ES2539284T3 - Procedimiento de producción de VWF maduro a partir del propéptido de VWF - Google Patents
Procedimiento de producción de VWF maduro a partir del propéptido de VWF Download PDFInfo
- Publication number
- ES2539284T3 ES2539284T3 ES08754504.2T ES08754504T ES2539284T3 ES 2539284 T3 ES2539284 T3 ES 2539284T3 ES 08754504 T ES08754504 T ES 08754504T ES 2539284 T3 ES2539284 T3 ES 2539284T3
- Authority
- ES
- Spain
- Prior art keywords
- vwf
- propeptide
- furin
- mature
- maturation
- 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.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 71
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 108010047303 von Willebrand Factor Proteins 0.000 claims abstract description 211
- 102100036537 von Willebrand factor Human genes 0.000 claims abstract description 210
- 229960001134 von willebrand factor Drugs 0.000 claims abstract description 209
- 238000010828 elution Methods 0.000 claims abstract description 21
- 230000000694 effects Effects 0.000 claims abstract description 20
- 239000003957 anion exchange resin Substances 0.000 claims abstract description 18
- 239000000427 antigen Substances 0.000 claims abstract description 7
- 108091007433 antigens Proteins 0.000 claims abstract description 7
- 102000036639 antigens Human genes 0.000 claims abstract description 7
- 108090001126 Furin Proteins 0.000 claims description 59
- 102000004961 Furin Human genes 0.000 claims description 59
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical group O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 claims description 44
- 230000008569 process Effects 0.000 claims description 22
- 238000011534 incubation Methods 0.000 claims description 14
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 6
- 239000001110 calcium chloride Substances 0.000 claims description 6
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 6
- 235000011148 calcium chloride Nutrition 0.000 claims description 6
- 239000011347 resin Substances 0.000 abstract description 10
- 229920005989 resin Polymers 0.000 abstract description 10
- 230000003100 immobilizing effect Effects 0.000 abstract description 2
- 125000000129 anionic group Chemical group 0.000 abstract 1
- 230000035800 maturation Effects 0.000 description 65
- 241001120659 Furina Species 0.000 description 40
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 28
- 102000004169 proteins and genes Human genes 0.000 description 23
- 108090000623 proteins and genes Proteins 0.000 description 23
- 239000011780 sodium chloride Substances 0.000 description 14
- 102000035195 Peptidases Human genes 0.000 description 13
- 108091005804 Peptidases Proteins 0.000 description 13
- 239000004365 Protease Substances 0.000 description 13
- 239000000872 buffer Substances 0.000 description 11
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 239000003456 ion exchange resin Substances 0.000 description 8
- 229920003303 ion-exchange polymer Polymers 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000011575 calcium Substances 0.000 description 7
- 238000004113 cell culture Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 239000007995 HEPES buffer Substances 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000011020 pilot scale process Methods 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 101000926140 Homo sapiens Gem-associated protein 2 Proteins 0.000 description 5
- 101000716750 Homo sapiens Protein SCAF11 Proteins 0.000 description 5
- 101000723833 Homo sapiens Zinc finger E-box-binding homeobox 2 Proteins 0.000 description 5
- 102100020876 Protein SCAF11 Human genes 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 230000002255 enzymatic effect Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 238000011109 contamination Methods 0.000 description 3
- 239000012228 culture supernatant Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000010198 maturation time Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000017854 proteolysis Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 2
- 208000002109 Argyria Diseases 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 102000006437 Proprotein Convertases Human genes 0.000 description 2
- 108010044159 Proprotein Convertases Proteins 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 238000000246 agarose gel electrophoresis Methods 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 230000004481 post-translational protein modification Effects 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 230000005070 ripening Effects 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 108010076181 Proinsulin Proteins 0.000 description 1
- 108010078762 Protein Precursors Proteins 0.000 description 1
- 102000014961 Protein Precursors Human genes 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 208000027276 Von Willebrand disease Diseases 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 238000000429 assembly Methods 0.000 description 1
- 230000000712 assembly Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 229940019700 blood coagulation factors Drugs 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 238000011210 chromatographic step Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000013024 dilution buffer Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012149 elution buffer Substances 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 210000002288 golgi apparatus Anatomy 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 210000003593 megakaryocyte Anatomy 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000010411 postconditioning Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- -1 trimethyl-aminoethyl groups Chemical group 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 208000012137 von Willebrand disease (hereditary or acquired) Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- 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
- C07K1/16—Extraction; Separation; Purification by chromatography
- C07K1/18—Ion-exchange chromatography
-
- 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
-
- 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
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Analytical Chemistry (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Enzymes And Modification Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US93089107P | 2007-05-18 | 2007-05-18 | |
| US930891P | 2007-05-18 | ||
| PCT/US2008/006291 WO2008143977A1 (en) | 2007-05-18 | 2008-05-16 | Method for producing mature vwf from vwf pro-peptide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2539284T3 true ES2539284T3 (es) | 2015-06-29 |
Family
ID=39666205
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES08754504.2T Active ES2539284T3 (es) | 2007-05-18 | 2008-05-16 | Procedimiento de producción de VWF maduro a partir del propéptido de VWF |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US8058411B2 (enExample) |
| EP (1) | EP2152735B1 (enExample) |
| JP (2) | JP5053435B2 (enExample) |
| KR (1) | KR101156263B1 (enExample) |
| CN (1) | CN101679496B (enExample) |
| AU (1) | AU2008254522B2 (enExample) |
| BR (1) | BRPI0811649B8 (enExample) |
| CA (1) | CA2684151A1 (enExample) |
| DK (1) | DK2152735T3 (enExample) |
| ES (1) | ES2539284T3 (enExample) |
| HU (1) | HUE025257T2 (enExample) |
| MX (1) | MX2009012387A (enExample) |
| NZ (1) | NZ581582A (enExample) |
| PL (1) | PL2152735T3 (enExample) |
| PT (1) | PT2152735E (enExample) |
| WO (1) | WO2008143977A1 (enExample) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG191186A1 (en) * | 2010-12-15 | 2013-07-31 | Baxter Int | Eluate collection using conductivity gradient |
| US20140276101A1 (en) * | 2013-03-14 | 2014-09-18 | Boston Scientific Scimed, Inc. | Medical device for detecting a target and related methods of use |
| TWI666319B (zh) * | 2014-08-12 | 2019-07-21 | 美商巴克斯歐塔公司 | 在分泌ｆｕｒｉｎ之哺乳動物表現系統中生產經完全加工且具功能性之因子Ｘ |
| CN111183151B (zh) | 2017-06-23 | 2024-06-07 | 武田药品工业株式会社 | 因子viii亚种的纯化 |
| MX2020009788A (es) * | 2018-03-21 | 2020-12-09 | Takeda Pharmaceuticals Co | Separación de factor de von willebrand (vwf) y propéptido de factor de von willebrand (vwf) por métodos cromatográficos. |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT404838B (de) * | 1995-11-24 | 1999-03-25 | Immuno Ag | Herstellung von proteinen aus pro-proteinen durch fusionsproteine abgeleitet von furin oder furinanalogen |
| AT407750B (de) | 1999-02-19 | 2001-05-25 | Immuno Ag | Verfahren zur herstellung einer vwf-präparation |
| KR20070092754A (ko) * | 2004-12-27 | 2007-09-13 | 백스터 인터내셔널 인코포레이티드 | 중합체 - 폰 빌레브란트 인자 - 접합체 |
-
2008
- 2008-05-16 JP JP2010508442A patent/JP5053435B2/ja active Active
- 2008-05-16 PL PL08754504T patent/PL2152735T3/pl unknown
- 2008-05-16 EP EP08754504.2A patent/EP2152735B1/en active Active
- 2008-05-16 CN CN2008800163745A patent/CN101679496B/zh active Active
- 2008-05-16 AU AU2008254522A patent/AU2008254522B2/en active Active
- 2008-05-16 HU HUE08754504A patent/HUE025257T2/en unknown
- 2008-05-16 DK DK08754504T patent/DK2152735T3/en active
- 2008-05-16 ES ES08754504.2T patent/ES2539284T3/es active Active
- 2008-05-16 PT PT87545042T patent/PT2152735E/pt unknown
- 2008-05-16 KR KR1020097026328A patent/KR101156263B1/ko active Active
- 2008-05-16 BR BRPI0811649A patent/BRPI0811649B8/pt active IP Right Grant
- 2008-05-16 NZ NZ581582A patent/NZ581582A/en unknown
- 2008-05-16 MX MX2009012387A patent/MX2009012387A/es active IP Right Grant
- 2008-05-16 US US12/152,762 patent/US8058411B2/en active Active
- 2008-05-16 WO PCT/US2008/006291 patent/WO2008143977A1/en not_active Ceased
- 2008-05-16 CA CA2684151A patent/CA2684151A1/en not_active Abandoned
-
2012
- 2012-07-25 JP JP2012164790A patent/JP2012210226A/ja not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| HK1144577A1 (en) | 2011-02-25 |
| AU2008254522A2 (en) | 2010-02-18 |
| EP2152735B1 (en) | 2015-03-18 |
| JP5053435B2 (ja) | 2012-10-17 |
| BRPI0811649A2 (pt) | 2014-11-11 |
| DK2152735T3 (en) | 2015-04-20 |
| CA2684151A1 (en) | 2008-11-27 |
| PL2152735T3 (pl) | 2015-08-31 |
| JP2010527588A (ja) | 2010-08-19 |
| US8058411B2 (en) | 2011-11-15 |
| EP2152735A1 (en) | 2010-02-17 |
| NZ581582A (en) | 2012-02-24 |
| HUE025257T2 (en) | 2016-03-29 |
| US20090029918A1 (en) | 2009-01-29 |
| JP2012210226A (ja) | 2012-11-01 |
| BRPI0811649B1 (pt) | 2020-11-17 |
| KR101156263B1 (ko) | 2012-06-13 |
| BRPI0811649B8 (pt) | 2021-05-25 |
| KR20100028042A (ko) | 2010-03-11 |
| MX2009012387A (es) | 2010-02-10 |
| AU2008254522A1 (en) | 2008-11-27 |
| WO2008143977A1 (en) | 2008-11-27 |
| AU2008254522B2 (en) | 2012-07-12 |
| CN101679496B (zh) | 2013-03-13 |
| CN101679496A (zh) | 2010-03-24 |
| PT2152735E (pt) | 2015-07-21 |
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