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1. 发明申请

US20090083871A1 Targeting constructs for the functional disruption of avian immunoglobulin genes 审中-公开
标题翻译：针对禽类免疫球蛋白基因功能性破坏的构建体
公开(公告)号：US20090083871A1
公开(公告)日：2009-03-26
申请号：US11977538
申请日：2007-10-24
申请人： Robert J. Etches , Robert M. Kay , Lei Zhu
发明人： Robert J. Etches , Robert M. Kay , Lei Zhu
IPC分类号： A01K67/027 , C12N15/00
CPC分类号： C12N15/8509 , A01K2207/15 , A01K2217/00 , A01K2217/075 , A01K2227/30 , A01K2267/01 , A01K2267/0381 , C07K16/00 , C07K2317/21 , C07K2317/23 , C12N2800/30
摘要： A transgenic chicken is disclosed having disrupted endogenous immunoglobulin production. In one embodiment, a targeting construct is stably integrated into the genome of the chicken by homologous recombination in embryonic stem cells, and injection of the engineered embryonic stem cells into recipient embryos, thereby knocking out the endogenous immunoglobulin gene locus in resulting animals. The targeted disruption of the locus in embryonic stem cells is particularly useful in combination with the insertion of genetic elements encoding exogenous immunoglobulin molecules. After these chickens are cross-bred, a line of chickens is produced that has a reduction of endogenous immunoglobulin molecule production.
摘要翻译：公开了转基因鸡，其破坏了内源性免疫球蛋白产生。在一个实施方案中，靶向构建体通过胚胎干细胞中的同源重组稳定整合到鸡的基因组中，并将工程化的胚胎干细胞注射到受体胚胎中，从而敲出所得动物中的内源性免疫球蛋白基因座。胚胎干细胞中的位点的靶向破坏与编码外源性免疫球蛋白分子的遗传元件的插入特别有用。在这些鸡交叉繁殖后，产生一系列内源性免疫球蛋白分子产生的鸡。

2. 发明申请

US20120156771A1 FUNCTIONAL DISRUPTION OF AN IMMUNOGLOBULIN GENE IN AN AVIAN EMBRYONIC STEM CELL 审中-公开
标题翻译： AVIAN胚胎干细胞中免疫球蛋白基因的功能性破坏
公开(公告)号：US20120156771A1
公开(公告)日：2012-06-21
申请号：US13281362
申请日：2011-10-25
申请人： Robert J. Etches , Robert M. Kay , Lei Zhu
发明人： Robert J. Etches , Robert M. Kay , Lei Zhu
IPC分类号： C12N5/10
CPC分类号： C12N15/8509 , A01K2207/15 , A01K2217/00 , A01K2217/075 , A01K2227/30 , A01K2267/01 , A01K2267/0381 , C07K16/00 , C07K2317/21 , C07K2317/23 , C12N2800/30
摘要： A transgenic chicken is disclosed having disrupted endogenous immunoglobulin production. In one embodiment, a targeting construct is stably integrated into the genome of the chicken by homologous recombination in embryonic stem cells, and injection of the engineered embryonic stem cells into recipient embryos, thereby knocking out the endogenous immunoglobulin gene locus in resulting animals. The targeted disruption of the locus in embryonic stem cells is particularly useful in combination with the insertion of genetic elements encoding exogenous immunoglobulin molecules. After these chickens are cross-bred, a line of chickens is produced that has a reduction of endogenous immunoglobulin molecule production.
摘要翻译：公开了转基因鸡，其破坏了内源性免疫球蛋白产生。在一个实施方案中，靶向构建体通过胚胎干细胞中的同源重组稳定整合到鸡的基因组中，并将工程化的胚胎干细胞注射到受体胚胎中，从而敲出所得动物中的内源性免疫球蛋白基因座。胚胎干细胞中的位点的靶向破坏与编码外源性免疫球蛋白分子的遗传元件的插入特别有用。在这些鸡交叉繁殖后，产生一系列内源性免疫球蛋白分子产生的鸡。

3. 发明申请

US20110023160A1 Functional Disruption Of Avian Immunoglobulin Genes 审中-公开
标题翻译：禽类免疫球蛋白基因的功能性破坏
公开(公告)号：US20110023160A1
公开(公告)日：2011-01-27
申请号：US12896681
申请日：2010-10-01
申请人： Robert J. Etches , Robert M. Kay , Lei Zhu
发明人： Robert J. Etches , Robert M. Kay , Lei Zhu
IPC分类号： A01K67/027 , C12N15/64
CPC分类号： C12N15/8509 , A01K2207/15 , A01K2217/00 , A01K2217/075 , A01K2227/30 , A01K2267/01 , A01K2267/0381 , C07K16/00 , C07K2317/21 , C07K2317/23 , C12N2800/30
摘要： A transgenic chicken is disclosed having disrupted endogenous immunoglobulin production. In one embodiment, a targeting construct is stably integrated into the genome of the chicken by homologous recombination in embryonic stem cells, and injection of the engineered embryonic stem cells into recipient embryos, thereby knocking out the endogenous immunoglobulin gene locus in resulting animals. The targeted disruption of the locus in embryonic stem cells is particularly useful in combination with the insertion of genetic elements encoding exogenous immunoglobulin molecules. After these chickens are cross-bred, a line of chickens is produced that has a reduction of endogenous immunoglobulin molecule production.
摘要翻译：公开了转基因鸡，其破坏了内源性免疫球蛋白产生。在一个实施方案中，靶向构建体通过胚胎干细胞中的同源重组稳定整合到鸡的基因组中，并将工程化的胚胎干细胞注射到受体胚胎中，从而敲出所得动物中的内源性免疫球蛋白基因座。胚胎干细胞中的位点的靶向破坏与编码外源性免疫球蛋白分子的遗传元件的插入特别有用。在这些鸡交叉繁殖后，产生一系列内源性免疫球蛋白分子产生的鸡。

4. 发明申请

US20110277048A1 Transgenic Aves Producing Human Polyclonal Antibodies 审中-公开
标题翻译：转基因产生人多克隆抗体
公开(公告)号：US20110277048A1
公开(公告)日：2011-11-10
申请号：US12835721
申请日：2010-07-13
申请人： Robert J. Etches , Robert M. Kay , Philip Leighton , Lei Zhu
发明人： Robert J. Etches , Robert M. Kay , Philip Leighton , Lei Zhu
IPC分类号： A01K67/027 , C12N5/10 , C12N5/16
CPC分类号： C07K16/461 , A01K67/0275 , A01K67/0278 , A01K2207/15 , A01K2217/00 , A01K2217/075 , A01K2227/30 , A01K2267/01 , C07K14/70503 , C07K16/02 , C07K2317/21 , C12N15/8509 , C12N2800/204 , C12N2800/30
摘要： Human antibodies are produced in transgenic chickens having functional genetic components of the human immune system stably integrated in the genome. Techniques are described to integrate unrearranged human heavy and light chain immunoglobulin loci into the genome of the transgenic chicken.The functional description of the endogenous immunoglobulin loci yields an animal whose antibody repertoire in response to antigen is fully human.In the preferred embodiment, the human immunoglobulin locus is at least as large as the native human locus and exhibits functional class switching to yield IgG isotype antibodies. In addition to monoclonal antibodies secreted from immortalized B cell populations, polyclonal antibodies may be obtained from eggs laid by the transgenic chickens of the invention.
摘要翻译：在具有稳定整合在基因组中的人免疫系统的功能性遗传成分的转基因鸡中产生人抗体。描述了将未经排列的人重链和轻链免疫球蛋白基因座整合到转基因鸡的基因组中的技术。内源性免疫球蛋白基因座的功能描述产生一种抗体对抗原作出全部反应的动物。在优选的实施方案中，人免疫球蛋白基因座至少与天然人基因座一样大，并显示功能类转换以产生IgG同种型抗体。除了从永生化的B细胞群体分泌的单克隆抗体之外，多克隆抗体可以从本发明的转基因鸡放置的卵中获得。

5. 发明授权

US07041871B1 Transgenic non-human animals capable of producing heterologous antibodies 有权
标题翻译：能够产生异源抗体的转基因非人动物
公开(公告)号：US07041871B1
公开(公告)日：2006-05-09
申请号：US09724965
申请日：2000-11-28
申请人： Nils Lonberg , Robert M. Kay
发明人： Nils Lonberg , Robert M. Kay
IPC分类号： A01K67/027 , C12N15/00 , C12N15/63 , C12N15/74 , C12N5/00
CPC分类号： C07K16/462 , A01K67/0275 , A01K67/0276 , A01K67/0278 , A01K2217/05 , A01K2227/105 , A01K2267/01 , C07K16/00 , C07K2317/21 , C07K2317/24 , C07K2317/52 , C07K2317/56 , C12N15/8509
摘要： The invention relates to transgenic non-human animals capable of producing heterologous antibodies and methods for producing human sequence antibodies which bind to human antigens with substantial affinity.
摘要翻译：本发明涉及能够产生异源抗体的转基因非人动物和用于产生以大量亲和力结合人抗原的人序列抗体的方法。

6. 发明授权

US06300129B1 Transgenic non-human animals for producing heterologous antibodies 失效
标题翻译：用于产生异源抗体的转基因非人动物
公开(公告)号：US06300129B1
公开(公告)日：2001-10-09
申请号：US08758417
申请日：1996-12-02
申请人： Nils Lonberg , Robert M. Kay
发明人： Nils Lonberg , Robert M. Kay
IPC分类号： C12N1586
CPC分类号： C12N15/8509 , A01K67/0276 , A01K67/0278 , A01K2207/15 , A01K2217/00 , A01K2217/05 , A01K2217/072 , A01K2217/075 , A01K2227/105 , A01K2267/01 , A01K2267/025 , A61K38/00 , C07K14/7051 , C07K16/00 , C07K16/2812 , C07K16/3007 , C07K16/4266 , C07K16/4291 , C07K16/44 , C07K16/462 , C07K2317/21 , C07K2317/24 , C07K2317/52 , C07K2317/56 , C07K2317/76 , C07K2319/00 , C12N5/163 , C12N15/00 , C12N15/113 , C12N15/85 , C12N15/87 , C12N15/90 , C12N15/907 , C12N2800/206 , C12N2800/70 , C12N2830/30 , C12N2830/36 , C12N2830/85
摘要： The invention relates to transgenic non-human animals capable of producing heterologous antibodies and methods for producing human sequence antibodies which bind to human antigens with substantial affinity.
摘要翻译：本发明涉及能够产生异源抗体的转基因非人动物和用于产生以大量亲和力结合人抗原的人序列抗体的方法。

7. 发明授权

US5981175A Methods for producing recombinant mammalian cells harboring a yeast artificial chromosome 失效
标题翻译：用于产生含有酵母人造染色体的重组哺乳动物细胞的方法
公开(公告)号：US5981175A
公开(公告)日：1999-11-09
申请号：US187161
申请日：1994-01-25
申请人： Jeanne F. Loring , Theodore Choi , Robert M. Kay
发明人： Jeanne F. Loring , Theodore Choi , Robert M. Kay
IPC分类号： C12Q1/68
CPC分类号： C12N15/88 , A01K67/0275 , A01K2217/05 , A01K2217/052 , A01K2227/105 , A01K2267/01 , A01K2267/0312 , A01K2267/0387
摘要： The present invention provides methods and compositions for transferring large transgene polynucleotides and unlinked selectable marker polynucleotides into eukaryotic cells by a novel method designated co-lipofection. The methods and compositions of the invention are used to produce novel transgenic non-human animals harboring large transgenes, such as a transgene comprising a human APP gene or human immunoglobulin gene.
摘要翻译：本发明提供了通过称为协同脂转染的新方法将大转基因多核苷酸和未连接的选择标记多核苷酸转移到真核细胞中的方法和组合物。本发明的方法和组合物用于产生携带大转基因的新型转基因非人动物，例如包含人APP基因或人免疫球蛋白基因的转基因。

8. 发明授权

US5416584A Sinusoidal noise injection into the dither of a ring laser gyroscope 失效
标题翻译：正弦噪声注入环形激光陀螺仪的抖动
公开(公告)号：US5416584A
公开(公告)日：1995-05-16
申请号：US233162
申请日：1994-04-25
申请人： Robert M. Kay
发明人： Robert M. Kay
IPC分类号： G01C19/68 , G01C19/70
CPC分类号： G01C19/68
摘要： Method and apparatus for reducing the effects of lock-in in a ring laser gyroscope. A sinusoidal noise signal is generated having a peak amplitude which shifts as a function of a dither drive monitor signal to new, random, peak amplitude levels. In the preferred embodiment, the peak amplitude level changes at each zero crossing of the dither drive monitor signal. Each new peak amplitude level is determined as a function of a value provided by a passband filtered random or pseudo random noise source. A step noise signal representative of that passband filtered value is multiplied by the dither drive monitor signal and the resulting sinusoidal noise signal is summed into the dither drive monitor signal. The resulting signal is then used to introduce a frequency bias, electrically or mechanically in at least one of the RLG light beams.
摘要翻译：减少环形激光陀螺仪锁定效果的方法和装置。产生正弦噪声信号，其具有作为抖动驱动监视信号的函数的峰值幅度移动到新的，随机的峰值振幅电平。在优选实施例中，峰值振幅电平在抖动驱动监视信号的每个过零点处改变。每个新的峰值振幅电平被确定为由通带滤波的随机噪声源或伪随机噪声源提供的值的函数。表示通带滤波值的步进噪声信号乘以抖动驱动监视信号，并将所得到的正弦噪声信号求和到抖动驱动监视信号中。然后，所得信号用于在至少一个RLG光束中电或机械地引入频率偏置。

9. 发明授权

US5661016A Transgenic non-human animals capable of producing heterologous antibodies of various isotypes 失效
标题翻译：能够产生各种同种型的异源抗体的转基因非人动物
公开(公告)号：US5661016A
公开(公告)日：1997-08-26
申请号：US53131
申请日：1993-04-26
申请人： Nils Lonberg , Robert M. Kay
发明人： Nils Lonberg , Robert M. Kay
IPC分类号： A01K67/027 , C07K16/00 , C07K16/28 , C07K16/30 , C07K16/44 , C12N15/85 , C12N15/90 , C12N15/00 , A61K39/00 , C12P19/34
CPC分类号： C12N15/90 , A01K67/0278 , C07K16/00 , C07K16/2812 , C07K16/3007 , C07K16/44 , C12N15/8509 , A01K2207/15 , A01K2217/00 , A01K2217/05 , A01K2217/072 , A01K2227/105 , A01K2267/01 , A01K2267/0381 , C07K2317/21 , C07K2317/24 , C07K2317/52 , C07K2317/56
摘要： The invention relates to transgenic non-human animals capable of producing heterologous antibodies and transgenic non-human animals having inactivated endogenous immunoglobulin genes. In one aspect of the invention, endogenous immunoglobulin genes are suppressed by antisense polynucleotides and/or by antiserum directed against endogenous immunoglobulins. Heterologous antibodies are encoded by immunoglobulin genes not normally found in the genome of that species of non-human animal. In one aspect of the invention, one or more transgenes containing sequences of unrearranged heterologous human immunoglobulin heavy chains are introduced into a non-human animal thereby forming a transgenic animal capable of functionally rearranging transgenic immunoglobulin sequences and producing a repertoire of antibodies of various isotypes encoded by human immunoglobulin genes. Such heterologous human antibodies are produced in B-cells which are thereafter immortalized, e.g., by fusing with an immortalizing cell line such as a myeloma or by manipulating such B-cells by other techniques to perpetuate a cell line capable of producing a monoclonal heterologous antibody. The invention also relates to heavy and light chain immunoglobulin transgenes for making such transgenic non-human animals as well as methods and vectors for disrupting endogenous immunoglobulin loci in the transgenic animal.
摘要翻译：本发明涉及能够产生具有失活的内源免疫球蛋白基因的异源抗体和转基因非人动物的转基因非人动物。在本发明的一个方面，内源性免疫球蛋白基因被反义多核苷酸和/或针对内源性免疫球蛋白的抗血清抑制。异源抗体由非人动物种类的基因组中通常不存在的免疫球蛋白基因编码。在本发明的一个方面，将含有未经排列的异源人免疫球蛋白重链序列的一个或多个转基因引入非人动物中，从而形成能够功能重排转基因免疫球蛋白序列并产生编码的各种同种型抗体的所有组成的转基因动物通过人免疫球蛋白基因。这样的异源人抗体是在B细胞中产生的，其后被永生化，例如通过与永生化细胞系如骨髓瘤融合，或者通过其它技术操纵这样的B细胞，使能够产生单克隆异源抗体的细胞系。本发明还涉及用于制备这种转基因非人动物的重链和轻链免疫球蛋白转基因以及用于破坏转基因动物内源性免疫球蛋白基因座的方法和载体。

10. 发明授权

US5569825A Transgenic non-human animals capable of producing heterologous antibodies of various isotypes 失效
标题翻译：能够产生各种同种型的异源抗体的转基因非人动物
公开(公告)号：US5569825A
公开(公告)日：1996-10-29
申请号：US810279
申请日：1991-12-17
申请人： Nils Lonberg , Robert M. Kay
发明人： Nils Lonberg , Robert M. Kay
IPC分类号： A01K67/027 , A61K38/00 , A61K39/395 , C07K14/725 , C07K16/00 , C07K16/18 , C07K16/28 , C07K16/30 , C07K16/42 , C07K16/44 , C07K16/46 , C12N5/10 , C12N5/16 , C12N15/00 , C12N15/09 , C12N15/13 , C12N15/85 , C12N15/87 , C12N15/90 , C12P21/08 , C07H21/04
CPC分类号： C12N15/907 , A01K67/0278 , C07K14/7051 , C07K16/00 , C07K16/2812 , C07K16/3007 , C07K16/4266 , C07K16/4291 , C07K16/44 , C12N15/00 , C12N15/85 , C12N15/8509 , C12N15/87 , C12N15/90 , C12N5/163 , A01K2207/15 , A01K2217/00 , A01K2217/05 , A01K2227/105 , A01K2267/01 , A61K38/00 , C07K2317/21 , C07K2317/24 , C07K2317/52 , C07K2317/56 , C12N2830/008 , C12N2830/15 , C12N2830/36 , C12N2830/60 , C12N2840/44
摘要： The invention relates to transgenic non-human animals capable of producing heterologous antibodies of multiple isotypes. Heterologous antibodies are encoded by immunoglobulin heavy chain genes not normally found in the genome of that species of non-human animal. In one aspect of the invention, one or more transgenes containing sequences that permit isotype switching of encoded unrearranged heterologous human immunoglobulin heavy chains are introduced into a non-human animal thereby forming a transgenic animal capable of producing antibodies of various isotypes encoded by human immunoglobulin genes. Such heterologous human antibodies are produced in B-cells which are thereafter immortalized, e.g., by fusing with an immortalizing cell line such as a myeloma or by manipulating such B-cells by other techniques to perpetuate a cell line capable of producing a monoclonal heterologous antibody. The invention also relates to heavy and light chain immunoglobulin transgenes for making such transgenic non-human animals as well as methods and vectors for disrupting endogenous immunoglobulin loci in the transgenic animal.
摘要翻译：本发明涉及能够产生多重同种型的异源抗体的转基因非人动物。异源抗体由非人动物种类的基因组中通常不存在的免疫球蛋白重链基因编码。在本发明的一个方面，将含有允许编码的未经排除的异源人免疫球蛋白重链的同种型切换的一个或多个转基因导入非人动物，从而形成能够产生由人免疫球蛋白基因编码的各种同种型的抗体的转基因动物。这样的异源人抗体是在B细胞中产生的，其后被永生化，例如通过与永生化细胞系如骨髓瘤融合，或者通过其它技术操纵这样的B细胞，使能够产生单克隆异源抗体的细胞系。本发明还涉及用于制备这种转基因非人动物的重链和轻链免疫球蛋白转基因以及用于破坏转基因动物内源性免疫球蛋白基因座的方法和载体。

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