ES2534040T3 - Plasmina modificada de forma recombinante - Google Patents
Plasmina modificada de forma recombinante Download PDFInfo
- Publication number
- ES2534040T3 ES2534040T3 ES08857923.0T ES08857923T ES2534040T3 ES 2534040 T3 ES2534040 T3 ES 2534040T3 ES 08857923 T ES08857923 T ES 08857923T ES 2534040 T3 ES2534040 T3 ES 2534040T3
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- seq
- plasminogen
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- tal6003
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- 229940012957 plasmin Drugs 0.000 title description 4
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 abstract description 6
- 101000605403 Homo sapiens Plasminogen Proteins 0.000 abstract description 4
- 229920001184 polypeptide Polymers 0.000 abstract description 4
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 4
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 4
- 239000004472 Lysine Substances 0.000 abstract description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 abstract description 3
- 108091033319 polynucleotide Proteins 0.000 abstract description 3
- 239000002157 polynucleotide Substances 0.000 abstract description 3
- 102000040430 polynucleotide Human genes 0.000 abstract description 3
- 239000002773 nucleotide Substances 0.000 abstract description 2
- 125000003729 nucleotide group Chemical group 0.000 abstract description 2
- 102000012479 Serine Proteases Human genes 0.000 abstract 1
- 108010022999 Serine Proteases Proteins 0.000 abstract 1
- 230000004913 activation Effects 0.000 abstract 1
- 125000000539 amino acid group Chemical group 0.000 abstract 1
- 210000004899 c-terminal region Anatomy 0.000 abstract 1
- 238000003776 cleavage reaction Methods 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- 241000588724 Escherichia coli Species 0.000 description 4
- 102000013566 Plasminogen Human genes 0.000 description 4
- 108010051456 Plasminogen Proteins 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 125000003275 alpha amino acid group Chemical group 0.000 description 3
- 239000013604 expression vector Substances 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 2
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 108010087750 lysyl-plasminogen Proteins 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 238000012270 DNA recombination Methods 0.000 description 1
- 241001522878 Escherichia coli B Species 0.000 description 1
- 241000701959 Escherichia virus Lambda Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- -1 V11) corresponding Chemical compound 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 101150079601 recA gene Proteins 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001018 virulence Effects 0.000 description 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)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6435—Plasmin (3.4.21.7), i.e. fibrinolysin
-
- 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
-
- 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
- C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
- C12N11/02—Enzymes or microbial cells immobilised on or in an organic carrier
- C12N11/04—Enzymes or microbial cells immobilised on or in an organic carrier entrapped within the carrier, e.g. gel or hollow fibres
-
- 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)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21007—Plasmin (3.4.21.7), i.e. fibrinolysin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- General Health & Medical Sciences (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biomedical Technology (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Enzymes And Modification Thereof (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
Abstract
Polinucleótido, caracterizado porque comprende una secuencia de nucleótidos que codifica un polipéptido que es por lo menos 95% idéntico a la SEQ ID NO: 2, que tiene a) un dominio kringle N-terminal único homólogo a un dominio kringle del plasminógeno humano nativo, en el que los cuatro últimos residuos de aminoácidos dentro del dominio kringle son V, P, Q y C; y b) un sitio de activación del dominio C-terminal y un dominio de serina proteasa homólogos a los dominios correspondientes en el plasminógeno humano; en los que el polipéptido se une a lisina inmovilizada.
Description
E08857923
30-03-2015
EJEMPLOS
5 La secuencia de aminoácidos para (TLA6003)-plasminógeno se muestra en SEQ ID NO: 2. En un polinucleótido que tiene la secuencia de nucleótidos que codifica (TAL6003)-plasminógeno se optimizaron los codones por la expresión de
E. coli y la estabilidad de ARNm para proporcionar la secuencia de ADN tal como se muestra en SEQ ID NO: 1. Este polinucleótido se clonó en los sitios Ndel y BamHI del vector de expresión de E. coli pET24b(+) (Novagen; Madison, WI) para producir la proteína citosólica.
10 Como se ilustra en la tabla 1, la expresión en bacterias (por ejemplo E. coli) proporciona un polipéptido (TAL6003)-plasminógeno recombinante que tiene la secuencia de aminoácidos tal como se muestra en SEQ ID NO: 2 (es decir, un (TAL6003)-plasminógeno recombinante con una metionina N-terminal (es decir, M1) que precede inmediatamente el residuo de aminoácidos de arginina (es decir, R2) correspondiente a la arginina en la posición 70 (es
15 decir, R70) de la secuencia de aminoácidos de plasminógeno humano nativo mostrado en SEQ ID NO: 4 (véase también, por ejemplo, la Figura 3). Dicho producto recombinante es susceptible a escisión adicional para producir proteínas adicionales que tienen extremos N-terminales diferentes que incluyen una proteína con una lisina N-terminal (es decir, K10) o valina (es decir, V11) correspondiente, respectivamente, a la lisina en la posición 78 (es decir, K78) o la valina en la posición 79 (es decir, V79) de plasminógeno humano nativo.
20
- Tabla 1: Extremos N-terminales de plasmina(plasminógeno) nativo (por ejemplo, basado en SEQ ID NO:4) y (TAL6003)-plasmina(plasminógeno) (por ejemplo, basado en SEQ ID NO: 2, o su variante)
- Plasminógeno nativo que comprende una secuencia lectora de 19 aminoácidos (por ejemplo basado en SEQ ID NO: 4):
- “Lys-plasminógeno” nativo (es decir, escisión de secuencia lectora): (véase SEQ ID NO:5)
- Especies de plasmina nativa posibles basadas en escisión, si es cualquiera, de Lys-Plasminógeno: (véase SEQ ID NO: 14) (véase SEQ ID NO: 13) (véase SEQ ID NO: 12)
- Polipéptidos de (TAL6003)-plasminógeno recombinantes de la presente invención: (por ejemplo, basados en SEQ ID NO: 2)
- Proteínas adicionales basadas en escisión adicional de un (TAL6003)-plasminógeno (por ejemplo, basadas en SEQ ID NO: 2) (véase SEQ ID NO: 11) K10V11YLSEC ….. (SEQ ID NO: 5) V11YLSEC …..
- ↓ indica sitios de escisión potencial
El vector de expresión que comprende el ADN que codifica (TAL6003)-plasminógeno se transforma en una variedad de
25 células que incluyen Bl21(DE3)RIL (Stratagene, La Jolla, CA), BL21(DE3) (genotipo: F -ompT hsdSB (rB-mB-) gal dcm (DE3)) (EMB Biosciences, Inc., San Diego, CA), y BLR(DE3) (genotipo: F-ampT hsdSB (rB -mB -) gal dcm (DE3) Δ(srl-recA)306::Tn10(TetR)), y la sobreexpresión de proteína seguida por la inducción por IPTG 1mM (isopropil-beta-D-tiogalactopiranósido) se analizó por SDS-PAGE. Los estimados de expresión fueron, como mínimo, de aproximadamente 250 mg/l de cultivo celular en matraces agitadores.
30 La célula tipo BL21(DE3)RIL se diseña para expresar ARNt de E. coli raros que codifican para Arg, IIe, y Leu. Además, tanto BL21(DE3) como BLR(DE3) son cepas B de E. coli que se clasifican como no patogénicas para humanos y animales basados en la ausencia de factores de virulencia y colonización. Las células BLR(DE3) carecen del gen recA para recombinación de ADN, y no se ha informado de la inducción de fago lambda con estas células. Un banco celular
11
Claims (1)
-
imagen1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US99114807P | 2007-11-29 | 2007-11-29 | |
| US991148P | 2007-11-29 | ||
| PCT/US2008/084645 WO2009073471A1 (en) | 2007-11-29 | 2008-11-25 | Recombinantly modified plasmin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2534040T3 true ES2534040T3 (es) | 2015-04-16 |
Family
ID=40379999
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES08857923.0T Active ES2534040T3 (es) | 2007-11-29 | 2008-11-25 | Plasmina modificada de forma recombinante |
Country Status (17)
| Country | Link |
|---|---|
| US (3) | US8101394B2 (es) |
| EP (1) | EP2220221B1 (es) |
| JP (1) | JP5539896B2 (es) |
| KR (1) | KR101529743B1 (es) |
| CN (1) | CN101918548B (es) |
| AU (1) | AU2008331545B2 (es) |
| BR (1) | BRPI0819780B1 (es) |
| CA (1) | CA2707266C (es) |
| ES (1) | ES2534040T3 (es) |
| HU (1) | HUE024916T2 (es) |
| IL (1) | IL205936A (es) |
| MX (1) | MX2010005947A (es) |
| NZ (2) | NZ585715A (es) |
| PL (1) | PL2220221T3 (es) |
| PT (1) | PT2220221E (es) |
| WO (1) | WO2009073471A1 (es) |
| ZA (1) | ZA201003730B (es) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1961070A (zh) | 2004-04-22 | 2007-05-09 | 泰勒克里斯生物治疗学公司 | 重组修饰的纤溶酶 |
| JP5539896B2 (ja) | 2007-11-29 | 2014-07-02 | グリフオルス・セラピユーテイクス・インコーポレーテツド | 組換え的に改変されたプラスミン |
| WO2009149199A2 (en) | 2008-06-04 | 2009-12-10 | Talecris Biotherapeutics, Inc. | Composition, method and kit for preparing plasmin |
| PT2403865E (pt) * | 2009-03-03 | 2015-11-18 | Grifols Therapeutics Inc | Métodos de preparação de plasminogénio |
| KR20120050442A (ko) | 2009-07-10 | 2012-05-18 | 쓰롬보제닉스 엔.브이. | 플라스미노겐 및 플라스민의 변이체 |
| US20120189609A1 (en) | 2009-08-28 | 2012-07-26 | Thrombogenics Nv | Improvement to trabeculectomy |
| CN102121023B (zh) * | 2010-12-22 | 2012-07-04 | 中山大学 | 突变型人纤溶酶原kringle5及其制备方法及应用 |
| EP2661493B1 (en) | 2011-01-05 | 2016-03-30 | ThromboGenics N.V. | Plasminogen and plasmin variants |
| JP6000353B2 (ja) | 2011-08-12 | 2016-09-28 | スロンボジェニックス・ナムローゼ・フェンノートシャップＴｈｒｏｍｂｏＧｅｎｉｃｓ ＮＶ | プラスミノーゲンおよびプラスミンの変異体 |
| CN103205410B (zh) * | 2012-01-13 | 2018-03-06 | 蔺莹莹 | 重组微纤维蛋白溶酶及其制备方法和应用 |
| SG11201506886TA (en) | 2013-03-14 | 2015-09-29 | Bayer Healthcare Llc | Monoclonal antibodies against antithrombin beta complexed with heparin |
| DE102014112212A1 (de) * | 2014-08-26 | 2016-03-03 | Akesion Gmbh | Rekombinante Fusionsproteine zur Vorbeugung oder Behandlung von Adhäsionen bei Geweben oder Organen |
| FR3035120B1 (fr) * | 2015-04-15 | 2020-02-07 | Arcadophta | Composition de plasminogenase immobilisee, procede de preparation, utilisation et dispositif comprenant une telle composition |
| ES2982294T3 (es) | 2015-12-18 | 2024-10-15 | Talengen Int Ltd | Plasminógeno para su uso en el tratamiento o prevención de lesiones nerviosas por diabetes mellitus |
| DK3395354T3 (da) | 2015-12-18 | 2024-06-03 | Talengen Int Ltd | Plasminogen til anvendelse i behandling af diabetisk nefropati |
| CN108463240A (zh) | 2015-12-18 | 2018-08-28 | 泰伦基国际有限公司 | 一种预防或治疗糖尿病性视网膜病变的方法 |
| DK3391902T5 (da) | 2015-12-18 | 2024-09-23 | Talengen Int Ltd | Plasminogen til anvendelse i behandlingen af diabetisk angiokardiopati |
| CN110198732A (zh) * | 2016-12-15 | 2019-09-03 | 泰伦基国际有限公司 | 一种促进胰岛素受体底物-2表达的方法 |
| JP7213552B2 (ja) | 2016-12-15 | 2023-01-27 | タレンゲン インターナショナル リミテッド | 肝の繊維化を予防及び治療するための方法 |
| CN108210905A (zh) * | 2016-12-15 | 2018-06-29 | 深圳瑞健生命科学研究院有限公司 | 预防和治疗皮肤纤维化的药物及其用途 |
| JP7168990B2 (ja) | 2016-12-15 | 2022-11-10 | タレンゲン インターナショナル リミテッド | 肥満症を予防および治療するための方法および薬物 |
| TWI677348B (zh) | 2016-12-15 | 2019-11-21 | 大陸商深圳瑞健生命科學研究院有限公司 | 一種改善心臟病變的方法 |
| WO2018107686A1 (zh) * | 2016-12-15 | 2018-06-21 | 深圳瑞健生命科学研究院有限公司 | 一种治疗动脉粥样硬化及其并发症的方法 |
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| CN118308334B (zh) * | 2024-06-06 | 2024-10-08 | 深圳市卫光生物制品股份有限公司 | 一种重组人纤溶酶原及其制备方法和应用 |
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| US7253264B1 (en) * | 1990-06-28 | 2007-08-07 | Sanofi-Arentideutschland GmbH | Immunoglobulin fusion proteins, their production and use |
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| CN1961070A (zh) * | 2004-04-22 | 2007-05-09 | 泰勒克里斯生物治疗学公司 | 重组修饰的纤溶酶 |
| US8231869B2 (en) * | 2005-10-20 | 2012-07-31 | Grifols Therapeutics Inc. | Recombinant plasmin for opthalmic indications |
| JP5539896B2 (ja) | 2007-11-29 | 2014-07-02 | グリフオルス・セラピユーテイクス・インコーポレーテツド | 組換え的に改変されたプラスミン |
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2008
- 2008-11-25 JP JP2010536117A patent/JP5539896B2/ja active Active
- 2008-11-25 CN CN2008801232704A patent/CN101918548B/zh active Active
- 2008-11-25 BR BRPI0819780-6A patent/BRPI0819780B1/pt not_active IP Right Cessation
- 2008-11-25 KR KR1020107014243A patent/KR101529743B1/ko not_active Expired - Fee Related
- 2008-11-25 NZ NZ585715A patent/NZ585715A/en not_active IP Right Cessation
- 2008-11-25 EP EP08857923.0A patent/EP2220221B1/en active Active
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- 2008-11-25 AU AU2008331545A patent/AU2008331545B2/en active Active
- 2008-11-25 US US12/744,376 patent/US8101394B2/en active Active
- 2008-11-25 PL PL08857923T patent/PL2220221T3/pl unknown
- 2008-11-25 WO PCT/US2008/084645 patent/WO2009073471A1/en not_active Ceased
- 2008-11-25 HU HUE08857923A patent/HUE024916T2/en unknown
- 2008-11-25 PT PT88579230T patent/PT2220221E/pt unknown
- 2008-11-25 ES ES08857923.0T patent/ES2534040T3/es active Active
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Also Published As
| Publication number | Publication date |
|---|---|
| JP5539896B2 (ja) | 2014-07-02 |
| PL2220221T3 (pl) | 2015-07-31 |
| ZA201003730B (en) | 2012-11-28 |
| JP2011505140A (ja) | 2011-02-24 |
| NZ593837A (en) | 2013-01-25 |
| BRPI0819780A2 (pt) | 2015-08-11 |
| US8101394B2 (en) | 2012-01-24 |
| KR20100102135A (ko) | 2010-09-20 |
| US8182808B2 (en) | 2012-05-22 |
| CN101918548B (zh) | 2013-10-16 |
| EP2220221B1 (en) | 2014-12-31 |
| US20120093799A1 (en) | 2012-04-19 |
| HUE024916T2 (en) | 2016-02-29 |
| HK1146089A1 (en) | 2011-05-13 |
| MX2010005947A (es) | 2010-09-10 |
| BRPI0819780B1 (pt) | 2023-01-24 |
| EP2220221A1 (en) | 2010-08-25 |
| NZ585715A (en) | 2011-11-25 |
| US8512980B2 (en) | 2013-08-20 |
| US20110003332A1 (en) | 2011-01-06 |
| CA2707266C (en) | 2013-12-31 |
| IL205936A0 (en) | 2010-11-30 |
| CA2707266A1 (en) | 2009-06-11 |
| KR101529743B1 (ko) | 2015-06-17 |
| IL205936A (en) | 2015-04-30 |
| CN101918548A (zh) | 2010-12-15 |
| PT2220221E (pt) | 2015-04-16 |
| AU2008331545A1 (en) | 2009-06-11 |
| US20120276611A1 (en) | 2012-11-01 |
| WO2009073471A1 (en) | 2009-06-11 |
| AU2008331545B2 (en) | 2014-01-16 |
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