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1. 发明申请

WO0156532A9 NEUROPROTECTIVE, ANTITHROMBOTIC AND ANTI-INFLAMMATORY USES OF ACTIVATED PROTEIN C (APC) 审中-公开
标题翻译：活性蛋白C（APC）的神经保护，抗血栓形成和抗炎作用
公开(公告)号：WO0156532A9
公开(公告)日：2003-01-09
申请号：PCT/US0103758
申请日：2001-02-05
申请人： SCRIPPS RESEARCH INST , UNIV SOUTHERN CALIFORNIA , GRIFFIN JOHN H , ZLOKOVIC BERISLAV Y
发明人： GRIFFIN JOHN H , ZLOKOVIC BERISLAV Y
IPC分类号： A61K45/00 , A61K38/00 , A61K38/48 , A61K38/49 , A61P9/02 , A61P9/10 , A61P25/08 , A61P25/16 , A61P25/28 , A61P29/00 , A61P43/00 , C12N9/64 , A61K38/43 , A61K39/00 , C07K2/00
CPC分类号： A61K38/49 , A61K38/4866 , C12N9/6464 , C12Y304/21069 , A61K2300/00
摘要： The present invention provides methods for treating subjects having or at risk of having a neuropathological disorder or brain inflammatory diseases with and without vascular involvement, and systemic inflammatory vascular disease by administering a therapeutically effective amount of Activated Protein C (APC) to the subject. Brain disorders and brain inflammatory vascular diseases that can be treated by the invention method include all neurodegenerative diseases with different types of neuronal dysfunction, including stroke, Alzheimer's disease, Parkinson's disease, Huntington disease, neuroimmunological disorders such as multiple sclerosis and Gullian-Barre, encephalitis, meningitis, as well as other peripheral vascular diseases, such as diabetes, hypertension, artheriosclerosis. Also included are methods of treatment using APC in combination with a co-factor, such as Protein S.
摘要翻译：本发明提供了通过向受试者施用治疗有效量的活化蛋白C（APC）来治疗患有或具有神经病理学障碍或伴有和不伴有血管受累的脑炎性疾病和全身炎性血管疾病的风险的受试者的方法。可以通过本发明方法治疗的脑部疾病和脑炎性血管疾病包括具有不同类型的神经元功能障碍的所有神经变性疾病，包括中风，阿尔茨海默氏病，帕金森病，亨廷顿舞蹈病，神经免疫学疾病如多发性硬化和古利 - 巴雷，脑炎，脑膜炎，以及其他外周血管疾病，如糖尿病，高血压，动物硬化。还包括使用APC与辅因子如蛋白S组合的治疗方法。

2. 发明申请

WO0156532A2 NEUROPROTECTIVE, ANTITHROMBOTIC AND ANTI-INFLAMMATORY USES OF ACTIVATED PROTEIN C (APC) 审中-公开
标题翻译：活性蛋白C（APC）的神经保护，抗血栓形成和抗炎作用
公开(公告)号：WO0156532A2
公开(公告)日：2001-08-09
申请号：PCT/US0103758
申请日：2001-02-05
申请人： SCRIPPS RESEARCH INST , UNIV SOUTHERN CALIFORNIA , GRIFFIN JOHN H , ZLOKOVIC BERISLAV Y
发明人： GRIFFIN JOHN H , ZLOKOVIC BERISLAV Y
IPC分类号： A61K45/00 , A61K38/00 , A61K38/48 , A61K38/49 , A61P9/02 , A61P9/10 , A61P25/08 , A61P25/16 , A61P25/28 , A61P29/00 , A61P43/00 , C12N9/64 , A61K
CPC分类号： A61K38/49 , A61K38/4866 , C12N9/6464 , C12Y304/21069 , A61K2300/00
摘要： The present invention provides methods for treating subjects having or at risk of having a neuropathological disorder or brain inflammatory diseases with and without vascular involvement, and systemic inflammatory vascular disease by administering a therapeutically effective amount of Activated Protein C (APC) to the subject. Brain disorders and brain inflammatory vascular diseases that can be treated by the invention method include all neurodegenerative diseases with different types of neuronal dysfunction, including stroke, Alzheimer's disease, Parkinson's disease, Huntington disease, neuroimmunological disorders such as multiple sclerosis and Gullian-Barre, encephalitis, meningitis, as well as other peripheral vascular diseases, such as diabetes, hypertension, artheriosclerosis. Also included are methods of treatment using APC in combination with a co-factor, such as Protein S.
摘要翻译：本发明提供了通过向受试者施用治疗有效量的活化蛋白C（APC）来治疗患有或具有神经病理学障碍或伴有和不伴有血管受累的脑炎性疾病和全身炎性血管疾病的风险的受试者的方法。可以通过本发明方法治疗的脑部疾病和脑炎性血管疾病包括具有不同类型的神经元功能障碍的所有神经变性疾病，包括中风，阿尔茨海默氏病，帕金森病，亨廷顿舞蹈病，神经免疫学疾病如多发性硬化和古利 - 巴雷，脑炎，脑膜炎，以及其他外周血管疾病，如糖尿病，高血压，动物硬化。还包括使用APC与辅因子如蛋白S组合的治疗方法。

3. 发明申请

WO2008055145A3 ACTIVATED PROTEIN C VARIANTS WITH NORMAL CYTOPROTECTIVE ACTIVITY BUT REDUCED ANTICOAGULANT ACTIVITY 审中-公开
标题翻译：具有正常CYTOPROTECTIVE活性的活化蛋白C变体，但降低抗血小板活性
公开(公告)号：WO2008055145A3
公开(公告)日：2009-04-09
申请号：PCT/US2007082980
申请日：2007-10-30
申请人： SCRIPPS RESEARCH INST , GRIFFIN JOHN H , MOSNIER LAURENT O , GALE ANDREW J
发明人： GRIFFIN JOHN H , MOSNIER LAURENT O , GALE ANDREW J
IPC分类号： A61K38/17 , A61K38/36 , C12N9/50
CPC分类号： A61K38/4866 , C12N9/6464 , C12Y304/21069
摘要： Variants (mutants) of recombinant activated protein C (APC) or recombinant protein C (prodrug, capable of being converted to APC) that have substantial reductions in anticoagulant activity but that retain normal levels of anti-apoptotic activity are provided. Three examples of such recombinant APC mutants are KKK191-193AAA-APC, RR229/230AA-APC, and RR229/230AA plus KKK191-193AAA-APC. APC variants and prodrugs of the invention have the desirable property of being cytoprotective (anti-apoptotic effects), while having significantly reduced risk of bleeding. The invention also provides a method of using the APC variants or prodrugs of the invention to treat subjects who will benefit from APC's cytoprotective activities that are independent of APC's anticoagulant activity. These subjects include patients at risk of damage to blood vessels or tissue in various organs caused, at least in part, by apoptosis. At risk patients include, for example, those suffering (severe) sepsis, ischemia/reperfusion injury, ischemic stroke, acute myocardial infarction, acute or chronic neurodegenerative diseases, or those undergoing organ transplantation or chemotherapy, among other conditions. Methods of screening for variants of recombinant protein C or APC that are useful in accordance with the invention are also provided.
摘要翻译：提供重组活化蛋白C（APC）或重组蛋白C（前体药物，能够转化为APC）的变体（突变体），其具有显着降低抗凝活性，但保持正常水平的抗凋亡活性。这些重组APC突变体的三个实例是KKK191-193AAA-APC，RR229 / 230AA-APC和RR229 / 230AA加上KKK191-193AAA-APC。本发明的APC变体和前药具有细胞保护性（抗凋亡作用）的期望性质，同时具有显着降低的出血风险。本发明还提供了使用本发明的APC变体或前药来治疗受益于APC的细胞保护活性而不受APC抗凝活性影响的受试者的方法。这些受试者包括至少部分地通过细胞凋亡而导致各种器官的血管损伤或组织损伤风险的患者。在危险中，患者包括例如患有（严重）败血症，缺血/再灌注损伤，缺血性卒中，急性心肌梗死，急性或慢性神经变性疾病或经历器官移植或化疗的患者等。还提供了筛选根据本发明有用的重组蛋白C或APC的变体的方法。

4. 发明申请

WO2008073603A2 DOSING REGIMEN OF ACTIVATED PROTEIN C AND VARIANTS HAVING REDUCED ANTICOAGULANT ACTIVITY 审中-公开
标题翻译：活化蛋白C的剂量和具有降低抗血小板活性的变体
公开(公告)号：WO2008073603A2
公开(公告)日：2008-06-19
申请号：PCT/US2007083249
申请日：2007-10-31
申请人： SCRIPPS RESEARCH INST , BLOODCT RES FOUNDATION , GRIFFIN JOHN H , WEILER HARTMUT
发明人： GRIFFIN JOHN H , WEILER HARTMUT
IPC分类号： A61K38/36
CPC分类号： A61K38/4866
摘要： Recombinant activated protein C (APC) and APC variants with reduced anticoagulant activity were used to reduce mortality in murine models of sepsis. These models included endotoxemia and bacteremia models. We discovered that single or multiple bolus doses of APC, especially of APC variants such as RR230/231AA-APC, KKK192-194AAA-APC and 5A-APC (containing the combination of mutations present in the first two APC variants) given as a single bolus reduces 7-day mortality of mice given lethal doses of endotoxin. Administrations of a single bolus of 5A-APC after the initiation of sepsis also reduces mortality caused by LPS. 5A-APC with = 8 % of normal anticoagulant activity (which has reduced risk of bleeding) reduces mortality when given as two bolus administrations at 3 hours and then at 10 hours after initiation of bacterial infection, i.e. after onset of sepsis. This shows, first, that one or more bolus injections of APC or of APC variants, especially 5A-APC, can reduce mortality when given beginning hours after the onset of sepsis and, second, that it is not necessary to administer APC as a continuous infusion which is the current standard of practice because one or more bolus administrations can reduce mortality. Furthermore, dosages of approximately 0.06 to 0.4 mg/kg of APC and APC variants are identified to be sufficient to reduce mortality in sepsis.
摘要翻译：使用具有降低的抗凝活性的重组活化蛋白C（APC）和APC变体降低脓毒病鼠模型的死亡率。这些模型包括内毒素血症和菌血症模型。我们发现单次或多次推注剂量的APC，特别是APC变体如RR230 / 231AA-APC，KKK192-194AAA-APC和5A-APC（含有前两个APC变体中存在的突变的组合）作为单一推注减少给予致死剂量的内毒素的小鼠的7天死亡率。开始脓毒症后单次推注5A-APC的主管部门也降低了LPS引起的死亡率。具有正常抗凝血活性（降低出血风险）的8％的5A-APC在3小时，然后在细菌感染开始后10小时，即败血症发作后的两次推注给药时，降低死亡率。这显示，首先，APC或APC变体，特别是5A-APC的一次或多次推注注射可以在脓毒症发作开始后几小时减少死亡率，其次，不必将APC作为连续的输注是目前的实践标准，因为一次或多次推注给药可以降低死亡率。此外，鉴定了大约0.06至0.4mg / kg APC和APC变体的剂量足以降低败血症的死亡率。

5. 发明申请

WO2004030619A3 PROTEIN S PROTECTS THE NERVOUS SYSTEM FROM INJURY 审中-公开
标题翻译：蛋白S保护神经系统免受伤害
公开(公告)号：WO2004030619A3
公开(公告)日：2005-06-02
申请号：PCT/US0330638
申请日：2003-09-30
申请人： SOCRATECH L L C , UNIV ROCHESTER , SCRIPPS RESEARCH INST , ZLOKOVIC BERISLAV V , GRIFFIN JOHN H
发明人： ZLOKOVIC BERISLAV V , GRIFFIN JOHN H
IPC分类号： A61K38/36 , C07K14/81 , A61K38/00
CPC分类号： C07K14/8128 , A61K38/36 , G01N2500/10 , G01N2510/00
摘要： Protein S is a significant neuroprotectant when administered after focal ischemic stroke and prevents hypoxic/re-oxygenation injury. Purified human plasma-derived or recombinant protein S improves motor neurological function after stroke, and reduced brain infarction and edema. Protein S also enhances post-ischemic reperfusion and reduced brain fibrin and neutrophil deposition. Cortical neurons are protected from hypoxia/re-oxygenation-induced apoptosis. Thus, protein S and variants thereof are prototypes of a class of agents for preventing injury of the nervous system. In particular, a disease or other pathological condition (e.g., stroke) may be treated with such agents having one or more protein S activities (e.g., anti-thrombotic and anti-inflammatory activities, direct cellular neuronal protective effects) although the latter activities are not be required.
摘要翻译：当局部缺血性中风后施用时，蛋白S是一种显着的神经保护剂，可预防缺氧/再氧合损伤。纯化的人血浆来源或重组蛋白S改善中风后的运动神经功能，减少脑梗塞和水肿。蛋白S还增强了缺血后再灌注和减少脑纤维蛋白和嗜中性粒细胞沉积。皮质神经元被保护免受缺氧/再氧合诱导的细胞凋亡。因此，蛋白质S及其变体是用于预防神经系统损伤的一类试剂的原型。特别地，可以用具有一种或多种蛋白S活性（例如，抗血栓形成和抗炎活性，直接细胞神经元保护作用）的药物治疗疾病或其它病理状况（例如中风），尽管后者的活性是不需要。

6. 发明申请

WO2005007820A3 ACTIVATED PROTEIN C VARIANTS WITH NORMAL CYTOPROTECTIVE ACTIVITY BUT REDUCED ANTICOAGULANT ACTIVITY 审中-公开
标题翻译：具有正常细胞保护活性但活性降低的抗凝活性的活化蛋白C变体
公开(公告)号：WO2005007820A3
公开(公告)日：2005-09-29
申请号：PCT/US2004021797
申请日：2004-07-08
申请人： SCRIPPS RESEARCH INST , GRIFFIN JOHN H , MOSNIER LAURENT O , GALE ANDREW J
发明人： GRIFFIN JOHN H , MOSNIER LAURENT O , GALE ANDREW J
IPC分类号： A01N1/02 , A61K38/36 , C12N20060101 , C12N9/64 , C12P21/02
CPC分类号： C12Y304/21069 , A61K38/4866 , C12N9/6464
摘要： Variants (mutants) of recombinant activated protein C (APC) or recombinant protein C (prodrug, capable of being converted to APC) that have substantial reductions in anticoagulant activity but that retain normal levels of anti-apoptotic activity are provided. Two examples of such recombinant APC mutants are 3K3A-APC and 229/230-APC. APC variants and prodrugs of the invention have the desirable property of being cytoprotective (anti-apoptotic effects), while having significantly reduced risk of bleeding. The invention also provides a method of using the APC variants or prodrugs of the invention to treat subjects who will benefit from APC's cytoprotective activities that are independent of APC's anticoagulant activity. These subjects include patients at risk of damage to blood vessels or tissue in various organs caused, at least in part, by apoptosis. At risk patients include, for example, those suffering (severe) sepsis, ischemia/reperfusion injury, ischemic stroke, acute myocardial infarction, acute or chronic neurodegenerative diseases, or those undergoing organ transplantation or chemotherapy, among other conditions. Methods of screening for variants of recombinant protein C or APC that are useful in accordance with the invention are also provided.
摘要翻译：提供了重组活化蛋白C（APC）或重组蛋白C（前体药物，能够转化为APC）的变体（突变体），其抗凝血活性显着降低但保留了正常水平的抗凋亡活性。这种重组APC突变体的两个例子是3K3A-APC和229/230-APC。本发明的APC变体和前药具有期望的细胞保护性（抗细胞凋亡效应）性质，同时具有显着降低的出血风险。本发明还提供了使用本发明的APC变体或前体药物来治疗将受益于独立于APC的抗凝血活性的APC的细胞保护活性的受试者的方法。这些受试者包括处于各种器官中的血管或组织损伤风险的患者，至少部分由细胞凋亡引起。有风险的患者包括例如患有（严重）败血症，局部缺血/再灌注损伤，缺血性中风，急性心肌梗塞，急性或慢性神经退行性疾病或正在进行器官移植或化疗的患者等。还提供了筛选根据本发明有用的重组蛋白C或APC的变体的方法。

7. 发明申请

WO2004030619A8 PROTEIN S PROTECTS THE NERVOUS SYSTEM FROM INJURY 审中-公开
标题翻译：蛋白质S保护神经系统免受伤害
公开(公告)号：WO2004030619A8
公开(公告)日：2004-11-25
申请号：PCT/US0330638
申请日：2003-09-30
申请人： SOCRATECH L L C , UNIV ROCHESTER , SCRIPPS RESEARCH INST , ZLOKOVIC BERISLAV V , GRIFFIN JOHN H
发明人： ZLOKOVIC BERISLAV V , GRIFFIN JOHN H
IPC分类号： A61K38/36 , C07K14/81 , A61K
CPC分类号： C07K14/8128 , A61K38/36 , G01N2500/10 , G01N2510/00
摘要： Protein S is a significant neuroprotectant when administered after focal ischemic stroke and prevents hypoxic/re-oxygenation injury. Purified human plasma-derived or recombinant protein S improves motor neurological function after stroke, and reduced brain infarction and edema. Protein S also enhances post-ischemic reperfusion and reduced brain fibrin and neutrophil deposition. Cortical neurons are protected from hypoxia/re-oxygenation-induced apoptosis. Thus, protein S and variants thereof are prototypes of a class of agents for preventing injury of the nervous system. In particular, a disease or other pathological condition (e.g., stroke) may be treated with such agents having one or more protein S activities (e.g., anti-thrombotic and anti-inflammatory activities, direct cellular neuronal protective effects) although the latter activities are not be required.
摘要翻译：蛋白S在局灶性缺血性中风后施用时是重要的神经保护剂并且防止缺氧/再氧化损伤。纯化的人血浆或重组蛋白S可改善中风后的运动神经功能，并减少脑梗塞和水肿。蛋白S还增强了缺血后再灌注并减少了脑纤维蛋白和中性粒细胞的沉积。保护皮质神经元免于缺氧/再氧化诱导的细胞凋亡。因此，蛋白质S及其变体是用于预防神经系统损伤的一类药剂的原型。特别地，可以用具有一种或多种蛋白质S活性（例如抗血栓形成和抗炎活性，直接细胞神经元保护作用）的药剂治疗疾病或其他病理学病症（例如中风），尽管后者的活性是不是必需的。

8. 发明申请

WO2013070256A2 PROTEASE ACTIVATED RECEPTOR-1 (PAR1) DERIVED CYTOPROTECTIVE POLYPEPTIDES AND RELATED METHODS 审中-公开
标题翻译：蛋白酶活化的受体-1（PAR1）衍生的细胞增殖性多肽及相关方法
公开(公告)号：WO2013070256A2
公开(公告)日：2013-05-16
申请号：PCT/US2012000546
申请日：2012-11-07
申请人： SCRIPPS RESEARCH INST , MOSNIER LAURENT O , GRIFFIN JOHN H
发明人： MOSNIER LAURENT O , GRIFFIN JOHN H
CPC分类号： C07K14/705 , A61K38/00 , A61K38/177
摘要： The present invention provides novel PAR 1derived cytoprotective oligopeptides or polypeptides which typically contain at least the first 4 N-terminal residues that are substantially identical to the corresponding N-terminal residues of Met1 -Arg46 deleted human PAR 1 sequence. These cytoprotective oligopeptides or polypeptides are capable of activating PAR 1 and promoting PAR 1 cytoprotective signaling activities. The invention also provides engineered cells or transgenic non-human animals which harbor in their genome an altered PAR 1 gene that is resistant to cleavage at Arg41 and/or Arg46 residues. Additionally provided in the invention are methods of screening candidate compounds to identity additional cytoprotective compounds or cytoprotective proteases. The invention further provides therapeutic use or methods of employing a PAR 1 derived cytoprotective oligopeptide or polypeptide to treat conditions associated with tissue injuries or undesired apoptosis.
摘要翻译：本发明提供了新的PAR1衍生的细胞保护性寡肽或多肽，其通常至少含有与Met1-Arg46缺失的人PAR1序列的相应N端残基基本相同的前4个N端残基。这些细胞保护性寡肽或多肽能够激活PAR1并促进PAR1细胞保护性信号传导活性。本发明还提供了工程改造的细胞或转基因非人动物，它们在其基因组中具有对Arg41和/或Arg46残基处的切割有抗性的改变的PAR1基因。本发明另外提供了筛选候选化合物以鉴定另外的细胞保护性化合物或细胞保护性蛋白酶的方法。本发明还提供了治疗用途或使用PAR1衍生的细胞保护性寡肽或多肽来治疗与组织损伤或不希望的细胞凋亡相关的病症的方法。

9. 发明申请

WO2008157593A3 PROTEIN C FOR USE IN MAINTAINING HEMOSTASIS 审中-公开
标题翻译：蛋白C用于维持HEMOSTASIS
公开(公告)号：WO2008157593A3
公开(公告)日：2009-03-19
申请号：PCT/US2008067321
申请日：2008-06-18
申请人： UNIV OREGON HEALTH & SCIENCE , SCRIPPS RESEARCH INST , MCCARTY OWEN J T , GRUBER ANDRAS , GRIFFIN JOHN H
发明人： MCCARTY OWEN J T , GRUBER ANDRAS , GRIFFIN JOHN H
IPC分类号： A61K38/48 , A61P7/02 , A61P7/04
CPC分类号： A61K38/4866
摘要： It is disclosed herein that protein C functions as a hemostatic agent. Thus, provided is a method of preventing, treating or ameliorating abnormal bleeding in a subject, comprising administering to the subject a protein C polypeptide or polynucleotide. Abnormal bleeding can result from a bleeding disorder, such as hemophilia or a platelet disorder, or from a bleeding episode, such as from a traumatic injury.
摘要翻译：本文公开了蛋白C作为止血剂。因此，提供了预防，治疗或改善受试者异常出血的方法，其包括对受试者施用蛋白C多肽或多核苷酸。异常出血可能是出血性疾病，如血友病或血小板疾病，或出血发作，如创伤性损伤。

10. 发明申请

WO2008055145A9 ACTIVATED PROTEIN C VARIANTS WITH NORMAL CYTOPROTECTIVE ACTIVITY BUT REDUCED ANTICOAGULANT ACTIVITY 审中-公开
标题翻译：具有正常CYTOPROTECTIVE活性的活化蛋白C变体，但降低抗血小板活性
公开(公告)号：WO2008055145A9
公开(公告)日：2008-07-31
申请号：PCT/US2007082980
申请日：2007-10-30
申请人： SCRIPPS RESEARCH INST , GRIFFIN JOHN H , MOSNIER LAURENT O , GALE ANDREW J
发明人： GRIFFIN JOHN H , MOSNIER LAURENT O , GALE ANDREW J
IPC分类号： A01N1/02 , A61K38/36 , A61K38/54
CPC分类号： A61K38/4866 , C12N9/6464 , C12Y304/21069
摘要： Variants (mutants) of recombinant activated protein C (APC) or recombinant protein C (prodrug, capable of being converted to APC) that have substantial reductions in anticoagulant activity but that retain normal levels of anti-apoptotic activity are provided. Three examples of such recombinant APC mutants are KKK191-193AAA-APC, RR229/230AA-APC, and RR229/230AA plus KKK191-193AAA-APC. APC variants and prodrugs of the invention have the desirable property of being cytoprotective (anti-apoptotic effects), while having significantly reduced risk of bleeding. The invention also provides a method of using the APC variants or prodrugs of the invention to treat subjects who will benefit from APC's cytoprotective activities that are independent of APC's anticoagulant activity. These subjects include patients at risk of damage to blood vessels or tissue in various organs caused, at least in part, by apoptosis. At risk patients include, for example, those suffering (severe) sepsis, ischemia/reperfusion injury, ischemic stroke, acute myocardial infarction, acute or chronic neurodegenerative diseases, or those undergoing organ transplantation or chemotherapy, among other conditions. Methods of screening for variants of recombinant protein C or APC that are useful in accordance with the invention are also provided.
摘要翻译：提供重组活化蛋白C（APC）或重组蛋白C（前体药物，能够转化为APC）的变体（突变体），其具有显着降低抗凝活性，但保持正常水平的抗凋亡活性。这些重组APC突变体的三个实例是KKK191-193AAA-APC，RR229 / 230AA-APC和RR229 / 230AA加上KKK191-193AAA-APC。本发明的APC变体和前药具有细胞保护性（抗凋亡作用）的期望性质，同时具有显着降低的出血风险。本发明还提供了使用本发明的APC变体或前药来治疗受益于APC的细胞保护活性而不受APC抗凝活性影响的受试者的方法。这些受试者包括至少部分地通过细胞凋亡导致各种器官的血管损伤或组织损伤的患者。在危险中，患者包括例如患有（严重）败血症，缺血/再灌注损伤，缺血性卒中，急性心肌梗死，急性或慢性神经变性疾病或经历器官移植或化疗的患者等。还提供了筛选根据本发明有用的重组蛋白C或APC的变体的方法。

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