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1. 发明申请

WO1992019734A1 BINDING DOMAINS IN NOTCH AND DELTA PROTEINS 审中-公开
标题翻译：杂交和蛋白质中的结合域
公开(公告)号：WO1992019734A1
公开(公告)日：1992-11-12
申请号：PCT/US1992003651
申请日：1992-05-01
申请人： YALE UNIVERSITY , INDIANA UNIVERSITY FOUNDATION
发明人： YALE UNIVERSITY , INDIANA UNIVERSITY FOUNDATION , ARTAVANIS-TSAKONAS, Spyridon , MUSKAVITCH, Marc, Alan, Telander , FEHON, Richard, Grant , REBAY, Ilaria , BLAUMUELLER, Christine, Marie , SHEPARD, Scott, Brockewell
IPC分类号： C12N15/12
CPC分类号： C07K16/18 , A61K38/00 , C07K14/705 , C07K2319/00 , Y10S530/839
摘要： The present invention relates to nucleotide sequences of the human Notch and Delta genes, and amino acid sequences of their encoded proteins, as well as fragments thereof containing an antigenic determinant or which are functionally active. The invention is also directed to fragments (termed herein "adhesive fragments"), and the sequences thereof, of the proteins ("toporythmic proteins") encoded by toporythmic genes which mediate homotypic or heterotypic binding to toporythmic proteins. Toporythmic genes, as used herein, refers to the genes Notch, Delta and Serrate, as well as other members of the Delta/Serrate family which may be identified, e.g., by the methods described herein. Antibodies to human Notch and to adhesive fragments are additionally provided.
摘要翻译：本发明涉及人Notch和Delta基因的核苷酸序列及其编码蛋白质的氨基酸序列，以及其含有抗原决定簇或其功能活性的片段。本发明还涉及由介导与拓扑蛋白质的同型或异型结合的拓扑学基因编码的蛋白质（“拓扑蛋白”）的片段（称为“粘合片段”）及其序列。本文使用的拓扑基因是指Notch，Delta和Serrate基因以及Delta / Serrate家族的其他成员，例如通过本文所述的方法鉴定。另外提供人类Notch和粘合剂片段的抗体。

2. 发明公开

EP0576623A1 BINDING DOMAINS IN NOTCH AND DELTA PROTEINS 失效
标题翻译：结合结构域在Notch和DELTA蛋白质。
公开(公告)号：EP0576623A1
公开(公告)日：1994-01-05
申请号：EP92911557.0
申请日：1992-05-01
申请人： YALE UNIVERSITY , INDIANA UNIVERSITY FOUNDATION
发明人： ARTAVANIS-TSAKONAS, Spyridon , MUSKAVITCH, Marc, Alan, Telander , FEHON, Richard, Grant , REBAY, Ilaria , BLAUMUELLER, Christine, Marie , SHEPARD, Scott, Brockewell
IPC分类号： C12N15 , C07K14 , C07K16 , C07K19 , C12N5 , C12P21 , A61K38 , C12R1
CPC分类号： C07K16/18 , A61K38/00 , C07K14/705 , C07K2319/00 , Y10S530/839
摘要： Cette invention concerne des séquences de nucléotides des gènes humains Notch et Delta, des séquences d'acides aminés de leurs protéines codées, ainsi que des fragments de ces dernières qui contiennent un déterminant antigénique ou qui sont actifs du point de vue fonctionnel. Cette invention concerne également des fragments (appelés "fragments adhésifs") et leurs séquences, des protéines (protéines toporythmiques) codées par les gènes toporythmiques qui assurent la liaison homotypique ou hétérotypique sur les protéines toporythmiques. Dans cette invention, les gènes toporythmiques sont les gènes Notch, Delta et Serrate ainsi que d'autres membres de la famille Delta/Serrate qu'on peut identifier par exemple, à l'aide des procédés décrits dans l'invention. Des anticorps du gène humain Notch et aux fragments adhésifs sont également décrits.

3. 发明申请

WO1993012141A1 NUCLEOTIDE AND PROTEIN SEQUENCES OF THE SERRATE GENE AND METHODS BASED THEREON 审中-公开
标题翻译：基因的核苷酸和蛋白质序列及其基因
公开(公告)号：WO1993012141A1
公开(公告)日：1993-06-24
申请号：PCT/US1991009240
申请日：1991-12-11
申请人： YALE UNIVERSITY
发明人： YALE UNIVERSITY , FLEMING, Robert, J. , ARTAVANIS-TSAKONAS, Spyridon
IPC分类号： C07K13/00
CPC分类号： C07K14/43581 , C07K14/705 , C07K16/18
摘要： The present invention relates to nucleotide sequences of Serrate genes, and amino acid sequences of their encoded proteins, as well as derivatives (e.g., fragments) and analogs thereof. In a specific embodiment, the Serrate protein is a human protein. The invention relates to Serrate derivatives and analogs of the invention which are functionally active, i.e., they are capable of displaying one or more known functional activities associated with the full-length (wild-type) Serrate protein. The invention further relates to fragments (and derivatives and analogs thereof) of Serrate which comprise one or more domains of the Serrate protein, including but not limited to the intracellular domain, extracellular domain, transmembrane region, membrane-associated region, or one or more EGF-like repeats of a Serrate protein, or any combination of the foregoing. Antibodies to Serrate, its derivatives and analogs, are additionally provided. Methods of production of the Serrate proteins, derivatives and analogs, e.g., by recombinant means, are also provided.
摘要翻译：本发明涉及Serrate基因的核苷酸序列及其编码的蛋白质的氨基酸序列，以及衍生物（例如片段）及其类似物。在一个具体实施方案中，所述丝氨酸蛋白是人蛋白质。本发明涉及功能活性的本发明的Serrate衍生物和类似物，即它们能够显示与全长（野生型）Serrate蛋白相关的一种或多种已知功能活性。本发明还涉及含有一个或多个丝氨酸蛋白结构域的丝氨酸的片段（及其衍生物和类似物），包括但不限于细胞内结构域，细胞外结构域，跨膜区，膜相关区或一个或多个丝氨酸蛋白的EGF样重复序列，或前述的任何组合。还提供了对Serrate及其衍生物和类似物的抗体。还提供了通过重组方法生产丝氨酸蛋白质，衍生物和类似物的方法。

4. 发明授权

EP0662827B1 DIAGNOSTIC METHODS AND PHARMACEUTICAL COMPOSITIONS BASED ON NOTCH PROTEINS AND NUCLEIC ACIDS 失效
标题翻译：诊断程序和药物组合ON NOTCH蛋白质和核酸
公开(公告)号：EP0662827B1
公开(公告)日：2002-04-17
申请号：EP93923752.5
申请日：1993-09-30
申请人： YALE UNIVERSITY
发明人： ARTAVANIS-TSAKONAS, Spyridon , FEHON, Richard Grant , ZAGOURAS, Panayiotis , BLAUMUELLER, Christine Marie, Dept. of Biology-KBT
IPC分类号： A61K31/00 , A61K31/70 , A61K38/00 , A61K39/44 , A61K39/395 , C07H21/04 , G01N33/53 , G01N33/68 , G01N33/574 , C07K14/47
CPC分类号： A61K31/70 , A61K38/00 , C07K14/43581 , C07K14/47 , C07K14/705 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/20 , C07K2319/23 , C07K2319/70 , C07K2319/95 , C12N15/62 , G01N33/57411 , G01N33/57415 , G01N33/57419 , G01N33/57484 , G01N33/6893 , Y10S436/811 , Y10S436/813 , Y10S436/815
摘要： The present invention relates to therapeutic and diagnostic methods and compositions based on Notch proteins and nucleic acids. Figure 17 displays the sequences of human Notch DNA and the encoded human Notch protein. The invention provides for treatment of disorders of cell fate or differentiation by administration of a therapeutic compound of the invention. Such therapeutic compounds (termed herein 'Therapeutics') include Notch proteins and analogs and derivatives (including fragments) thereof, antibodies thereto, nucleic acids encoding the Notch proteins, analogs, or derivatives, Notch antisense nucleic acids, as well as toporythmic proteins and derivatives which bind to or otherwise interact with Notch proteins, their encoding nucleic acids or antibodies. In a preferred embodiment, a Therapeutic of the invention is administered to treat a cancerous condition, or to prevent progression from a pre-neoplastic or non-malignant state into a neoplastic or a malignant state.

5. 发明申请

WO1995019779A1 DELTEX PROTEINS, NUCLEIC ACIDS, AND ANTIBODIES, AND RELATED METHODS AND COMPOSITIONS 审中-公开
标题翻译： DELTEX蛋白，核酸和抗体及相关方法和组合物
公开(公告)号：WO1995019779A1
公开(公告)日：1995-07-27
申请号：PCT/US1995000825
申请日：1995-01-20
申请人： YALE UNIVERSITY
发明人： YALE UNIVERSITY , ARTAVANIS-TSAKONAS, Spyridon , BUSSEAU, Isabelle , DIEDERICH, Robert, J. , XU, Tian , MATSUNO, Kenji
IPC分类号： A61K35/12
CPC分类号： C07H21/00 , A61K38/00 , C07K14/435 , C07K14/47 , C07K16/18 , C07K2319/00
摘要： The present invention relates to nucleotide sequences of deltex genes, and amino acid sequences of the encoded deltex proteins. The invention further relates to fragments and other derivatives, and analogs, of deltex proteins, as well as antibodies thereto. Nucleic acids encoding such fragments or derivatives are also within the scope of the invention. Production of the foregoing proteins and derivatives, e.g., by recombinant methods, is provided. In a specific embodiment, the invention relates to Drosophila deltex nucleic acids and proteins. In another embodiment, the invention relates to human deltex nucleic acids and proteins. In specific embodiments, the invention relates to deltex protein derivatives and analogs of the invention which are functionally active, or which comprise one or more domains of a deltex protein, including but not limited to the Glu-rich clusters, SH3 binding domains, domains which mediate binding to Notch or to a Notch derivative containing Notch cdc10/SW16/ankyrin ("ANK") repeats, domains which mediate binding to a second deltex protein, or any combination of the foregoing. The present invention also relates to therapeutic and diagnostic methods and compositions based on deltex proteins, nucleic acids, and antibodies.
摘要翻译：本发明涉及deltex基因的核苷酸序列和编码的deltex蛋白的氨基酸序列。本发明还涉及脱落蛋白的片段和其它衍生物和类似物，以及其抗体。编码这种片段或衍生物的核酸也在本发明的范围内。提供了上述蛋白质和衍生物的生产，例如通过重组方法。在具体实施方案中，本发明涉及果蝇脱粒酶核酸和蛋白质。在另一个实施方案中，本发明涉及人类脱屑酶核酸和蛋白质。在具体实施方案中，本发明涉及在功能上有活性或包含一个或多个deltex蛋白结构域的本发明的脱胶蛋白衍生物和类似物，包括但不限于富含Glu的簇，SH3结合结构域，介导与Notch或含有Notch cdc10 / SW16 / ankyrin（“ANK”）的Notch衍生物的结合重复，介导与第二脱胶蛋白结合的结构域或前述的任何组合。本发明还涉及基于脱胶蛋白，核酸和抗体的治疗和诊断方法和组合物。

6. 发明授权

EP0948348B1 MANIPULATION OF NON-TERMINALLY DIFFERENTIATED CELLS USING THE NOTCH PATHWAY 失效
标题翻译：不是最终的分化细胞下的使用NOTCH-WAY操纵
公开(公告)号：EP0948348B1
公开(公告)日：2014-01-01
申请号：EP96933960.5
申请日：1996-09-27
申请人： Yale University
发明人： ARTAVANIS-TSAKONAS, Spyridon , FORTINI, Mark, E. , MATSUNO, Kenji
IPC分类号： C12N5/10 , A61K38/17 , A61K39/395
CPC分类号： C12N5/0623 , A61K35/12 , A61K38/00 , C07K14/47 , C12N5/0018 , C12N5/0601 , C12N2501/42
摘要： The present invention is directed to methods for the expansion of non-terminally differentiated cells ("precursor cells") using agonists of Notch function, by inhibiting the differentiation of the cells without inhibiting proliferation (mitotic activity) such that an expanded population of non-terminally differentiated cells is obtained. The cells are preferably stem or progenitor cells. These expanded cells can be used in cell replacement therapy to provide desired cell populations and help in the regeneration of diseased and/or injured tissues. The expanded cell populations can also be made recombinant and used for gene therapy, or can be used to supply functions associated with a particular precursor cell or its progeny cell.

7. 发明授权

EP0861261B1 NUCLEOTIDE AND PROTEIN SEQUENCES OF VERTEBRATE DELTA GENES AND METHODS BASED THEREON 失效
标题翻译： NUARATID-UND PROTEINSEQUENZEN VON DELTA-GENEN VON VERTEBRATEN UND DARAUF BASIERENDE METHODEN
公开(公告)号：EP0861261B1
公开(公告)日：2009-09-09
申请号：EP96924334.4
申请日：1996-06-28
申请人： IMPERIAL CANCER RESEARCH TECHNOLOGY LIMITED , Yale University
发明人： ISH-HOROWICZ, David , HENRIQUE, Domingo, M., P. , LEWIS, Julian, H. , ARTAVANIS-TSAKONAS, Spyridon , GRAY, Grace, E.
IPC分类号： C07H17/00 , C07K14/00 , C12P21/06 , C12N5/00 , C12N15/00 , C07K14/705
CPC分类号： C07K14/47 , A61K38/00 , C07K14/705 , C07K2319/00
摘要： The present invention relates to nucleotide sequences of vertebrate Delta genes, and amino acid sequences of their encoded proteins, as well as derivatives (e.g., fragments) and analogs thereof. In a specific embodiment, the vertebrate Delta protein is a human protein. The invention further relates to fragments (and derivatives and analogs thereof) of Delta which comprise one or more domains of the Delta protein, including but not limited to the intracellular domain, extracellular domain, DSL domain, domain amino-terminal to the DSL domain, transmembrane region, or one or more EGF-like repeats of a Delta protein, or any combination of the foregoing. Antobidies to Delta, its derivatives and analogs, are additionally provided. Methods of production of the Delta proteins, derivatives and analogs, e.g., by recombinant means, are also provided. Therapeutic and diagnostic methods and pharmaceutical compositions are provided. In specific examples, isolated Delta genes, from Xenopus, chick, mouse, and human, are provided.
摘要翻译：本发明涉及脊椎动物Delta基因的核苷酸序列及其编码的蛋白质的氨基酸序列以及衍生物（例如片段）及其类似物。在具体实施方案中，脊椎动物Delta蛋白是人蛋白质。本发明还涉及包含Delta蛋白的一个或多个结构域的Delta的片段（及其衍生物和类似物），包括但不限于细胞内结构域，细胞外结构域，DSL结构域，DSL结构域的氨基末端，跨膜区域，或一种或多种Delta蛋白质的EGF样重复序列，或上述的任何组合。另外还提供了针对三角洲及其衍生物和类似物的抗体。还提供了通过重组方法生产Delta蛋白质，衍生物和类似物的方法。提供了治疗和诊断方法和药物组合物。在具体实例中，提供了来自爪蟾，小鸡，小鼠和人的孤立的Delta基因。

9. 发明公开

EP1096946A2 DELTA CLEAVAGE PRODUCTS AND METHODS BASED THEREON 审中-公开
标题翻译： DELTA-SPLIT产品和相关程序
公开(公告)号：EP1096946A2
公开(公告)日：2001-05-09
申请号：EP99935534.0
申请日：1999-07-13
申请人： YALE UNIVERSITY
发明人： ARTAVANIS-TSAKONAS, Spyridon , RAND, Matthew, D. , QI, Huilin
IPC分类号： A61K38/00 , A61K31/70 , C07K7/00 , C07K16/00 , C07K17/00 , C12P21/06 , C12P21/08 , C07H21/04 , A01N37/18 , A01N43/04 , G01N33/48 , G01N33/53 , G01N33/574
CPC分类号： C07K14/705 , A01K2217/075 , A61K38/00
摘要： The present invention is directed to a Delta cleavage peptide and fragments, derivative and analogs thereof, and its encoding nucleic acids. The present invention is also directed to a soluble Delta peptide and fragments, derivative and analogs thereof, and its encoding nucleic acids. The present invention is also directed to protein complexes of Delta and Kuz. The present invention is also directed to methods for detecting or measuring Delta activation by observing or measuring Delta cleavage products that are indicative of Delta activation. The present invention is also directed to methods for detecting or measuring Kuz activation by observing or measuring Delta cleavage products that are indicative of Kuz activation. The present invention is also directed to methods for detecting a molecule that modulates Delta activation or Kuz function by observing or measuring a change in the amount of or pattern of Delta cleavage products. The present invention is based, at least in part, on the discovery that Delta in its active form, i.e., the form that mediates signal transduction and that binds Notch, is a soluble fragment consisting of the extracellular domain.

10. 发明授权

EP0861261B9 NUCLEOTIDE AND PROTEIN SEQUENCES OF VERTEBRATE DELTA GENES AND METHODS BASED THEREON 失效
标题翻译：核苷酸和DELTA基因的蛋白序列和基于事实的方法脊椎动物
公开(公告)号：EP0861261B9
公开(公告)日：2010-02-24
申请号：EP96924334.4
申请日：1996-06-28
申请人： IMPERIAL CANCER RESEARCH TECHNOLOGY LIMITED , Yale University
发明人： ISH-HOROWICZ, David , HENRIQUE, Domingo, M., P. , LEWIS, Julian, H. , ARTAVANIS-TSAKONAS, Spyridon , GRAY, Grace, E.
IPC分类号： C07H17/00 , C07K14/00 , C12P21/06 , C12N5/00 , C12N15/00 , C07K14/705
CPC分类号： C07K14/47 , A61K38/00 , C07K14/705 , C07K2319/00

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