MODULATION OF TYPE IIbeta PHOSPHOINOSITIDE PHOSPHATE KINASE 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
WO03064451 A2 2003-08-07 [WO200364451]WO03064451 A3 2003-09-04 [WO200364451] / 2003-08-072003-09-04
申请号/申请日
2003WO-US03065 / 2003-02-03
发明人
CANTLEY LEWIS C;LAMIA KATJA A;RAMEH LUCIA;KAHN BARBARA;PERONI ODILE;
申请人
BETH ISRAEL HOSPITAL;
主分类号
IPC分类号
A01K-067/027A61K-031/155A61K-031/198A61K-031/427A61K-031/4439A61K-031/4453A61K-031/64A61K-031/7088A61K-038/00A61K-038/28A61K-045/00A61K-045/06A61K-049/00A61P-003/04A61P-003/10A61P-043/00C12N-009/12C12N-015/09C12N-015/85C12Q-001/02C12Q-
摘要
(WO200364451) The invention provides methods for modulating type IIbeta phosphoinisitide phosphate kinase PIPKIIbeta activity for treating PIPKIIbeta-associated disorders.  The invention also provides methods of identifying candidate agents for treating PIPKIIbeta-associated disorders.
机翻摘要
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地址
代理人
代理机构
;
优先权号
2002US-60353758 2002-02-01
主权利要求
(WO200364451) Claims 1. A method of treating a subject having or suspected of having type II diabetes comprising: administering to a subject in need of such treatment an effective amount of an agent that reduces the activity of PEPKII/3 in the subject, as a treatment for the type II diabetes. 2. The method of claim 1, further comprising administering a pharmaceutical agent that increases sensitivity of tissues to insulin to the subject. 3. The method of claim 2, wherein the pharmaceutical agent is selected from the group consisting of: metformin, pioglitazone, and rosiglitazone. 4. The method of claim 1, further comprising administering a pharmaceutical agent that increases insulin release. 5. The method of claim 4, wherein the pharmaceutical agent is selected from the group consisting of sulfonylureas, nateglinide and repaglinide. 6. The method of claim 5, wherein the sulfonylurea is selected from the group consisting of: glibenclamide (glyburide), gliclazide and glimepiride. 7. The method of claim 1, further comprising administering insulin to the subject. 8. The method of claim 1 , wherein the agent is a PIPKII/3 inhibitor. 9. The method of claim 1, wherein the agent is an PEPKII/3 antisense sequence. 10. A method of treating a subject having or suspected of having reduced insulin sensitivity comprising: administering to a subject in need of such treatment an effective amount of an agent that reduces the activity of PEPKII/3 in the subject, as a treatment for the reduced insulin sensitivity. 11. The method of claim 10, further comprising administering a pharmaceutical agent that increases sensitivity of tissues to insulin to the subject. 12. The method of claim 11, wherein the pharmaceutical agent is selected from the group consisting of: metformin, pioglitazone, and rosiglitazone. 13. The method of claim 10, further comprising administering a pharmaceutical agent that increases insulin release. 14. The method of claim 13, wherein the pharmaceutical agent is selected from the group consisting of sulfonylureas, nateglinide and repaglinide. 15. The method of claim 14, wherein the sulfonylurea is selected from the group consisting of: glibenclamide (glyburide), gliclazide and glimepiride. 16. The method of claim 10, further comprising administering insulin to the subject. 17. The method of claim 10, wherein the agent is a PIPKII/3 inhibitor. 18. The method of claim 10, wherein the agent is an PEPKII/S antisense sequence. 19. A method of treating a subject having or suspected of having obesity comprising: administering to a subject in need of such treatment an effective amount of an agent that reduces the activity of PEPKII/3 in the subject, as a treatment for the obesity. 20. The method of claim 19, wherein the agent is a PIPKII/3 inhibitor. 21. The method of claim 19, wherein the agent is an PEPKII/3 antisense sequence. 22. A method of treating a subject having or suspected of having excess fat accumulation comprising: administering to a subject in need of such treatment an effective amount of an agent that reduces the activity of PEPKIIjS in the subject, as a treatment for the excess fat accumulation. 23. The method of claim 22, wherein the agent is a PEPKIIjS inhibitor. 24. The method of claim 22, wherein the agent is an PEPKIIS antisense sequence. 25. A method of treating a subject having or suspected of having an increased sensitivity to insulin comprising: administering to a subject in need of such treatment an agent that increases the activity of PEPKII/3 in the subject, as a treatment for increased sensitivity to insulin. 26. A method for identifying an agent that decreases PEPKIIjS activity, comprising: determining a first amount of activity of a PEPKII/3 polypeptide, contacting the PEPKII/3 polypeptide with a candidate pharmacological agent, determining the amount of activity of the contacted PEPKII/3 polypeptide, wherein a decrease in the amount of activity of the contacted PEPKII/3 polypeptide relative to the first amount of activity of the PPKII/3 polypeptide is an indication that the candidate pharmacological agent decreases PEPKII/3 activity. 27. The method of claim 26, wherein the PEPKII/3 polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ED NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ED NO:l . 28. The method of claim 26, wherein the PEPKII/3 polypeptide comprises an amino acid sequence set forth as SEQ ED NO: 2. 29. A method for identifying an agent that increases PEPKIIjS activity, comprising: determining a first amount of activity of a PEPKII/3 polypeptide, contacting the PEPKIIjS polypeptide with a candidate pharmacological agent, determining the amount activity of the contacted PEPKIIjS polypeptide, wherein an increase in the amount of activity in the contacted PEPKIIjS polypeptide relative to the first amount of activity of the PEPKII/3 polypeptide is an indication that the candidate pharmacological agent increases PEPKIIjS activity. 30. The method of claim 29, wherein the PEPKIIjS polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ID NO: 1 , or having at least about 95% homology to the nucleotide sequence set forth as SEQ ED NO: 1. 31. The method of claim 29, wherein the PEPKII/3 polypeptide comprises an amino acid sequence set forth as SEQ ID NO: 2. 32. A method of diagnosing a PEPKIIjS-associated disorder in a subject comprising: obtaining a biological sample from a subject, determining the level of activity of a PEPKII/3 polypeptide molecule in the biological sample, comparing the level of activity of the PEPKII/3 polypeptide molecule in the biological sample with the level of activity of a PEPKII/3 polypeptide molecule in a control tissue, wherein a higher level of activity of the PEPKIIjS polypeptide molecule in the biological sample from the subject than the activity of the PIPKIIjS polypeptide molecule in the control sample is diagnostic for a PEPKII/3-associated disorder in the subject. 33. The method of claim 32, wherein the PIPKIIjS polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ID NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ED NO: 1. 34. The method of claim 32, wherein the PEPKII/3 polypeptide comprises an amino acid sequence set forth as SEQ ID NO: 2. 35. The method of claim 32, wherein the biological sample is selected from the group consisting of: tissue and cells. 36. The method of claim 35, wherein the tissue or cells is selected from the group consisting of: skeletal muscle, brain, and adipose tissue. 37. The method of claim 32, wherein the activity is determined with a kinase assay. 38. The method of claim 32, wherein the PEPKII/3-associated disorder is selected from the group consisting of: diabetes and obesity. 39. A method for preparing an animal model of a disorder characterized by increased activity of a PEPKIIjS molecule, comprising: introducing into a non-human subject a PEPKIIjS molecule that increases PIPKII/3 activity. 40. The method of claim 39, wherein the PIPKII/3 molecule is a PEPKIIjS nucleic acid molecule. 41. The method of claim 40, wherein the PEPKIIjS nucleic acid molecule comprises a nucleotide sequence set forth as SEQ ED NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO:l. 42. The method of claim 39, wherein the PIPKIIjS molecule is a PEPKIIjS polypeptide. 43. The method of claim 42, wherein the PIPKIIjS polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ED NO: 1 , or having at least about 95% homology to the nucleotide sequence set forth as SEQ ED NO:l. 44. The method of claim 42, wherein the PIPKII/3 polypeptide comprises an amino acid sequence set forth as SEQ ED NO: 2. 45. The method of claim 39, wherein the animal model is of a disorder that is selected from the group consisting of: type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity. 46. A method for preparing an animal model of a disorder characterized by decreased expression of a PEPKII/3 molecule, comprising: introducing into a non-human subject, a mutant PIPKII/3 molecule, that decreases PEPKII/3 activity. 47. The method of claim 46, wherein the PEPKII/3 molecule is a mutant PEPKII/3 nucleic acid molecule. 48. The method of claim 46, wherein the PEPKII/3 molecule is a mutant PEPKII/3 polypeptide. 49. A method for evaluating the effect of a candidate pharmacological agent on a PEPKII/3-associated disorder, comprising: administering a candidate pharmaceutical agent to a subject with a PEPKII/3-associated disorder; determining the effect of the candidate pharmaceutical agent on the activity level of a PEPKII/3 polypeptide relative to the activity level of a PEPKII/3 polypeptide in a subject to which no candidate pharmaceutical agent is administered, wherein a relative increase or relative decrease in the activity level of the PEPKII/3 polypeptide indicates an effect of the pharmaceutical agent on the PEPKIIjS-associated disorder 50. The method of claim 49, wherein the activity level of the PEPKIIjS polypeptide is determined with a kinase assay. 51. The method of claim 49, wherein the PEPKII/3 polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ID NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO: 1. 52. The method of claim 49, wherein the PEPKII/3 polypeptide comprises an amino acid sequence set forth as SEQ ID NO: 2. 53. The method of claim 49, wherein the PEPKII/3-associated disorder is selected from the group consisting of: type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity. 54. A method for evaluating the effect of a candidate pharmacological agent on a PEPKII/3-associated disorder, comprising: administering a candidate pharmaceutical agent to a subject with a PEPKII/3-associated disorder; determining the effect of the candidate pharmaceutical agent on the level of expression of a PEPKII/3 molecule relative to the level of expression of a PIPKII/3 molecule in a subject to which no candidate pharmaceutical agent is administered, wherein a relative increase or relative decrease in the level of expression of a PEPKIIjS molecule indicates an effect of the pharmaceutical agent on the PEPKIIjS-associated disorder. 55. The method of claim 54, wherein the PEPKII/3 molecule is a PEPKII/3 nucleic acid molecule. 56. The method of claim 55, wherein the PIPKII/3 nucleic acid molecule comprises a nucleotide sequence set forth as SEQ ED NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO:l. 57. The method of claim 54, wherein the PEPKII/3 molecule is a PEPKII/3 polypeptide. 58. The method of claim 57, wherein the PEPKII/3 polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ED NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ED NO:l. 59. The method of claim 57, wherein the PEPKIIjS polypeptide comprises an amino acid sequence set forth as SEQ ID NO: 2. 60. The method of claim 54, wherein the animal model is of a disorder that is selected from the group consisting of: type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity. 61. A method of diagnosing a PEPKIIjS-associated disorder in a subject comprising: obtaining a biological sample from a subject, deteπnining the level of expression of a PEPKII/3 nucleic acid molecule in the biological sample, comparing the level of expression in the biological sample with the level of expression of the nucleic acid molecule in a control biological sample, wherein a higher level of expression of the PEPKIIjS nucleic acid molecule in the biological sample from the subject than in the control biological sample is diagnostic for a PIPKII/3-associated disorder in the subject. 62. The method of claim 61, wherein the PIPKII/3 nucleic acid molecule comprises a nucleotide sequence set forth as SEQ ID NO: 1 , or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO:l. 63. The method of claim 61, wherein the biological sample is selected from the group consisting of: tissue and cells. 64. The method of claim 63, wherein the tissue or cells is selected from the group consisting of: skeletal muscle, brain, and adipose tissue. 65. The method of claim 61, wherein the PEPKIIjS-associated disorder is selected from the group consisting of: type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity. 66. The method of claim 61, wherein the level of expression of PEPKII/3 nucleic acid molecules is determined by a method selected from the group consisting of nucleic acid hybridization and nucleic acid amplification. 67. The method of claim 66, wherein the nucleic acid hybridization is performed using a nucleic acid microarray. 68. The method of claim 66, wherein the nucleic acid amplification is selected from the group consisting of PCR, RT-PCR, and real-time PCR. 69. A method for determining progression or regression of a PEPKII/3-associated disorder in a subject comprising: obtaining from a subject two biological samples, wherein the samples comprise the same tissue type and are obtained at different times, determining a level of expression of a PIPKII/3 nucleic acid molecule in the two biological samples, and comparing the levels of expression in the two biological samples, wherein a higher level of expression of the PEPKII/3 nucleic acid molecule in the first biological sample than in the second biological sample indicates regression of a PEPKII/3- associated disorder, wherein a lower level of expression of the PEPKIIjS nucleic acid molecule in the first biological sample than the second biological sample indicates progression of a PEPKIIjS- associated disorder. 70. The method of claim 69, wherein the PEPKII/3 nucleic acid molecule comprises a nucleotide sequence set forth as SEQ ID NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ED NO:l. 71. The method of claim 69, wherein the biological sample is selected from the group consisting of: tissue and cells. 72. The method of claim 71, wherein the tissue or cells is selected from the group consisting of: skeletal muscle, brain, and adipose tissue. 73. The method of claim 69, wherein the PEPKIIjS-associated disorder is selected from the group consisting of: type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity. 74. The method of claim 69, wherein the level of expression of PEPKIIjS nucleic acid molecules is determined by a method selected from the group consisting of nucleic acid hybridization and nucleic acid amplification. 75. The method of claim 74, wherein the nucleic acid hybridization is performed using a nucleic acid microanay. 76. The method of claim 74, wherein the nucleic acid amplification is selected from the group consisting of PCR, RT-PCR, and real-time PCR. 77. A method of diagnosing a PEPKII/3-associated disorder in a subject comprising: obtaining a biological sample from a subject, comparing the level of PIPKII/3 polypeptide in the biological sample with the level of PEPKII/3 polypeptide in a control biological sample, wherein a level of PEPKII/3 polypeptide in the biological sample from the subject that is higher than the level of PEPKII/3 polypeptide in the control biological sample is diagnostic for a PIPKII/3-associated disorder in the subject. 78. The method of claim 77, wherein the PEPKII/3 polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ID NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO: 1. 79. The method of claim 77, wherein the PEPKII/3 polypeptide comprises an amino acid sequence set forth as SEQ ED NO: 2. 80. The method of claim 77, wherein the biological sample is selected from the group consisting of: tissue and cells. 81. The method of claim 80, wherein the tissue or cells is selected from the group consisting of: skeletal muscle, brain, and adipose tissue. 82. The method of claim 77, wherein the PEPKII/3-associated disorder is selected from the group consisting of: type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity. 83. The method of claim 77, wherein the level of expression of the PEPKII/3 polypeptide is determined by a method selected from the group consisting of immunohistochemistry and immunoprecipitation. 84. A method for determining progression or regression of a PEPKIIjS-associated disorder in a subject comprising: obtaining from a subject two biological samples, wherein the samples comprise the same tissue type and are obtained at different times, comparing the levels of PIPKII/3 polypeptide in the two biological samples, wherein a higher level of PEPKII/3 polypeptide in the first biological sample than in the second biological sample indicates regression of a PEPKIIjS-associated disorder, wherein a lower level of PEPKII/3 polypeptide in the first biological sample than the second biological sample indicates progression of a PEPKII/3-associated disorder. 85. The method of claim 84, wherein the PEPKII/3 polypeptide is encoded by a nucleic acid molecule comprising a nucleotide sequence set forth as SEQ ID NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ED NO:l. 86. The method of claim 84, wherein the PEPKII/3 polypeptide comprises an amino acid sequence set forth as SEQ ED NO: 2. 87. The method of claim 84, wherein the biological sample is selected from the group consisting of: tissue and cells. 88. The method of claim 87, wherein the tissue or cells is selected from the group consisting of: skeletal muscle, brain, and adipose tissue. 89. The method of claim 84, wherein the PEPKII/3-associated disorder is selected from the group consisting of: type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity. 90. The method of claim 84, wherein the level of expression of the PEPKII/3 polypeptide is determined by a method selected from the group consisting of immunohistochemistry and immunoprecipitation. 91. A method of diagnosing a PEPKIIjS-associated disorder in a subject comprising: obtaining a biological sample from a subject, determining the nucleotide sequence of a PEPKII/3 nucleic acid molecule in the biological sample, comparing the nucleotide sequence in the subject sample with the nucleotide sequence of a control PIPKII/3 nucleic acid molecule, wherein a difference between the nucleotide sequence in the subject biological sample and the control PEPKII/3 nucleic acid molecule is diagnostic for a PIPKII/3-associated disorder in the subject. 92. The method of claim 91, wherein the PIPKII/3 nucleic acid molecule comprises a nucleotide sequence set forth as SEQ ID NO: 1, or having at least about 95% homology to the nucleotide sequence set forth as SEQ ID NO: 1. 93. The method of claim 91, wherein the biological sample is selected from the group consisting of: tissue and cells. 94. The method of claim 93, wherein the tissue or cells is selected from the group consisting of: skeletal muscle, brain, and adipose tissue. 95. The method of claim 91, wherein the PEPKIIjS-associated disorder is selected from the group consisting of: type II diabetes, insensitivity to insulin, excess fat accumulation, and obesity.
法律状态
(WO200364451) LEGAL DETAILS FOR WO03064451  Actual or expected expiration date=2005-08-01    Legal state=DEAD    Status=LAPSED     Event publication date=2003-02-03  Event code=WO/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=WO WOUS0303065  Application date=2003-02-03  Standardized application number=2003WO-US03065     Event publication date=2003-08-07  Event code=WO/A2  Event type=Examination events  International application published without international search report  Publication country=WO  Publication number=WO03064451  Publication stage Code=A2  Publication date=2003-08-07  Standardized publication number=WO200364451     Event publication date=2003-08-07  Event code=WO/AL  Event indicator=Pos  Event type=Designated states  Designated countries for regional patents GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG    Event publication date=2003-08-07  Event code=WO/AK  Event indicator=Pos  Event type=Designated states  Designated states AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZW    Event publication date=2003-09-04  Event code=WO/A3  Event indicator=Pos  Event type=Examination events  Later publication of ISR with revised front page  Publication country=WO  Publication number=WO03064451  Publication stage Code=A3  Publication date=2003-09-04  Standardized publication number=WO200364451     Event publication date=2003-10-30  Event code=WO/DFPE  Event type=Examination events  Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)    Event publication date=2005-08-01  Event code=WO/EETL  Event type=Event indicating Not In Force  PCT Application validity period expired. 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