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11. 发明授权

US06869930B1 Acylated insulin 失效
标题翻译：酰化胰岛素
公开(公告)号：US06869930B1
公开(公告)日：2005-03-22
申请号：US09398365
申请日：1999-09-17
申请人： Svend Havelund , John Halstrom , Ib Jonassen , Asser Sloth Andersen , Jan Markussen
发明人： Svend Havelund , John Halstrom , Ib Jonassen , Asser Sloth Andersen , Jan Markussen
IPC分类号： A61K38/00 , C07K14/62 , A61K38/28
CPC分类号： C07K14/62 , A61K38/00 , Y10S514/866
摘要： The present invention relates to protracted human insulin derivatives in which the A21 and the B3 amino acid residues are, independently, any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys; PheB1 may be deleted; the B30 amino acid residue is (a) a non-codable, lipophilic amino acid having from 10 to 24 carbon atoms, in which case an acyl group of a carboxylic acid with up to 5 carbon atoms is bound to the ε-amino group of LysB29; or (b) the B30 amino acid residue is deleted or is any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys, in any of which cases the ε-amino group of LysB29 has a lipophilic substituent; and any Zn2+ complexes thereof with the proviso that when B30 is Thr or Ala and A21 and B3 are both Asn, and PheB1 is present, then the insulin derivative is always present as a Zn2+ complex.
摘要翻译：本发明涉及延长的人胰岛素衍生物，其中A21和B3氨基酸残基独立地是可由遗传密码编码的除Lys，Arg和Cys之外的任何氨基酸残基; Phe 可能被删除; B30氨基酸残基是（a）具有10-24个碳原子的不可编码的亲脂性氨基酸，在这种情况下，具有至多5个碳原子的羧酸的酰基与ε-氨基的ε-氨基结合 Lys ; 或（b）B30氨基酸残基被缺失，或者是任何氨基酸残基，其可以通过除Lys，Arg和Cys之外的遗传密码进行编码，在这些情况下，Lys 的ε-氨基具有亲油取代基; 和任何Zn 2+络合物，条件是当B30是Thr或Ala，A21和B3都是Asn和Phe 时，胰岛素衍生物总是作为Zn 2+络合物存在。

12. 发明授权

US06620780B2 Insulin derivatives 有权
公开(公告)号：US06620780B2
公开(公告)日：2003-09-16
申请号：US09861687
申请日：2001-05-21
申请人： Jan Markussen , Ib Jonassen , Svend Havelund , Jakob Brandt , Peter Kurtzhals , Per Hertz Hansen , Niels Christian Kaarsholm
发明人： Jan Markussen , Ib Jonassen , Svend Havelund , Jakob Brandt , Peter Kurtzhals , Per Hertz Hansen , Niels Christian Kaarsholm
IPC分类号： C07K1462
CPC分类号： C07K14/62 , Y10S514/866
摘要： The present invention relates to insulin derivatives in which a lipophilic group having from 12 to 40 carbon atoms is attached to the &agr;-amino group of the N-terminal amino acid in the B-chain or to the carboxy group of the C-terminal amino acid in the B-chain have a protracted profile of action.

13. 发明授权

US6011007A Acylated insulin 失效
标题翻译：酰化胰岛素
公开(公告)号：US6011007A
公开(公告)日：2000-01-04
申请号：US975365
申请日：1997-11-20
申请人： Svend Havelund , John Halstrom , Ib Jonassen , Asser Sloth Andersen , Jan Markussen
发明人： Svend Havelund , John Halstrom , Ib Jonassen , Asser Sloth Andersen , Jan Markussen
IPC分类号： A61K38/00 , C07K14/62 , A61K38/28
CPC分类号： C07K14/62 , A61K38/00 , Y10S514/866
摘要： The present invention relates to protracted human insulin derivatives in which the A21 and the B3 amino acid residues are, independently, any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys; Phe.sup.B1 may be deleted; the B30 amino acid residue is (a) a non-codable, lipophilic amino acid having from 10 to 24 carbon atoms, in which case an acyl group of a carboxylic acid with up to 5 carbon atoms is bound to the .epsilon.-amino group of Lys.sup.B29 ; or (b) the B30 amino acid residue is deleted or is any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys, in any of which cases the .epsilon.-amino group of Lys.sup.B29 has a lipophilic substituent; and any Zn.sup.2+ complexes thereof with the proviso that when B30 is Thr or Ala and A21 and B3 are both Asn, and Phe.sup.B1 is present, then the insulin derivative is always present as a Zn.sup.2+ complex.
摘要翻译：本发明涉及延长的人胰岛素衍生物，其中A21和B3氨基酸残基独立地是可由遗传密码编码的除Lys，Arg和Cys之外的任何氨基酸残基; PheB1可能被删除; B30氨基酸残基是（a）具有10至24个碳原子的非可编码的亲脂性氨基酸，在这种情况下，具有至多5个碳原子的羧酸的酰基与ε-氨基的ε-氨基结合 LysB29; 或（b）B30氨基酸残基被缺失或者是任何氨基酸残基，其可以通过除Lys，Arg和Cys之外的遗传密码进行编码，在这些情况下，LysB29的ε-氨基具有亲脂性取代基; 和任何Zn 2+配合物，条件是当B30是Thr或Ala，A21和B3都是Asn和PheB1时，胰岛素衍生物总是作为Zn 2+络合物存在。

14. 发明申请

US20060003421A1 Method for purifying a fermentation-derived product 审中-公开
标题翻译：纯化发酵产物的方法
公开(公告)号：US20060003421A1
公开(公告)日：2006-01-05
申请号：US11220266
申请日：2005-09-06
申请人： Jan Markussen , Ivan Diers
发明人： Jan Markussen , Ivan Diers
IPC分类号： C12P21/06
CPC分类号： C07K1/30 , C07K14/62
摘要： Process for purifying a fermentation-derived product.
摘要翻译：纯化发酵产物的方法。

15. 发明授权

US5008241A Novel insulin peptides 失效
标题翻译：新型胰岛素肽
公开(公告)号：US5008241A
公开(公告)日：1991-04-16
申请号：US424503
申请日：1989-10-20
申请人： Jan Markussen , Kjeld Norris , Liselotte Langkjaer
发明人： Jan Markussen , Kjeld Norris , Liselotte Langkjaer
IPC分类号： A61K38/00 , C07K14/62 , A61K37/26 , C07K7/40 , C07K7/42
CPC分类号： C07K14/62 , A61K38/00 , Y10S514/866
摘要： Insulin analogs characterized by amino acid residue at A21 other than Asn, with a resulting improvement in stability of insulin solutions at acid pH levels. Some insulin analogs may also have amino acid residue changes elsewhere so that these insulin analogs exhibit at least about one charge more than human insulin at a pH value of 7, with preferred substitutions being made for the glutamic acid residues at A4, A17, B13, B21 and/or a basic amino acid residue being substituted at B27. Also contemplated is optional blocking the C-terminal carboxyl group of the B-chain with an amido or ester residue.
摘要翻译：胰岛素类似物的特征在于As21以外的A21处的氨基酸残基，导致胰岛素溶液在酸性pH水平下的稳定性得到改善。一些胰岛素类似物也可能在其他地方具有氨基酸残基变化，使得这些胰岛素类似物在pH值为7时表现出比人胰岛素更多的至少约一个电荷，对A4，A17，B13的谷氨酸残基进行优选的取代， B21和/或在B27被取代的碱性氨基酸残基。还考虑到任选地用酰氨基或酯残基封闭B链的C-末端羧基。

16. 发明授权

US09260501B2 Peptide extended insulins 有权
标题翻译：肽延长胰岛素
公开(公告)号：US09260501B2
公开(公告)日：2016-02-16
申请号：US12312132
申请日：2007-10-29
申请人： Thomas Høeg-Jensen , Thomas Børglum Kjeldsen , Jan Markussen
发明人： Thomas Høeg-Jensen , Thomas Børglum Kjeldsen , Jan Markussen
IPC分类号： A61K38/28 , C07K14/62 , A61K47/48
CPC分类号： C07K14/62 , A61K47/48246 , A61K47/64
摘要： Insulins to which there is connected an amino acid oligomer have satisfactory properties.
摘要翻译：与氨基酸低聚物连接的胰岛素具有令人满意的性能。

17. 发明授权

US4489159A Process for preparing esters of human insulin 失效
标题翻译：制备人胰岛素酯的方法
公开(公告)号：US4489159A
公开(公告)日：1984-12-18
申请号：US406571
申请日：1982-08-09
申请人： Jan Markussen
发明人： Jan Markussen
IPC分类号： C12P21/02 , A61K38/00 , C07K1/113 , C07K14/575 , C07K14/62 , C12P21/04 , C12N9/76
CPC分类号： C07K14/62 , A61K38/00
摘要： A process for converting human des-B30-insulin, namely ##STR1## into h-In-Thr.sup.B30 esters through amidation with an L-threonine ester in a mixture of water and a water miscible solvent in the presence of trypsin and optionally an acid.Yields in excess of at least 90% are obtained by limiting water content to 10%-30% v/v of the reaction mixture.
摘要翻译：通过在胰蛋白酶和任选的酸存在下，在水与水混溶性溶剂的混合物中与L-苏氨酸进行酰胺化，将人类des-B30-胰岛素即IAG转化成h-In-ThrB30酯的方法。通过将水含量限制在10％-30％v / v的反应混合物中，可获得超过至少90％的产率。

18. 发明申请

US20060264606A1 Processes for making acylated insulin 失效
标题翻译：制备酰化胰岛素的方法
公开(公告)号：US20060264606A1
公开(公告)日：2006-11-23
申请号：US11418004
申请日：2006-05-03
申请人： Thomas Kjeldsen , Jan Markussen
发明人： Thomas Kjeldsen , Jan Markussen
IPC分类号： A61K38/28 , C07K14/62
CPC分类号： C12P21/06 , C07K14/62
摘要： A method is provided which allows high yields of acylated insulin. The method comprises expressing a singe-chain insulin precursor, preferably in yeast, cleaving the single-chain insulin precursor with a suitable protease which will open the peptide bond between the C-terminal amino group in the B-chain and a connecting peptide connecting the B chain with the A-chain, acylating the two-chain insulin intermediate in the ε-amino group in LysB29 and subjecting the acylated two-chain insulin intermediate to a proteolytic enzyme which will cleave of the N-terminal extension on the B- and A-chains on the precursor molecule.
摘要翻译：提供了一种允许高产量的酰化胰岛素的方法。所述方法包括将优选在酵母中的单链胰岛素前体表达，用合适的蛋白酶切割单链胰岛素前体，所述蛋白酶将打开B链中的C末端氨基与连接肽之间的连接肽 B链与A链反应，在Lys B29中的ε-氨基中酰化两链胰岛素中间体，并使酰化的双链胰岛素中间体进行蛋白水解酶，其将切割N 在前体分子上的B-链和A链上的末端延伸。

19. 发明授权

US4916212A DNA-sequence encoding biosynthetic insulin precursors and process for preparing the insulin precursors and human insulin 失效
标题翻译：编码生物合成胰岛素前体的DNA序列和制备胰岛素前体和人胰岛素的方法
公开(公告)号：US4916212A
公开(公告)日：1990-04-10
申请号：US739123
申请日：1985-05-29
申请人： Jan Markussen , Niels Fiil , Mogens T. Hansen , Kjeld Norris , Gustav Ammerer , Lars Thim , Hans O. Voigt
发明人： Jan Markussen , Niels Fiil , Mogens T. Hansen , Kjeld Norris , Gustav Ammerer , Lars Thim , Hans O. Voigt
IPC分类号： C07K14/575 , C07K14/62 , C12N1/16 , C12N1/19 , C12N15/00 , C12N15/09 , C12N15/17 , C12N15/62 , C12N15/69 , C12N15/81 , C12P21/02 , C12R1/865
CPC分类号： C12N15/69 , C07K14/62 , C12N15/62 , C12N15/81 , C07K2319/02 , Y10S435/942
摘要： Human insulin precursors containing the peptide chain B(1-29)-A(1-21) of human insulin and derivatives thereof with a bridging chain connecting the carboxyl terminus of the B(1-29)-chain with the amino terminus of the A(1-21)-chain are prepared by culturing a yeast host transformed with a replicable expression vehicle capable of expressing a DNA-sequence encoding the insulin precursor. The bridging chain is preferably relatively short and contains preferably from 2 to 8 amino acid residues. The bridging chain must not contain two adjacent basic amino acid residues (Lys or Arg) and has one Lys or Arg connected to the amino terminus of the A(1-21)-chain. Human insulin is prepared from the insulin precursors by in vitro conversion.
摘要翻译：含有人胰岛素的肽链B（1-29）-A（1-21）及其衍生物的人胰岛素前体与将B（1-29）链的羧基末端与氨基末端连接的桥连链通过培养用能够表达编码胰岛素前体的DNA序列的可复制表达载体转化的酵母宿主制备A（1-21）链。桥连链优选相对较短，优选含有2-8个氨基酸残基。桥连链不能包含两个相邻的碱性氨基酸残基（Lys或Arg），并且具有连接到A（1-21）链氨基末端的一个Lys或Arg。通过体外转化从胰岛素前体制备人胰岛素。

20. 发明申请

US20100069605A1 PEPTIDE EXTENDED INSULINS 有权
标题翻译：肽延长胰岛素
公开(公告)号：US20100069605A1
公开(公告)日：2010-03-18
申请号：US12312132
申请日：2007-10-29
申请人： Thomas Høeg-Jensen , Thomas Børglum Kjeldsen , Jan Markussen
发明人： Thomas Høeg-Jensen , Thomas Børglum Kjeldsen , Jan Markussen
IPC分类号： C07K14/62
CPC分类号： C07K14/62 , A61K47/48246 , A61K47/64
摘要： Insulins to which there is connected an amino acid oligomer have satisfactory properties.
摘要翻译：与氨基酸低聚物连接的胰岛素具有令人满意的性能。

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