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1. 发明授权

US06423333B1 Sealing or filling tissue defects using polyfunctional crosslinking agents and protein polymers 失效
标题翻译：使用多官能交联剂和蛋白质聚合物密封或填充组织缺陷
公开(公告)号：US06423333B1
公开(公告)日：2002-07-23
申请号：US09451206
申请日：1999-11-29
申请人： Erwin R. Stedronsky , Joseph Cappello
发明人： Erwin R. Stedronsky , Joseph Cappello
IPC分类号： A61K31785
CPC分类号： A61L27/227 , A61K38/00 , A61L24/106 , A61L24/108 , C07K14/001 , Y10S530/81
摘要： Proteinaceous polymers having repetitive units from naturally occurring structural proteins are employed as backbones for functionalities for crosslinking to provide strongly adherent tissue adhesive compositions for bonding together separated tissue, and for sealing or filling tissue defects by injecting the compositions into the defects. Particularly, block copolymers having repeating units of elastin and fibroin are employed having lysine substitutions in spaced apart units, where the amino group can be crosslinked using difunctional crosslinking agents such as glutaraldehyde, activated diolefins, diisocyanates, acid anhydrides or diamines. The protein polymer contains at least 40 weight percent of repetitive units of 3 to 30 amino acids, preferably 3 to 15 amino acids, of at least one naturally occurring structural protein and at least two amino acids containing a functional group capable of reacting with the crosslinking agent. The protein polymer generally has a molecular weight of at least about 30 kD and not more than 250 kD. A preferred protein polymer contains at least 70 weight percent of repetitive units of Gly-Ala-Gly-Ala-Gly-Ser and Gly-Val-Gly-Val-Pro, where in at least two units an amino acid is substituted with one of lysine or arginine, and the protein polymer has a lysine and arginine equivalent weight in the range of 1 to 20 kD and contains at least two amino acids having a functional group capable of reacting with at least one of aldehyde, isocyanate, thioisocyanate and activated carboxy. The protein polymer is produced by recombinant DNA technology, and a kit may be formed containing the crosslinking agent and protein polymer.
摘要翻译：具有来自天然存在的结构蛋白质的重复单元的蛋白质聚合物用作用于交联的官能团的主链，以提供用于将分离的组织粘合在一起的强粘附组织粘合剂组合物，以及通过将组合物注入缺陷中来密封或填充组织缺陷。特别地，使用具有弹性蛋白和丝心蛋白重复单元的嵌段共聚物，其间隔开的单元具有赖氨酸取代，其中氨基可以使用双功能交联剂如戊二醛，活化的二烯烃，二异氰酸酯，酸酐或二胺进行交联。蛋白质聚合物含有至少40重量％的3至30个氨基酸，优选3至15个氨基酸的至少一种天然存在的结构蛋白的重复单元和至少两个含有能够与交联反应的官能团的氨基酸代理商蛋白质聚合物通常具有至少约30kD且不超过250kD的分子量。优选的蛋白质聚合物含有至少70重量％的Gly-Ala-Gly-Ala-Gly-Ser和Gly-Val-Gly-Val-Pro的重复单元，其中在至少两个单元中氨基酸被赖氨酸或精氨酸，并且蛋白质聚合物的赖氨酸和精氨酸当量的重量在1至20kD的范围内并且包含至少两个具有能够与醛，异氰酸酯，硫代异氰酸酯和活化羧基中的至少一种反应的官能团的氨基酸。蛋白质聚合物通过重组DNA技术生产，并且可以形成含有交联剂和蛋白质聚合物的试剂盒。

2. 发明授权

US5817303A Bonding together tissue with adhesive containing polyfunctional crosslinking agent and protein polymer 失效
标题翻译：用含多官能交联剂和蛋白质聚合物的粘合剂将组织粘合在一起
公开(公告)号：US5817303A
公开(公告)日：1998-10-06
申请号：US435641
申请日：1995-05-05
申请人： Erwin R. Stedronsky , Joseph Cappello
发明人： Erwin R. Stedronsky , Joseph Cappello
IPC分类号： A61K38/00 , A61L24/10 , A61P17/00 , C07K5/117 , C07K7/06 , C07K14/00 , C12N5/02 , A61K31/785 , A01N37/18 , C07K1/00 , C12N11/00
CPC分类号： A61L27/227 , A61L24/106 , A61L24/108 , C07K14/001 , A61K38/00 , Y10S530/81
摘要： Proteinaceous polymers having repetitive units from naturally occurring structural proteins are employed as backbones for functionalities for crosslinking to provide strongly adherent tissue adhesives and sealants. Particularly, block copolymers having repeating units of elastin and fibroin are employed having lysine substitutions in spaced apart units, where the amino group can be crosslinked using difunctional crosslinking agents. The protein polymer contains at least 40 weight percent of repetitive units of 3 to 15 amino acids of at least one naturally occurring protein and in at least two units an amino acid is substituted by an amino acid containing a functional group capable of reacting with a crosslinking agent to form a strongly adherent adhesive composition for bonding together separated tissue or for sealing tissue defects. A preferred adhesive composition contains glutaraldehyde or polymethylene diisocyanate and a protein block copolymer of at least 30 kD containing at least 70 weight percent of repetitive units of Gly-Ala-Gly-Ala-Gly-Ser and Gly-Val-Gly-Val-Pro, where in at least two units an amino acid is substituted with lysine and the copolymer has a lysine equivalent weight in the range of 1 to 20 kD. The protein polymer is produced by recombinant DNA technology, and a kit can be formed containing the crosslinking agent and protein polymer.
摘要翻译：具有来自天然存在的结构蛋白质的重复单元的蛋白质聚合物用作用于交联的功能的主链，以提供强烈粘附的组织粘合剂和密封剂。特别地，使用具有弹性蛋白和丝心蛋白重复单元的嵌段共聚物，其间隔开的单元具有赖氨酸取代，其中氨基可以使用双功能交联剂进行交联。蛋白质聚合物含有至少40重量％的至少一种天然蛋白质的3至15个氨基酸的重复单元，并且在至少两个单元中氨基酸被含有能够与交联反应的官能团的氨基酸取代以形成用于将分离的组织粘合在一起或用于密封组织缺陷的强粘附性粘合剂组合物。优选的粘合剂组合物包含戊二醛或聚亚甲基二异氰酸酯和至少30kD的蛋白质嵌段共聚物，其含有至少70重量％的Gly-Ala-Gly-Ala-Gly-Ser和Gly-Val-Gly-Val-Pro的重复单元其中在至少两个单元中氨基酸被赖氨酸取代，并且所述共聚物的赖氨酸当量重量在1至20kD的范围内。通过重组DNA技术生产蛋白质聚合物，并且可以形成含有交联剂和蛋白质聚合物的试剂盒。

3. 发明申请

US20090028813A1 Methods for Treating Body Tissue 审中-公开
标题翻译：治疗身体组织的方法
公开(公告)号：US20090028813A1
公开(公告)日：2009-01-29
申请号：US11877572
申请日：2007-10-23
申请人： Erwin R. Stedronsky , Joseph Cappello
发明人： Erwin R. Stedronsky , Joseph Cappello
IPC分类号： A61K31/74 , A61P17/02 , A61P41/00
CPC分类号： A61L27/227 , A61K38/00 , A61L24/106 , A61L24/108 , C07K14/001 , Y10S530/81
摘要： Methods of treating body tissue including repairing defects in body tissue as well as augmenting body tissue. Body tissue defects are repaired by injecting a polymeric adhesive composition through an injector into the region of the defect and allowing the adhesive composition to cure to repair the defect or to form an implant that adheres to at least one surface tissue in the region of the defect. Body tissue is augmented by filling a defect void with a polymeric adhesive composition and allowing it to cure.
摘要翻译：治疗身体组织的方法，包括修复身体组织中的缺陷以及增加身体组织。通过将聚合物粘合剂组合物通过注射器注射到缺陷的区域中并使粘合剂组合物固化以修复缺陷或形成粘附于缺陷区域中的至少一个表面组织的植入物来修复身体组织缺陷。通过用聚合物粘合剂组合物填充缺陷空隙并使其固化来增加身体组织。

4. 发明授权

US06380154B1 Synthetic proteins for in vivo drug delivery and tissue augmentation 失效
标题翻译：用于体内药物递送和组织增生的合成蛋白质
公开(公告)号：US06380154B1
公开(公告)日：2002-04-30
申请号：US08806029
申请日：1997-02-24
申请人： Joseph Cappello , Erwin R. Stedronsky
发明人： Joseph Cappello , Erwin R. Stedronsky
IPC分类号： C07K706
CPC分类号： D01F4/00 , A61K38/00 , A61L17/10 , A61L27/227 , A61L31/047 , C07K14/00 , C07K14/78 , C07K2319/00 , C07K2319/02 , C07K2319/61 , C08J5/18 , C08J2389/00 , C12N15/11
摘要： Method and compositions are provided which are useful for delivering a biologically active substance to a localized site in vivo and for altering the physical dimensions of a body tissue. These method and compositions employ protein polymers having varying ratios of elastin-like collagen-like, keratin-like repeating units and repeating units which promote protein crystallization such as silk-like repeating units. By varying the length of segments of the repeating units and/or the concentration of the protein polymers in the composition, the rate of delivery of a biologically active substance to a localized site can be greatly varied. Moreover, because the compositions are capable of acquiring a non-liquid form under normal physiological conditions, they find use as biocompatible tissue augmentation products.
摘要翻译：提供了可用于将生物活性物质递送至体内局部位点并改变身体组织的物理尺寸的方法和组合物。这些方法和组合物使用具有弹性蛋白样胶原样，角蛋白样重复单元和促进蛋白质结晶的重复单元比例如丝状重复单元的蛋白质聚合物。通过改变组合物中重复单元的片段长度和/或蛋白质聚合物的浓度，可以极大地改变生物活性物质向局部位点递送的速度。此外，由于组合物能够在正常生理条件下获得非液体形式，因此它们可用作生物相容性组织增强产品。

5. 发明授权

US07300663B2 Adhesion and sealing of tissue with compositions containing polyfunctional crosslinking agents and protein polymers 失效
标题翻译：含有多官能交联剂和蛋白质聚合物的组合物与组织的粘附和密封
公开(公告)号：US07300663B2
公开(公告)日：2007-11-27
申请号：US10117931
申请日：2002-04-05
申请人： Erwin R. Stedronsky , Joseph Cappello
发明人： Erwin R. Stedronsky , Joseph Cappello
IPC分类号： A61L24/00 , A61K31/785 , C08L89/00 , A61F2/00 , C07K1/00 , C12N11/00
CPC分类号： A61L27/227 , A61K38/00 , A61L24/106 , A61L24/108 , C07K14/001 , Y10S530/81
摘要： Proteinaceous polymers having repetitive units from naturally occurring structural proteins are employed as backbones for functionalities for crosslinking to provide strongly adherent tissue adhesives and sealants. Particularly, block copolymers of elastin and fibroin are employed having lysine substitutions in spaced apart units, where the amino group can be crosslinked using difunctional crosslinking agents.
摘要翻译：具有来自天然存在的结构蛋白质的重复单元的蛋白质聚合物用作用于交联的功能的主链，以提供强烈粘附的组织粘合剂和密封剂。特别地，使用弹性蛋白和丝心蛋白的嵌段共聚物，其间隔开的单元具有赖氨酸取代，其中氨基可以使用双功能交联剂进行交联。

6. 发明授权

US6033654A Bonding together tissue with adhesive containing polyfunctional crosslinking agent and protein polymer 失效
标题翻译：用含多官能交联剂和蛋白质聚合物的粘合剂将组织粘合在一起
公开(公告)号：US6033654A
公开(公告)日：2000-03-07
申请号：US642246
申请日：1996-05-02
申请人： Erwin R. Stedronsky , Joseph Cappello
发明人： Erwin R. Stedronsky , Joseph Cappello
IPC分类号： A61K38/00 , A61L24/10 , A61P17/00 , C07K5/117 , C07K7/06 , C07K14/00 , C12N5/02 , A61K31/785 , A01N37/18 , C07K1/00 , C12N11/00
CPC分类号： A61L27/227 , A61L24/106 , A61L24/108 , C07K14/001 , A61K38/00 , Y10S530/81
摘要： Proteinaceous polymers having repetitive units from naturally occurring structural proteins are employed as backbones for functionalities for crosslinking to provide strongly adherent tissue adhesives and sealants. Particularly, block copolymers having repeating units of elastin and fibroin are employed having lysine substitutions in spaced apart units, where the amino group can be crosslinked using difunctional crosslinking agents. The protein polymer contains at least 40 weight percent of repetitive units of 3 to 30 amino acids of at least one naturally occurring structural protein and at least two functional groups capable of reacting with a crosslinking agent to form a strongly adherent adhesive composition for bonding together separated tissue or for sealing tissue defects. A preferred adhesive composition contains glutaraldehyde or polymethylene diisocyanate and a protein block copolymer of at least 30 kD containing at least 70 weight percent of repetitive units of Gly-Ala-Gly-Ala-Gly-Ser and Gly-Val-Gly-Val-Pro, where in at least two units an amino acid is substituted with one of lysine or arginine, and the copolymer has a lysine and arginine equivalent weight in the range of 3 to 15 kD. The protein polymer is produced by recombinant DNA technology, and a kit may be formed containing the crosslinking agent and protein polymer.
摘要翻译：具有来自天然存在的结构蛋白质的重复单元的蛋白质聚合物用作用于交联的功能的主链，以提供强烈粘附的组织粘合剂和密封剂。特别地，使用具有弹性蛋白和丝心蛋白重复单元的嵌段共聚物，其间隔开的单元具有赖氨酸取代，其中氨基可以使用双功能交联剂进行交联。蛋白质聚合物含有至少40重量％的至少一种天然存在的结构蛋白质的3至30个氨基酸的重复单元和至少两个能够与交联剂反应以形成强粘附性粘合剂组合物的官能团，用于将分离的组织或用于密封组织缺陷。优选的粘合剂组合物包含戊二醛或聚亚甲基二异氰酸酯和至少30kD的蛋白质嵌段共聚物，其含有至少70重量％的Gly-Ala-Gly-Ala-Gly-Ser和Gly-Val-Gly-Val-Pro的重复单元其中在至少两个单元中氨基酸被赖氨酸或精氨酸之一取代，并且所述共聚物的赖氨酸和精氨酸当量的重量在3至15kD的范围内。蛋白质聚合物通过重组DNA技术生产，并且可以形成含有交联剂和蛋白质聚合物的试剂盒。

7. 发明授权

US5514581A Functional recombinantly prepared synthetic protein polymer 失效
公开(公告)号：US5514581A
公开(公告)日：1996-05-07
申请号：US609716
申请日：1990-11-06
申请人： Franco A. Ferrari , Joseph Cappello
发明人： Franco A. Ferrari , Joseph Cappello
IPC分类号： A61L17/00 , A61L29/04 , C07K14/00 , C07K14/435 , C07K14/78 , C07K17/08 , C12N1/06 , C12N5/00 , C12N15/11 , C12N15/62 , C12N15/66 , C12N15/70 , C12N15/75 , G03C1/047 , C12N1/21 , C12N15/12
CPC分类号： A61L17/00 , A61L29/049 , C07K14/00 , C07K14/43586 , C07K14/78 , C07K17/08 , C12N1/06 , C12N15/11 , C12N15/62 , C12N15/66 , C12N15/70 , C12N15/75 , C12N5/0068 , C07K2319/00 , C07K2319/02 , C07K2319/33 , C07K2319/61 , C12N2533/30 , C12N2533/52 , G03C1/047
摘要： Novel polymers are provided which are produced by recombinant techniques. The polymers are characterized by having a small repeating sequence which provides for strands capable of associating, resulting in useful structural characteristics, where the strands are joined by turns or loops which are flexible and available for interaction with the environment. Specifically, repeating groups of naturally occurring proteins such as silk are modified by introduction of an amino-acid sequence at a site which provides for a turn between strands to provide for readily available oligopeptides capable of interacting with molecules in the environment.

8. 发明授权

US6018030A Peptides comprising repetitive units of amino acids and DNA sequences encoding the same 失效
标题翻译：包含氨基酸重复单元和编码氨基酸的DNA序列的肽
公开(公告)号：US6018030A
公开(公告)日：2000-01-25
申请号：US482085
申请日：1995-06-07
申请人： Franco A. Ferrari , Charles Richardson , James Chambers , Stuart Causey , Thomas J. Pollock , Joseph Cappello , John W. Crissman
发明人： Franco A. Ferrari , Charles Richardson , James Chambers , Stuart Causey , Thomas J. Pollock , Joseph Cappello , John W. Crissman
IPC分类号： C07K14/435 , C07K14/78 , C12N1/06 , C12N15/11 , C12N15/62 , C12N15/70 , C12N15/75 , A61K38/17 , C07H21/04 , C12N5/00
CPC分类号： C07K14/43586 , C07K14/78 , C12N1/06 , C12N15/11 , C12N15/62 , C12N15/66 , C12N15/70 , C12N15/75 , C07K2319/00 , C07K2319/02 , C07K2319/33 , C07K2319/61
摘要： Polypeptides comprising repetitive units of amino acids, as well as synthetic genes encoding the subject polypeptides are provided. The subject polypeptides are characterized by comprising repetitive units of amino acids, where the repetitive units are present in naturally occurring proteins, particularly naturally occurring structural proteins. The subject polypeptides find use in a variety of applications, such as structural components of prosthetic devices, synthetic fibers, and the like.
摘要翻译：提供了包含氨基酸重复单元的多肽，以及编码本发明多肽的合成基因。主题多肽的特征在于包含氨基酸的重复单元，其中重复单元存在于天然存在的蛋白质中，特别是天然存在的结构蛋白质中。主题多肽可用于各种应用，例如假体装置的结构部件，合成纤维等。

9. 发明授权

US5773577A Products comprising substrates capable of enzymatic cross-linking 失效
标题翻译：含有能够进行酶交联的底物的产品
公开(公告)号：US5773577A
公开(公告)日：1998-06-30
申请号：US397633
申请日：1995-03-02
申请人： Joseph Cappello
发明人： Joseph Cappello
IPC分类号： C12N15/09 , A61K38/17 , A61K38/43 , A61L24/10 , A61P7/04 , A61P17/00 , A61P17/02 , C07K14/435 , C07K14/47 , C07K14/745 , C07K14/78 , C12N9/10 , C12P21/02 , C12R1/19 , C07K14/00 , A61K38/00
CPC分类号： A61L24/10 , A61L24/106 , C07K14/47 , C07K14/4732 , C12N9/10
摘要： Polymers are provided comprising protein polymers comprising blocks of repeating units and sequences comprising amino acids, individually or in defined sequences, capable of enzyme catalyzed covalent bond formation for cross-linking, as exemplified by glutamine and/or lysine reactive for FXIII catalyzed isopeptide formation or non-amino acid polymers having side chains comprising such amino acids or sequences, which may be used for preparation of articles of manufacture, particularly cross-linkable compositions. By appropriate choice of the polymer, resorbable implantable polymers may be used in internal applications for mammals as formed objects or depots.
摘要翻译：提供聚合物，其包含蛋白质聚合物，其包含单独或以定义的序列包含能够进行酶催化的共价键形成用于交联的重复单元和序列的序列，如通过FXIII催化的多肽形成反应的谷氨酰胺和/或赖氨酸，具有包含这种氨基酸或序列的侧链的非氨基酸聚合物，其可用于制备制品，特别是可交联组合物。通过适当选择聚合物，可再吸收的可植入聚合物可用于作为成形物体或贮库的哺乳动物的内部应用。

10. 发明授权

US5770697A Peptides comprising repetitive units of amino acids and DNA sequences encoding the same 失效
公开(公告)号：US5770697A
公开(公告)日：1998-06-23
申请号：US477509
申请日：1995-06-07
申请人： Franco A. Ferrari , Charles Richardson , James Chambers , Stuart Causey , Thomas J. Pollock , Joseph Cappello , John W. Crissman
发明人： Franco A. Ferrari , Charles Richardson , James Chambers , Stuart Causey , Thomas J. Pollock , Joseph Cappello , John W. Crissman
IPC分类号： C07K14/435 , C07K14/78 , C12N1/06 , C12N15/11 , C12N15/62 , C12N15/70 , C12N15/75 , A61K38/17 , A61K38/39 , C12P21/02
CPC分类号： C12N15/62 , C07K14/43586 , C07K14/78 , C12N1/06 , C12N15/11 , C12N15/70 , C12N15/75 , C07K2319/00 , C07K2319/02 , C07K2319/61
摘要： Novel polypeptides comprising repetitive units of amino acids, as well as synthetic genes encoding the subject polypeptides are provided. The subject polypeptides are characterized by comprising repetitive units of amino acids, where the repetitive units are present in naturally occurring proteins, particularly naturally occurring structural proteins. The subject polypeptides find use in a variety of applications, such as structural components of prosthetic devices, synthetic fibers, and the like.

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