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1. 发明授权

US08828939B2 Modified vitamin K dependent polypeptides 有权
标题翻译：改良的维生素K依赖多肽
公开(公告)号：US08828939B2
公开(公告)日：2014-09-09
申请号：US11632552
申请日：2005-08-10
申请人： Thomas Weimer , Stefan Schulte , Kay Hofmann , Hans-Peter Hauser
发明人： Thomas Weimer , Stefan Schulte , Kay Hofmann , Hans-Peter Hauser
IPC分类号： A61K38/36 , C07K14/745 , C12N15/62 , C12N9/64
CPC分类号： C12N15/62 , C12N9/6424
摘要： The present invention relates to modified cDNA sequences coding for vitamin K-dependent polypeptides, in particular human Factor VII, human Factor VIIa, human Factor IX and human protein C and their derivatives with improved stability and extended plasma half life, recombinant expression vectors containing such cDNA sequences, host cells transformed with such recombinant expression vectors, recombinant polypeptides and derivatives which do have biological activities of the unmodified wild type protein but having improved stability and processes for the manufacture of such recombinant proteins and their derivatives. The invention also covers a transfer vector for use in human gene therapy, which comprises such modified DNA sequences.
摘要翻译：本发明涉及编码维生素K依赖多肽，特别是人因子VII，人因子VIIa，人因子IX和人蛋白C及其衍生物的修饰cDNA序列，其具有改善的稳定性和延长的血浆半衰期，含有这样的重组表达载体 cDNA序列，用这种重组表达载体转化的宿主细胞，确实具有未修饰的野生型蛋白质的生物活性但具有改进的稳定性的生物活性的重组多肽和衍生物，以及制备这些重组蛋白及其衍生物的方法。本发明还涵盖用于人基因治疗的转移载体，其包含这种修饰的DNA序列。

2. 发明申请

US20090130060A1 Modified Vitamin K Dependent Polypeptides 有权
标题翻译：修饰维生素K依赖性多肽
公开(公告)号：US20090130060A1
公开(公告)日：2009-05-21
申请号：US11632552
申请日：2005-08-10
申请人： Thomas Weimer , Stefan Schulte , Kay Hofmann , Hans-Peter Hauser
发明人： Thomas Weimer , Stefan Schulte , Kay Hofmann , Hans-Peter Hauser
IPC分类号： A61K35/74 , C07K1/00 , C07K14/00 , C12N9/50 , C12N15/11 , C12N15/00 , C12N1/21 , C12P21/04 , A61K38/16 , A61K31/7088
CPC分类号： C12N15/62 , C12N9/6424
摘要： The present invention relates to modified cDNA sequences coding for vitamin K-dependent polypeptides, in particular human Factor VII, human Factor VIIa, human Factor IX and human protein C and their derivatives with improved stability and extended plasma half life, recombinant expression vectors containing such cDNA sequences, host cells transformed with such recombinant expression vectors, recombinant polypeptides and derivatives which do have biological activities of the unmodified wild type protein but having improved stability and processes for the manufacture of such recombinant proteins and their derivatives. The invention also covers a transfer vector for use in human gene therapy, which comprises such modified DNA sequences.
摘要翻译：本发明涉及编码维生素K依赖多肽，特别是人因子VII，人因子VIIa，人因子IX和人蛋白C及其衍生物的修饰cDNA序列，其具有改善的稳定性和延长的血浆半衰期，含有这样的重组表达载体 cDNA序列，用这种重组表达载体转化的宿主细胞，确实具有未修饰的野生型蛋白质的生物活性但具有改进的稳定性的生物活性的重组多肽和衍生物，以及制备这些重组蛋白及其衍生物的方法。本发明还涵盖用于人基因治疗的转移载体，其包含这种修饰的DNA序列。

3. 发明申请

US20090175828A1 Coagulation Factor X Polypeptides With Modified Activation Properties 有权
标题翻译：凝血因子X多肽具有改良的激活特性
公开(公告)号：US20090175828A1
公开(公告)日：2009-07-09
申请号：US12224182
申请日：2007-02-19
申请人： Stefan Schulte , Hans-Peter Hauser , Uwe Kalina , Thomas Weimer
发明人： Stefan Schulte , Hans-Peter Hauser , Uwe Kalina , Thomas Weimer
IPC分类号： A61K38/36 , C07K14/745 , C12N15/12 , C12N15/63 , C12N5/10 , C12P21/00 , A61P7/02
CPC分类号： C12N9/647 , A61K38/012 , A61K38/36 , C12N9/6432 , C12Y304/21006
摘要： The present invention relates to modified cDNA sequences coding for factor X polypeptides, in particular human factor X and its derivatives which can bypass the need for either factor VIIIa/factor IXa or factor VIIa/tissue factor for activation. The invention relates further to recombinant expression vectors containing such modified cDNA sequences, host cells transformed with such recombinant expression vectors, recombinant polypeptides and derivatives which do have biological activities of the unmodified wild type protein but having altered activation properties, and processes for the manufacture of such recombinant proteins and their derivatives. The invention also covers a transfer vector for use in human gene therapy, which comprises such modified DNA sequences.
摘要翻译：本发明涉及编码因子X多肽，特别是人因子X及其衍生物的修饰的cDNA序列，其可以绕过对因子VIIIa /因子IXa或因子VIIa /组织因子进行活化的需要。本发明还涉及含有这种修饰的cDNA序列的重组表达载体，用这种重组表达载体转化的宿主细胞，确实具有未修饰的野生型蛋白的生物活性但具有改变的活化性质的重组多肽和衍生物，以及制备这些重组蛋白及其衍生物。本发明还涵盖用于人基因治疗的转移载体，其包含这种修饰的DNA序列。

4. 发明申请

US20090053185A1 Coagulation factor x polypeptides with modified activation properties 有权
标题翻译：凝血因子x多肽具有修饰的活化特性
公开(公告)号：US20090053185A1
公开(公告)日：2009-02-26
申请号：US11921399
申请日：2006-05-30
申请人： Stefan Schulte , Hans-Peter Hauser , Uwe Kalina , Thomas Weimer
发明人： Stefan Schulte , Hans-Peter Hauser , Uwe Kalina , Thomas Weimer
IPC分类号： A61K48/00 , C07K2/00 , C07H21/04 , C12N15/63 , C12N5/00 , C12P21/06 , A61K38/00 , A61K31/7088
CPC分类号： C12N9/6432 , C12Y304/21006
摘要： The present invention relates to modified cDNA sequences coding for human Factor X and their derivatives with improved stability and modified activation sequences, recombinant expression vectors containing such cDNA sequences, and host cells transformed with such recombinant expression vectors. The invention also relates to recombinant factor X polypeptides and derivatives which have biological activities of the unmodified wild type protein but with improved stability and processes for the manufacture of such recombinant proteins and their derivatives. The invention also covers a transfer vector for use in human gene therapy, which comprises such modified DNA.
摘要翻译：本发明涉及编码具有改善的稳定性和修饰的活化序列的人因子X及其衍生物的修饰的cDNA序列，含有此类cDNA序列的重组表达载体和用这些重组表达载体转化的宿主细胞。本发明还涉及具有未修饰的野生型蛋白的生物活性但具有改进的稳定性的重组因子X多肽和衍生物，以及用于制备这些重组蛋白及其衍生物的方法。本发明还涵盖用于人基因治疗的转移载体，其包含这种修饰的DNA。

5. 发明授权

US09347051B2 Coagulation factor X polypeptides with modified activation properties 有权
标题翻译：具有改变的活化特性的凝血因子X多肽
公开(公告)号：US09347051B2
公开(公告)日：2016-05-24
申请号：US12224182
申请日：2007-02-19
申请人： Stefan Schulte , Hans-Peter Hauser , Uwe Kalina , Thomas Weimer
发明人： Stefan Schulte , Hans-Peter Hauser , Uwe Kalina , Thomas Weimer
IPC分类号： C07K19/00 , C07K4/12 , C07K14/745 , C12N9/64 , A61K38/01 , A61K38/36
CPC分类号： C12N9/647 , A61K38/012 , A61K38/36 , C12N9/6432 , C12Y304/21006
摘要： The present invention relates to modified cDNA sequences coding for factor X polypeptides, in particular human factor X and its derivatives which can bypass the need for either factor VIIIa/factor IXa or factor VIIa/tissue factor for activation. The invention relates further to recombinant expression vectors containing such modified cDNA sequences, host cells transformed with such recombinant expression vectors, recombinant polypeptides and derivatives which do have biological activities of the unmodified wild type protein but having altered activation properties, and processes for the manufacture of such recombinant proteins and their derivatives. The invention also covers a transfer vector for use in human gene therapy, which comprises such modified DNA sequences.
摘要翻译：本发明涉及编码因子X多肽，特别是人因子X及其衍生物的修饰的cDNA序列，其可以绕过对因子VIIIa /因子IXa或因子VIIa /组织因子进行活化的需要。本发明还涉及含有这种修饰的cDNA序列的重组表达载体，用这种重组表达载体转化的宿主细胞，确实具有未修饰的野生型蛋白的生物活性但具有改变的活化性质的重组多肽和衍生物，以及制备这些重组蛋白及其衍生物。本发明还涵盖用于人基因治疗的转移载体，其包含这种修饰的DNA序列。

6. 发明授权

US09249404B2 Coagulation factor X polypeptides with modified activation properties 有权
标题翻译：具有改变的活化特性的凝血因子X多肽
公开(公告)号：US09249404B2
公开(公告)日：2016-02-02
申请号：US11921399
申请日：2006-05-30
申请人： Stefan Schulte , Hans-Peter Hauser , Uwe Kalina , Thomas Weimer
发明人： Stefan Schulte , Hans-Peter Hauser , Uwe Kalina , Thomas Weimer
IPC分类号： C12N9/64 , C12N15/57 , A61K38/48
CPC分类号： C12N9/6432 , C12Y304/21006
摘要： The present invention relates to modified cDNA sequences coding for human Factor X and their derivatives with improved stability and modified activation sequences, recombinant expression vectors containing such cDNA sequences, and host cells transformed with such recombinant expression vectors. The invention also relates to recombinant factor X polypeptides and derivatives which have biological activities of the unmodified wild type protein but with improved stability and processes for the manufacture of such recombinant proteins and their derivatives. The invention also covers a transfer vector for use in human gene therapy, which comprises such modified DNA.
摘要翻译：本发明涉及编码具有改善的稳定性和修饰的活化序列的人因子X及其衍生物的修饰cDNA序列，含有此类cDNA序列的重组表达载体和用这些重组表达载体转化的宿主细胞。本发明还涉及具有未修饰的野生型蛋白的生物活性但具有改进的稳定性的重组因子X多肽和衍生物，以及用于制备这些重组蛋白及其衍生物的方法。本发明还涵盖用于人基因治疗的转移载体，其包含这种修饰的DNA。

7. 发明申请

US20100279923A1 THERAPEUTIC APPLICATION OF KAZAL-TYPE SERINE PROTEASE INHIBITORS 有权
标题翻译：卡氏型丝氨酸蛋白酶抑制剂的治疗应用
公开(公告)号：US20100279923A1
公开(公告)日：2010-11-04
申请号：US12526758
申请日：2008-02-11
申请人： Stefan Schulte , Ulrich Kronthaler , Stefan Schmidbauer , Thomas Weimer , Kay Hofmann
发明人： Stefan Schulte , Ulrich Kronthaler , Stefan Schmidbauer , Thomas Weimer , Kay Hofmann
IPC分类号： A61K38/55 , C07K14/00 , C07K14/76 , C07K16/00 , A61P5/00 , A61P35/00 , A61P9/00 , A61P9/10 , C12P21/06
CPC分类号： C07K14/8135 , A61K38/00 , A61K47/64 , A61K47/643
摘要： The subject of the present invention is, in the most general aspect, the therapeutic application of the Kazal-type serine protease inhibitor Infestin or domains thereof or modified Kazal-type serine protease inhibitors based on Infestin homologs, which prevent the formation and/or stabilization of three-dimensional arterial or venous thrombi by interfering with proteins involved in activation of the so-called intrinsic coagulation pathway. In particular the present invention relates to the use of said Kazal-type serine protease inhibitors or fragments thereof or modified Kazal-type serine protease inhibitors, in the treatment or prophylaxis of a condition or disorder related to arterial thrombus formation, i. e. stroke or myocardial infarction, inflammation, complement activation, fibrinolysis, angiogenesis and/or diseases linked to pathological kinin formation such as hypotonic shock, edema including hereditary angioedema, bacterial infections, arthritis, pancreatitis, or articular gout, Disseminated Intravasal Coagulation (DIC) and sepsis.
摘要翻译：本发明的主题在最一般的方面是基于Infestin同系物的Kazal型丝氨酸蛋白酶抑制剂Infestin或其结构域或修饰的Kazal型丝氨酸蛋白酶抑制剂的治疗应用，其防止形成和/或稳定化通过干扰参与所谓的内在凝血途径的激活的蛋白质的三维动脉或静脉血栓。特别地，本发明涉及所述Kazal型丝氨酸蛋白酶抑制剂或其片段或修饰的Kazal型丝氨酸蛋白酶抑制剂在治疗或预防与动脉血栓形成相关的病症或障碍中的用途， e。中风或心肌梗塞，炎症，补体激活，纤维蛋白溶解，血管生成和/或与病理激肽形成相关的疾病，例如低渗休克，包括遗传性血管性水肿，细菌感染，关节炎，胰腺炎或关节痛风的水肿，弥散性内皮内凝血（DIC）和败血症

8. 发明授权

US08283319B2 Therapeutic application of Kazal-type serine protease inhibitors 有权
标题翻译： Kazal型丝氨酸蛋白酶抑制剂的治疗应用
公开(公告)号：US08283319B2
公开(公告)日：2012-10-09
申请号：US12526758
申请日：2008-02-11
申请人： Stefan Schulte , Ulrich Kronthaler , Stefan Schmidbauer , Thomas Weimer , Kay Hofmann
发明人： Stefan Schulte , Ulrich Kronthaler , Stefan Schmidbauer , Thomas Weimer , Kay Hofmann
IPC分类号： A61K38/16 , C07K14/00
CPC分类号： C07K14/8135 , A61K38/00 , A61K47/64 , A61K47/643
摘要： The present invention relates to the therapeutic application of the Kazal-type serine protease inhibitor Infestin or domains thereof or modified Kazal-type serine protease inhibitors based on Infestin homologs, which prevent the formation and/or stabilization of three-dimensional arterial or venous thrombi by interfering with proteins involved in activation of the so-called intrinsic coagulation pathway. The present invention also relates to the use of Kazal-type serine protease inhibitors or fragments thereof or modified Kazal-type serine protease inhibitors in the treatment or prophylaxis of a condition or disorder related to arterial thrombus formation, i.e. stroke or myocardial infarction, inflammation, complement activation, fibrinolysis, angiogenesis and/or diseases linked to pathological kinin formation such as hypotonic shock, edema including hereditary angioedema, bacterial infections, arthritis, pancreatitis, or articular gout, Disseminated Intravasal Coagulation (DIC) and sepsis.
摘要翻译：本发明涉及基于Infestin同系物的Kazal型丝氨酸蛋白酶抑制剂Infestin或其结构域或修饰的Kazal型丝氨酸蛋白酶抑制剂的治疗应用，其防止三维动脉或静脉血栓的形成和/或稳定化干扰参与所谓的内在凝血途径活化的蛋白质。本发明还涉及Kazal型丝氨酸蛋白酶抑制剂或其片段或修饰的Kazal型丝氨酸蛋白酶抑制剂在治疗或预防与动脉血栓形成有关的病症或障碍的应用，即中风或心肌梗塞，炎症，补体活化，纤维蛋白溶解，血管发生和/或与病理激肽形成相关的疾病，如低渗休克，水肿，包括遗传性血管性水肿，细菌感染，关节炎，胰腺炎或关节痛风，弥散性内皮内凝血（DIC）和败血症。

9. 发明申请

US20100120664A1 MODIFIED COAGULATION FACTORS WITH PROLONGED IN VIVO HALF-LIFE 有权
标题翻译：改良的凝血因子与生殖健康生活息息相关
公开(公告)号：US20100120664A1
公开(公告)日：2010-05-13
申请号：US12520840
申请日：2007-12-21
申请人： Stefan Schulte , Thomas Weimer , Hubert Metzner
发明人： Stefan Schulte , Thomas Weimer , Hubert Metzner
IPC分类号： A61K38/16 , C07K14/745 , C07K14/755 , C07H21/00 , C12N15/74 , C12N5/10 , C12P21/00 , A61P7/04
CPC分类号： C07K14/755 , C07K14/745 , C07K14/765 , C07K16/18 , C07K2319/31
摘要： The present invention relates to nucleic acid sequences coding for modified coagulation factors, preferably coagulation factor VIII, and their derivatives; recombinant expression vectors containing such nucleic acid sequences; host cells transformed with such recombinant expression vectors; and recombinant polypeptides and derivatives coded for by said nucleic acid sequences, whereby said recombinant polypeptides and derivatives have biological activities and prolonged in vivo half-lives compared to the unmodified wild-type proteins. The invention also relates to corresponding sequences that result in improved in vitro stability. The present invention further relates to processes for the manufacture of such recombinant proteins and their derivatives. The invention also relates to a transfer vector for use in human gene therapy, which comprises such nucleic acid sequences.
摘要翻译：本发明涉及编码改性凝血因子，优选凝血因子VIII及其衍生物的核酸序列; 含有该核酸序列的重组表达载体; 用这些重组表达载体转化的宿主细胞; 和由所述核酸序列编码的重组多肽和衍生物，其中与未修饰的野生型蛋白相比，所述重组多肽和衍生物具有生物学活性和延长的体内半衰期。本发明还涉及导致体外稳定性改善的相应序列。本发明还涉及制备这些重组蛋白及其衍生物的方法。本发明还涉及用于人基因治疗的转移载体，其包含这样的核酸序列。

10. 发明申请

US20080260755A1 Proteolytically cleavable fusion proteins with high molar specific activity 有权
标题翻译：具有高摩尔比活性的蛋白水解切割融合蛋白
公开(公告)号：US20080260755A1
公开(公告)日：2008-10-23
申请号：US12000739
申请日：2007-12-17
申请人： Hubert Metzner , Thomas Weimer , Stefan Schulte
发明人： Hubert Metzner , Thomas Weimer , Stefan Schulte
IPC分类号： A61K39/395 , C07K16/18 , C07K14/00 , C12N15/11 , A61K31/70 , A61P7/00 , A61K38/00 , C12N15/00 , C12N5/06 , C12P21/04
CPC分类号： C12N9/6437 , A61K38/00 , A61K48/00 , C07K14/745 , C07K14/755 , C07K14/76 , C07K14/765 , C07K2319/31 , C07K2319/50 , C12N9/6424 , C12N9/6443 , C12N9/6472 , C12Y304/21021 , C12Y304/21022
摘要： The invention relates to therapeutic fusion proteins in which a coagulation factor is fused to a half-life enhancing polypeptide, and in which both are connected by a linker peptide that is proteolytically cleavable. The cleavage of such linkers liberates the coagulation factor from activity-compromising steric hindrance caused by the half-life enhancing polypeptide and thereby allows the generation of fusion proteins may show relatively high molar specific activity when tested in coagulation-related assays. Furthermore, the fact that the linker is cleavable can enhance the rates of inactivation and/or elimination after proteolytic cleavage of the peptide linker compared to the rates measured for corresponding therapeutic fusion proteins linked by the non-cleavable linker having the amino acid sequence GGGGGGV.
摘要翻译：本发明涉及治疗融合蛋白，其中凝血因子与半衰期增强多肽融合，并且其中两者通过可蛋白水解切割的接头肽连接。这种接头的切割将凝血因子从半衰期增强多肽引起的活性损害的空间位阻释放，从而允许融合蛋白的产生在凝血相关测定中测试时可显示相对高的摩尔比活性。此外，与通过具有氨基酸序列GGGGGGV的不可切割接头连接的相应治疗性融合蛋白测量的速率相比，接头可切割的事实可增加肽接头的蛋白水解切割后的失活和/或消除速率。

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