773A1 (en) | 2010-07-23 | 2011-07-22 | Manufacture of inter -alpha - inhibitor proteins (iaip) from plasma |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2717177T3 true ES2717177T3 (es) | 2019-06-19 |
Family
ID=44534634
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES11749976T Active ES2717177T3 (es) | 2010-07-23 | 2011-07-22 | Fabricación de proteínas inhibidoras inter-alfa (IaIp) a partir de plasma |
Country Status (14)
| Country | Link |
|---|---|
| US (2) | US8841248B2 (enExample) |
| EP (1) | EP2596014B1 (enExample) |
| JP (1) | JP5830096B2 (enExample) |
| KR (1) | KR20130093607A (enExample) |
| CN (1) | CN103119058A (enExample) |
| AU (1) | AU2011280907B2 (enExample) |
| BR (1) | BR112013001753A2 (enExample) |
| CA (1) | CA2806645A1 (enExample) |
| CO (1) | CO6680653A2 (enExample) |
| EA (1) | EA201390156A1 (enExample) |
| ES (1) | ES2717177T3 (enExample) |
| MX (1) | MX2013000958A (enExample) |
| SG (1) | SG187599A1 (enExample) |
| WO (1) | WO2012012773A1 (enExample) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3087991A1 (en) | 2003-11-08 | 2016-11-02 | Prothera Biologics | Composition of inter-alpha inhibitor proteins from human plasma for therapeutic use |
| TR201808152T4 (tr) | 2008-05-28 | 2018-07-23 | Prothera Biologics Inc | Kandan inter-alfa inhibitör proteinlerinin hazırlanması ve bunların bileşimi. |
| AU2010202125B1 (en) | 2010-05-26 | 2010-09-02 | Takeda Pharmaceutical Company Limited | A method to produce an immunoglobulin preparation with improved yield |
| US8772462B2 (en) | 2010-05-26 | 2014-07-08 | Baxter International Inc. | Removal of serine proteases by treatment with finely divided silicon dioxide |
| BR112013001753A2 (pt) | 2010-07-23 | 2016-05-31 | Baxter Healthcare Sa | método para preparar uma composição d einter-alfa-inibidor (iaip) eriquecida de plasma, solução aquosa de iaip, e, método para tratar uma doença ou distúrbio associado com disfunção de iaip e associado com atividadede protease de serina no plasma aumentada. |
| TWI629283B (zh) | 2012-02-23 | 2018-07-11 | 巴克斯歐塔公司 | 來自血漿中的免疫球蛋白之ｉ-ｉｖ-１部分沉澱 |
| WO2014039987A2 (en) | 2012-09-09 | 2014-03-13 | Prothera Biologics, Inc. | Treatment of disease using inter-alpha inhibitor proteins |
| US20140206844A1 (en) * | 2013-01-18 | 2014-07-24 | Prothera Biologics | Methods for isolating blood products from an inter-alpha inhibitor protein-depleted blood product material |
| US20170232079A1 (en) * | 2015-10-06 | 2017-08-17 | Kieu Hoang | Method of manufacturing prothrombin complex concentrate from fraction iii and non-prothrombin complex concentrate from fraction iv |
| US20190269765A1 (en) | 2016-09-13 | 2019-09-05 | Prothera Biologics, Inc. | Methods for treating pulmonary disease using inter-alpha inhibitor proteins |
| AU2018258466B2 (en) | 2017-04-25 | 2025-05-22 | Prothera Biologics, Inc. | Methods for quantifying inter-alpha inhibitor proteins |
| JP7432506B2 (ja) | 2017-10-30 | 2024-02-16 | 武田薬品工業株式会社 | 脂質エンベロープウイルスを不活化するための環境適合性の界面活性剤 |
| EP3870147A4 (en) * | 2018-10-24 | 2022-08-31 | Prothera Biologics, Inc. | INTER-ALPHA INHIBITOR PROTEINS AND METHODS OF USE THEREOF |
| CN109867717A (zh) * | 2019-04-01 | 2019-06-11 | 山西瑞亚力生物技术有限公司 | 一种血浆中α1微球蛋白的提取方法 |
| KR20220029732A (ko) * | 2019-07-04 | 2022-03-08 | 체에스엘 베링 게엠베하 | C1-inh를 정제하는 방법 |
| CA3173539A1 (en) * | 2020-03-31 | 2021-10-07 | Takeda Pharmaceutical Company Limited | A method to produce an immunoglobulin preparation from c-1 inhibitor depleted plasma |
| EP4240757A2 (en) * | 2020-11-09 | 2023-09-13 | Takeda Pharmaceutical Company Limited | Purification of fviii from plasma using silicon oxide adsorption |
| US20230416342A1 (en) | 2020-11-16 | 2023-12-28 | Prothera Biologics, Inc. | Methods for purifying inter-alpha inhibitor proteins |
| JP2025514479A (ja) * | 2022-05-02 | 2025-05-02 | 武田薬品工業株式会社 | 血漿から限外濾過によりコーンプール濃縮物を調製する方法 |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2390074A (en) * | 1942-02-09 | 1945-12-04 | Research Corp | Protein product and process |
| DK166763C (da) | 1983-03-16 | 1993-07-12 | Immuno Ag | Immunoglobulin-g-holdig fraktion |
| US5055447A (en) * | 1988-07-28 | 1991-10-08 | Genentech, Inc. | Method and compositions for the treatment and prevention of septic shock |
| US5177194A (en) | 1990-02-01 | 1993-01-05 | Baxter International, Inc. | Process for purifying immune serum globulins |
| FR2711371B1 (fr) | 1993-10-18 | 1995-12-29 | Aetsrn | Procédé de préparation d'un concentré d'inter-alpha-trypsine inhibiteur à usage thérapeutique et concentré obtenu. |
| EP0764658B1 (de) * | 1995-09-22 | 2002-01-02 | ZLB Bioplasma AG | Verfahren zur Gewinnung von Immunglobulinen aus Fraktionen, die bei der Fraktionierung von menschlichem Blutplasma entstehen |
| JP2004511492A (ja) | 2000-10-13 | 2004-04-15 | オクタファルマ アクチェン ゲゼルシャフト | ビクニンを含む血漿画分、その調製方法、およびその使用 |
| EP3087991A1 (en) | 2003-11-08 | 2016-11-02 | Prothera Biologics | Composition of inter-alpha inhibitor proteins from human plasma for therapeutic use |
| CN101160133B (zh) * | 2004-11-05 | 2013-01-09 | 普罗瑟拉生物公司 | 治疗用途的来自人血浆的内-α抑制剂蛋白质的制备和组合物 |
| EP2129686B1 (en) | 2007-03-20 | 2016-07-13 | CSL Behring GmbH | Methods for industrial scale production of therapeutic complement factor h preparations from human plasma |
| TR201808152T4 (tr) * | 2008-05-28 | 2018-07-23 | Prothera Biologics Inc | Kandan inter-alfa inhibitör proteinlerinin hazırlanması ve bunların bileşimi. |
| WO2011011753A1 (en) | 2009-07-23 | 2011-01-27 | Baxter International Inc. | Manufacture of factor h (fh) and fh-derivatives from plasma |
| AU2010202125B1 (en) * | 2010-05-26 | 2010-09-02 | Takeda Pharmaceutical Company Limited | A method to produce an immunoglobulin preparation with improved yield |
| BR112013001753A2 (pt) | 2010-07-23 | 2016-05-31 | Baxter Healthcare Sa | método para preparar uma composição d einter-alfa-inibidor (iaip) eriquecida de plasma, solução aquosa de iaip, e, método para tratar uma doença ou distúrbio associado com disfunção de iaip e associado com atividadede protease de serina no plasma aumentada. |
-
2011
- 2011-07-22 BR BR112013001753A patent/BR112013001753A2/pt not_active Application Discontinuation
- 2011-07-22 KR KR1020137004453A patent/KR20130093607A/ko not_active Withdrawn
- 2011-07-22 US US13/189,390 patent/US8841248B2/en active Active
- 2011-07-22 EA EA201390156A patent/EA201390156A1/ru unknown
- 2011-07-22 ES ES11749976T patent/ES2717177T3/es active Active
- 2011-07-22 SG SG2013005640A patent/SG187599A1/en unknown
- 2011-07-22 EP EP11749976.4A patent/EP2596014B1/en active Active
- 2011-07-22 CA CA2806645A patent/CA2806645A1/en not_active Abandoned
- 2011-07-22 CN CN2011800457670A patent/CN103119058A/zh active Pending
- 2011-07-22 JP JP2013521858A patent/JP5830096B2/ja active Active
- 2011-07-22 WO PCT/US2011/045099 patent/WO2012012773A1/en not_active Ceased
- 2011-07-22 MX MX2013000958A patent/MX2013000958A/es not_active Application Discontinuation
- 2011-07-22 AU AU2011280907A patent/AU2011280907B2/en active Active
-
2013
- 2013-02-21 CO CO13035387A patent/CO6680653A2/es not_active Application Discontinuation
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2014
- 2014-08-19 US US14/463,533 patent/US9505814B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| US8841248B2 (en) | 2014-09-23 |
| CO6680653A2 (es) | 2013-05-31 |
| US20120053113A1 (en) | 2012-03-01 |
| JP5830096B2 (ja) | 2015-12-09 |
| JP2013535468A (ja) | 2013-09-12 |
| CA2806645A1 (en) | 2012-01-26 |
| KR20130093607A (ko) | 2013-08-22 |
| EA201390156A1 (ru) | 2014-01-30 |
| US20150045538A1 (en) | 2015-02-12 |
| MX2013000958A (es) | 2013-11-20 |
| WO2012012773A1 (en) | 2012-01-26 |
| CN103119058A (zh) | 2013-05-22 |
| SG187599A1 (en) | 2013-03-28 |
| EP2596014B1 (en) | 2018-11-28 |
| BR112013001753A2 (pt) | 2016-05-31 |
| US9505814B2 (en) | 2016-11-29 |
| EP2596014A1 (en) | 2013-05-29 |
| AU2011280907A1 (en) | 2013-02-07 |
| AU2011280907B2 (en) | 2016-02-04 |
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