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1. 发明申请

US20130338068A1 DOUBLE-ACYLATED GLP-1 DERIVATIVES WITH A LINKER 有权
标题翻译：具有连接子的双取代的GLP-1衍生物
公开(公告)号：US20130338068A1
公开(公告)日：2013-12-19
申请号：US13883946
申请日：2011-11-09
申请人： Jacob Kofoed , Jesper Lau , Lars Linderoth , Patrick William Garibay , Thomas Kruse
发明人： Jacob Kofoed , Jesper Lau , Lars Linderoth , Patrick William Garibay , Thomas Kruse
IPC分类号： C07K14/605
CPC分类号： C07K14/605 , A61K47/542
摘要： The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue at a position corresponding to position 18 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at another position, and a maximum of twelve amino acid changes as compared to GLP-1(7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is selected from HOOC—(CH2)x—CO-*, and Chem. 1: HOOC—C6H4-0-(CH2)y—CO-*, Chem. 2: in which x is an integer in the range of 6-18, and y is an integer in the range of 3-17; and the linker comprises *-NH—(CH2)q—CH[(CH2)w—NH2]—CO-*, Chem. 3: wherein q is an integer in the range of 0-5, and w is an integer in the range of 0-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptides and side chain intermediates. The derivatives are potent, protracted, and suitable for oral administration.
摘要翻译：本发明涉及GLP-1类似物的衍生物，其类似物包含在对应于GLP-1（7-37）（SEQ ID NO：1）的第18位的位置处的第一个K残基，另一个的第二个K残基位置和与GLP-1（7-37）相比最多12个氨基酸变化; 该衍生物分别包含通过接头分别连接到所述第一和第二K残基的两个伸长部分，其中伸长部分选自HOOC-（CH 2）x -CO- *和Chem。 1：HOOC-C6H4-0-（CH2）y-CO- *，Chem。 2：其中x是6-18的整数，y是3-17的整数; 并且连接体包含* -NH-（CH 2）q-CH [（CH 2）w -NH 2] -CO - *， 3：其中q是0-5的整数，w是0-5的整数; 或其药学上可接受的盐，酰胺或酯。本发明还涉及其药物用途，例如用于治疗和/或预防所有形式的糖尿病和相关疾病，以及相应的新型肽和侧链中间体。衍生物有效，延长，适合口服。

2. 发明授权

US09708383B2 Double-acylated GLP-1 derivatives 有权
公开(公告)号：US09708383B2
公开(公告)日：2017-07-18
申请号：US13882947
申请日：2011-11-09
申请人： Alice Ravn Madsen , Birgit Wieczorek , Jacob Kofoed , Jesper Lau , Jane Spetzler , Janos Tibor Kodra , Lars Linderoth , Patrick William Garibay , Per Sauerberg , Thomas Kruse
发明人： Alice Ravn Madsen , Birgit Wieczorek , Jacob Kofoed , Jesper Lau , Jane Spetzler , Janos Tibor Kodra , Lars Linderoth , Patrick William Garibay , Per Sauerberg , Thomas Kruse
IPC分类号： A61K38/00 , C07K14/605 , A61K47/48
CPC分类号： C07K14/605 , A61K47/542
摘要： The invention relates to a derivative of a GLP-1 analog, which analog comprises a first K residue at a position corresponding to position 18 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at another position, and a maximum of twelve amino acid changes as compared to GLP-1(7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is selected from Chem. 1, Chem. 2, and Chem. 3: HOOC—(CH2)x—CO—* Chem. 1: HOOC—C6H4—O—(CH2)y—CO—* Chem. 2: R2—C6H4—(CH2)z—CO—*, Chem. 3: in which x is an integer in the range of 6-18, y is an integer in the range of 3-17, z is an integer in the range of 1-5, and R2 is a group having a molar mass not higher than 150 Da; and the linker comprises *—NH—(CH2)2—(O—(CH2)2)k—O—(CH2)n—CO—*. Chem. 4: wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptides and side chain intermediates. The derivatives are suitable for oral administration.

3. 发明授权

US09006178B2 Double-acylated GLP-1 derivatives with a linker 有权
标题翻译：具有接头的双酰化GLP-1衍生物
公开(公告)号：US09006178B2
公开(公告)日：2015-04-14
申请号：US13883946
申请日：2011-11-09
申请人： Jacob Kofoed , Jesper Lau , Lars Linderoth , Patrick William Garibay , Thomas Kruse
发明人： Jacob Kofoed , Jesper Lau , Lars Linderoth , Patrick William Garibay , Thomas Kruse
IPC分类号： A61K38/26 , A61P3/10 , A61P7/12 , C07K14/605 , A61K38/28 , C07K5/00 , C07K7/00 , C07K16/00 , C07K17/00 , A61K47/48
CPC分类号： C07K14/605 , A61K47/542
摘要： The invention relates to a derivative of a GLP-1 analog, which analog comprises a first K residue at a position corresponding to position 18 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at another position, and a maximum of twelve amino acid changes as compared to GLP-1(7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is selected from Chem. 1: HOOC—(CH2)x—CO—*, and Chem. 2: HOOC—C6H4-0-(CH2)y—CO—*, in which x is an integer in the range of 6-18, and y is an integer in the range of 3-17; and the linker comprises Chem. 3: *—NH—(CH2)q—CH[(CH2)w—NH2]—CO—*, wherein q is an integer in the range of 0-5, and w is an integer in the range of 0-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptides and side chain intermediates. The derivatives are potent, protracted, and suitable for oral administration.
摘要翻译：本发明涉及GLP-1类似物的衍生物，其类似物包含在对应于GLP-1（7-37）（SEQ ID NO：1）的第18位的位置处的第一个K残基，另一个的第二个K残基位置和与GLP-1（7-37）相比最多12个氨基酸变化; 该衍生物分别包含通过接头分别连接到所述第一和第二K残基的两个伸长部分，其中伸长部分选自Chem。 1：HOOC-（CH 2）x-CO- *，和Chem。 2：HOOC-C6H4-0-（CH2）y-CO- *，其中x是6-18的整数，y是3-17的整数; 连接体包括Chem。 3：* -NH-（CH 2）q-CH [（CH 2）w -NH 2] -CO- *，其中q是0-5的整数，w是0-5的整数 ; 或其药学上可接受的盐，酰胺或酯。本发明还涉及其药物用途，例如用于治疗和/或预防所有形式的糖尿病和相关疾病，以及相应的新型肽和侧链中间体。衍生物有效，延长，适合口服。

4. 发明申请

US20130288960A1 Double-Acylated GLP-1 Derivatives 有权
标题翻译：双酰化GLP-1衍生物
公开(公告)号：US20130288960A1
公开(公告)日：2013-10-31
申请号：US13882947
申请日：2011-11-09
申请人： Alice Ravn Madsen , Birgit Wieczorek , Jacob Kofoed , Jesper Lau , Jane Spetzler , Janos Tibor Kodra , Lars Linderoth , Patrick William Garibay , Per Sauerberg , Thomas Kruse
发明人： Alice Ravn Madsen , Birgit Wieczorek , Jacob Kofoed , Jesper Lau , Jane Spetzler , Janos Tibor Kodra , Lars Linderoth , Patrick William Garibay , Per Sauerberg , Thomas Kruse
IPC分类号： C07K14/605
CPC分类号： C07K14/605 , A61K47/542
摘要： The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue at a position corresponding to position 18 of GLP-1 (7-37) (SEQ ID NO: 1), a second K residue at another position, and a maximum of twelve amino acid changes as compared to GLP-1 (7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is selected from Chem. 1, Chem. 2, and Chem. 3: Chem.: HOOC—(CH2)x—CO—* Chem. 2: HOOC—C6H4-0-(CH2)y—CO—* Chem. 3: R2—C6H4—(CH2)z—CO—*, in which x is an integer in the range of 6-18, y is an integer in the range of 3-17, z is an integer in the range of 1-5, and R2 is a group having a molar mass not higher than 150 Da; and the linker comprises Chem. 4: *—NH—(CH2)2-(0-(CH2)2)k-0-(CH2)n—CO—*. wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptides and side chain intermediates. The derivatives are suitable for oral administration.
摘要翻译：本发明涉及GLP-1类似物的衍生物，其类似物包含在对应于GLP-1（7-37）（SEQ ID NO：1）的第18位的位置处的第一个K残基，另一个的第二个K残基位置和与GLP-1（7-37）相比最多12个氨基酸变化; 该衍生物分别包含通过接头分别连接到所述第一和第二K残基的两个伸长部分，其中伸长部分选自Chem。 1，Chem。 2和Chem。 3：化学式：HOOC-（CH2）x-CO- * 2：HOOC-C6H4-0-（CH2）y-CO- * Chem。 3：R2-C6H4-（CH2）z-CO- *，其中x是6-18的整数，y是3-17的整数，z是1的整数 -5和R2是摩尔质量不高于150Da的基团; 连接体包括Chem。 4：* -NH-（CH 2）2 - （O-（CH 2）2）k -O-（CH 2）n -CO- *。其中k是1-5的整数，n是1-5的整数; 或其药学上可接受的盐，酰胺或酯。本发明还涉及其药物用途，例如用于治疗和/或预防所有形式的糖尿病和相关疾病，以及相应的新型肽和侧链中间体。该衍生物适用于口服给药。

5. 发明申请

US20130053311A1 GLP-1 ANALOGUES AND DERIVATIVES 有权
标题翻译： GLP-1类似物和衍生物
公开(公告)号：US20130053311A1
公开(公告)日：2013-02-28
申请号：US13516312
申请日：2010-12-16
申请人： Christoph Kalthoff , Jesper Lau , Jane Spetzler , Patrick William Garibay , Jacob Kofoed , Lars Linderoth
发明人： Christoph Kalthoff , Jesper Lau , Jane Spetzler , Patrick William Garibay , Jacob Kofoed , Lars Linderoth
IPC分类号： A61K38/26 , A61P3/10 , C07K14/605
CPC分类号： C07K14/65 , A61K38/00 , A61K47/542 , A61K47/60 , C07K14/605 , G01N2333/605
摘要： The invention relates to a GLP-1 analogue which comprises a histidine (H) residue at a position corresponding to position 31 of GLP-1 (7-37) (SEQ ID NO: 1), a glutamine (Q) residue at a position corresponding to position 34 of GLP-1 (7-37) (SEQ ID NO: 1), and a maximum of ten amino acid modifications as compared to GLP-1 (7-37) (SEQ ID NO: 1); wherein the H residue is designated H31, and the Q residue is designated Q34; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to derivatives thereof, as well as the pharmaceutical use of these analogues and derivatives, for example in the treatment and/or prevention of all forms of diabetes and related diseases. The invention furthermore relates to corresponding novel side chain intermediates. The derivatives are suitable for oral administration.
摘要翻译：本发明涉及GLP-1类似物，其包含在对应于GLP-1（7-37）（SEQ ID NO：1）的第31位的位置处的组氨酸（H）残基，位置上的谷氨酰胺（Q）残基对应于GLP-1（7-37）（SEQ ID NO：1）的位置34，与GLP-1（7-37）（SEQ ID NO：1）相比最多为10个氨基酸修饰。其中H残基指定为H31，Q残基指定为Q34; 或其药学上可接受的盐，酰胺或酯。本发明还涉及其衍生物，以及这些类似物和衍生物的药物用途，例如用于治疗和/或预防所有形式的糖尿病和相关疾病。本发明还涉及相应的新型侧链中间体。该衍生物适用于口服给药。

6. 发明授权

US08815802B2 GLP-1 analogues and derivatives 有权
标题翻译： GLP-1类似物和衍生物
公开(公告)号：US08815802B2
公开(公告)日：2014-08-26
申请号：US13516312
申请日：2010-12-16
申请人： Christoph Kalthoff , Jesper Lau , Jane Spetzler , Patrick William Garibay , Jacob Kofoed , Lars Linderoth
发明人： Christoph Kalthoff , Jesper Lau , Jane Spetzler , Patrick William Garibay , Jacob Kofoed , Lars Linderoth
IPC分类号： A61K38/26 , A61P3/10 , C07K14/605 , A61K38/00 , C07K14/65
CPC分类号： C07K14/65 , A61K38/00 , A61K47/542 , A61K47/60 , C07K14/605 , G01N2333/605
摘要： The invention relates to a GLP-1 analog which comprises a histidine (H) residue at a position corresponding to position 31 of GLP-1(7-37) (SEQ ID NO: 1), a glutamine (Q) residue at a position corresponding to position 34 of GLP-1 (7-37) (SEQ ID NO: 1), and a maximum of ten amino acid modifications as compared to GLP-1 (7-37) (SEQ ID NO: 1); wherein the H residue is designated H31, and the Q residue is designated Q34; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to derivatives thereof, as well as the pharmaceutical use of these analogs and derivatives, for example in the treatment and/or prevention of all forms of diabetes and related diseases. The invention furthermore relates to corresponding novel side chain intermediates. The derivatives are suitable for oral administration.
摘要翻译：本发明涉及GLP-1类似物，其在对应于GLP-1（7-37）（SEQ ID NO：1）的位置31的位置处的组氨酸（H）残基，位置上的谷氨酰胺（Q）残基对应于GLP-1（7-37）（SEQ ID NO：1）的位置34，与GLP-1（7-37）（SEQ ID NO：1）相比最多为10个氨基酸修饰。其中H残基指定为H31，Q残基指定为Q34; 或其药学上可接受的盐，酰胺或酯。本发明还涉及其衍生物，以及这些类似物和衍生物的药物用途，例如用于治疗和/或预防所有形式的糖尿病和相关疾病。本发明还涉及相应的新型侧链中间体。该衍生物适用于口服给药。

7. 发明申请

US20140303083A1 GLP-1 Derivatives 有权
标题翻译： GLP-1衍生物
公开(公告)号：US20140303083A1
公开(公告)日：2014-10-09
申请号：US14343152
申请日：2012-09-06
申请人： Jesper Lau , Paw Bloch , Jacob Kofoed , Patrick William Garibay
发明人： Jesper Lau , Paw Bloch , Jacob Kofoed , Patrick William Garibay
IPC分类号： C07K14/605
CPC分类号： C07K14/605 , A61K38/00 , A61K38/26
摘要： The invention relates to a derivative of a GLP-1 peptide, which peptide has two Lys residues, namely a first and a second Lys residue, and a maximum of eight amino acid changes as compared to GLP-1(7-37) (SEQ ID NO: 3), which derivative comprises two protracting moieties attached to the epsilon amino group of said first and second Lys residue, respectively, via a linker, wherein the protracting moiety is selected from Chem. 15: HOOC—(CH2)x-CO—*, and Chem. 16: HOOC—C6H4-O—(CH2)y-CO—*, in which x is an integer in the range of 10-16, and y is an integer in the range of 8-12; and the linker comprises a first linker element *—NH—CH(CH2OH)—CO—*. A preferred linker is g Glu-Ser-Ser-Gly-Ser-Ser-Gly (SEQ ID NO: 2). The derivative of the invention has a very good potency, and a very good binding to the GLP-1 receptor. The invention also relates to the pharmaceutical use of the derivative, for example in the treatment and/or prevention of all forms of diabetes and related diseases.
摘要翻译：本发明涉及GLP-1肽的衍生物，该肽与GLP-1（7-37）（SEQ）相比具有两个Lys残基，即第一和第二Lys残基，最多八个氨基酸变化 SEQ ID NO：3），该衍生物分别包含通过接头分别连接到所述第一和第二Lys残基的ε氨基的两个伸长部分，其中伸长部分选自Chem。 15：HOOC-（CH 2）x-CO- *，和Chem。 16：HOOC-C6H4-O-（CH2）y-CO- *，其中x是10-16的整数，y是8-12的整数; 并且连接体包含第一连接体元件* -NH-CH（CH 2 OH）-CO- *。优选的接头是g Glu-Ser-Ser-Gly-Ser-Ser-Gly（SEQ ID NO：2）。本发明的衍生物具有非常好的效力，并且与GLP-1受体具有非常好的结合。本发明还涉及衍生物的药物用途，例如用于治疗和/或预防所有形式的糖尿病和相关疾病。

8. 发明授权

US08648041B2 Double-acylated GLP-1 derivatives 有权
标题翻译：双酰化GLP-1衍生物
公开(公告)号：US08648041B2
公开(公告)日：2014-02-11
申请号：US12970196
申请日：2010-12-16
申请人： Patrick William Garibay , Lars Linderoth , Jesper Lau , Per Sauerberg
发明人： Patrick William Garibay , Lars Linderoth , Jesper Lau , Per Sauerberg
IPC分类号： A61K38/22 , C07K14/575
CPC分类号： C07K14/65 , A61K38/00 , A61K47/542 , A61K47/60 , C07K14/605 , G01N2333/605
摘要： The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue at a position corresponding to position 37 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at a position corresponding to position 26 of GLP-1(7-37), and a maximum of ten amino acid modifications as compared to GLP-1(7-37), wherein the first K residue is designated K37, and the second K residue is designated K26, which derivative comprises two albumin binding moieties attached to K26 and K37, respectively, wherein the albumin binding moiety comprises a protracting moiety selected from:Chem. 1, Chem. 2, Chem. 3 or Chem. 4; or a pharmaceutically acceptable salt, amide, or ester thereof.
摘要翻译：本发明涉及GLP-1类似物的衍生物，其类似物包含在对应于GLP-1（7-37）（SEQ ID NO：1）的第37位的位置处的第一个K残基，相对于GLP-1（7-37）的位置26的位置和与GLP-1（7-37）相比最多10个氨基酸修饰，其中第一个K残基指定为K37，第二个K残基是命名为K26，该衍生物分别包含与K26和K37连接的两个白蛋白结合部分，其中白蛋白结合部分包含选自下列的伸长部分： 1，Chem。 2，Chem。 3或Chem。 4; 或其药学上可接受的盐，酰胺或酯。

9. 发明申请

US20100292133A1 TRUNCATED GLP-1 DERIVATIES AND THEIR THERAPEUTICAL USE 审中-公开
标题翻译：截短的GLP-1衍生物及其治疗用途
公开(公告)号：US20100292133A1
公开(公告)日：2010-11-18
申请号：US12676453
申请日：2008-09-05
申请人： Jane Spetzler , Lauge Schäffer , Jesper Lau , János Tibor Kodra , Kjeld Madsen , Patrick William Garibay , Jacob Kofoed , Steffen Reedtz-Runge , Henning Thøgersen , Igrid Pettersson
发明人： Jane Spetzler , Lauge Schäffer , Jesper Lau , János Tibor Kodra , Kjeld Madsen , Patrick William Garibay , Jacob Kofoed , Steffen Reedtz-Runge , Henning Thøgersen , Igrid Pettersson
IPC分类号： C07K14/605 , A61K38/26 , A61P3/10 , A61P3/00 , A61P3/06 , A61P3/08 , A61P9/10 , A61P9/00
CPC分类号： C07K14/605 , A61K38/00
摘要： The invention relates to truncated GLP-1 analogues, in particular a GLP-1 analogue which is a modified GLP-1(7-35) (SEQ ID No 1) having: i) a total of 2, 3, 4, 5 6, 7, 8, or 9 amino acid substitutions as compared to GLP-1(7-35), including a) a Glu residue at a position equivalent to position 22 of GLP-1(7-35), and b) an Arg residue at a position equivalent to position 26 of GLP-1(7-35); as well as derivatives thereof, and therapeutic uses and compositions. These analogues and derivatives are highly potent, have a good binding affinity to the GLP-1 receptor, also to the extracellular domain of the GLP-1 receptor, which is of potential relevance achieving long-acting, stable GLP-1 compounds with a potential for once weekly administration.
摘要翻译：本发明涉及截短的GLP-1类似物，特别是GLP-1类似物，其是修饰的GLP-1（7-35）（SEQ ID No.1），其具有：i）总共2,3,4,5,6 ，7,8或9个氨基酸取代，其包括a）在等同于GLP-1（7-35）的位置22的位置上的Glu残基，和b）Arg 在等同于GLP-1（7-35）的第26位的位置上的残基; 以及其衍生物，以及治疗用途和组合物。这些类似物和衍生物是高度有效的，对GLP-1受体以及GLP-1受体的细胞外结构域具有良好的结合亲和力，这与具有潜在的长效，稳定的GLP-1化合物具有潜在的相关性每周一次行政。

10. 发明申请

US20110082079A1 GLUCAGON-LIKE PEPTIDE-1 DERIVATIVES AND THEIR PHARMACEUTICAL USE 有权
标题翻译： GLUCAGON-LIKE PEPTIDE-1衍生物及其药物用途
公开(公告)号：US20110082079A1
公开(公告)日：2011-04-07
申请号：US12676451
申请日：2008-09-05
申请人： Jane Spetzler , Lauge Schäffer , Jesper Lau , Thomas Kruse , Patrick William Garibay , Steffen Runge , Henning Thøgersen , Ingrid Petersson
发明人： Jane Spetzler , Lauge Schäffer , Jesper Lau , Thomas Kruse , Patrick William Garibay , Steffen Runge , Henning Thøgersen , Ingrid Petersson
IPC分类号： A61K38/22 , C07K14/575 , A61P3/10 , A61P9/12 , A61P3/04 , A61P9/10 , A61P1/00 , A61P1/04
CPC分类号： C07K14/605 , A61K38/26
摘要： The invention relates to protracted Glucagon-Like Peptide-1 (GLP-1) derivatives and therapeutic uses thereof. The GLP-1 derivative of the invention comprises a modified GLP-1(7-37) sequence having a total of 2-12 amino acid modifications, including Glu22 and Arg26, and being derivatised with an albumin binding residue or pegylated in position 18, 20, 23, 30, 31, 34, 36, 37, or 39. These compounds are useful in the treatment or prevention of diabetes type 2 and related diseases. The compounds are potent, stable, have long half-lives, a high affinity of binding to albumin, and/or a high affinity of binding to the extracellular domain of the GLP-1 receptor (GLP-1R), all of which is of potential relevance for the overall aim of achieving long-acting, stable and active GLP-1 derivatives with a potential for once weekly administration.
摘要翻译：本发明涉及长效的胰高血糖素样肽-1（GLP-1）衍生物及其治疗用途。本发明的GLP-1衍生物包含具有总共2-12个氨基酸修饰的修饰的GLP-1（7-37）序列，包括Glu22和Arg26，并用白蛋白结合残基衍生或在18位聚乙二醇化， 20,23,30,31,34,36,37或39.这些化合物可用于治疗或预防2型糖尿病和相关疾病。该化合物是有效的，稳定的，具有长的半衰期，与白蛋白结合的高亲和力，和/或与GLP-1受体（GLP-1R）细胞外结构域结合的高亲和力，所有这些都是对于实现长效，稳定和活性的GLP-1衍生物的总体目标的潜在相关性，具有每周一次行政的潜力。

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