Protein-protein interactions in neurodegenerative diseases 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
WO200233114 A2 2002-04-25 [WO200233114]WO200233114 A3 2003-02-13 [WO200233114] / 2002-04-252003-02-13
申请号/申请日
2001WO-US32199 / 2001-10-16
发明人
ROCH JEAN-MARC;BARTEL PAUL L;HEICHMAN KAREN;
申请人
MYRIAD GENETICS;
主分类号
IPC分类号
A61K-038/17A61K-039/395C07K-014/435C07K-014/47C07K-016/18C07K-016/28C12N-009/12C12N-009/64C12Q-001/68G01N-033/68
摘要
(WO200233114) The present invention relates to the discovery of protein-protein interactions that are involved in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD).  Thus, the present invention is directed to complexes of these proteins and/or their fragments, antibodies to the complexes, diagnosis of neurodegenerative disorders (including diagnosis of a predisposition to and diagnosis of the existence of the disorder), drug screening for agents which modulate the interaction of proteins described herein, and identification of additional proteins in the pathway common to the proteins described herein.
机翻摘要
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地址
代理人
代理机构
;
优先权号
2000US-60240790 2000-10-17
主权利要求
(WO200233114) WHAT IS CLAIMED IS: 1. An isolated protein complex comprising two proteins, the protein complex selected from the group consisting of: (i) a complex of a first protein and a second protein;  (ii) a complex of a fragment of said first protein and said second protein; (iii) a complex of said first protein and a fragment of said second protein; and (iv) a complex of a fragment of said first protein and a fragment of said second protein, wherein said first and second proteins are selected from the group consisting of: (a) said first protein being BAT3 and said second protein being selected from the group consisting of glypican, LRP2, LRPAPl and transthyretin;  (b) said first protein being Mintl and said second protein being selected from the group consisting of GS and KIAA0427;  (c) said first protein being CASK and said second protein being dystrophin; (d) said first protein being CIB and said second protein being selected from the group consisting of SIP, ATP-synthase and SCD-2;  (e) said first protein being Mint2 and said second protein being SIP;  (f) said first protein being PSl and said second protein being selected from the group consisting of Mintl, P-glycerate DH, beta-ETF and GAPDH; (g) said first protein being PS2 and said second protein being GAPDH;  (h) said first protein being KIAA0443 and said second protein being selected from the group consisting of PI-4 and 5HT-2A»R;  (i) said first protein being KIAA0351 and said second protein being TRIO;  (j) said first protein being BAX and said second protein being slo K+channel; (k) said first protein being FAK2 and said second protein being SURl ;  (1) said first protein being FAK and said second protein being selected from the group consisting of rabl 1, casein kinase II and GST trans.M3; and  (m) said first protein being Bcr and said second protein being selected from the group consisting of PSD95, DLG3, semaphorin F, HTF4A and SCRAP.  The protein complex of claim 1, wherein said protein complex comprises said first protein and said second protein. 3. The protein complex of claim 1 , wherein said protein complex comprises a fragment of said first protein and said second protein or said first protein and a fragment of said second protein. 4. The protein complex of claim 1 , wherein said protein complex comprises fragments of said first protein and said second protein. 5. An isolated antibody selectively immunoreactive with a protein complex of claim 1. 6. The antibody of claim 5, wherein said antibody is a monoclonal antibody. 7. A method for diagnosing a neurodegenerative disorder in an animal, which comprises assaying for: (a) whether a protein complex set forth in claim 1 is present in a tissue extract;  (b) the ability of proteins to form a protein complex set forth in claim 1; and  (c) a mutation in a gene encoding a protein of a protein complex set forth in claim 1. 8. The method of claim 7, wherein said animal is a human. 9. The method of claim 7, wherein the diagnosis is for a predisposition to said neurodegenerative disorder. 10. The method of claim 7, wherein the diagnosis is for the existence of said neurodegenerative disorder. 11. The method of any one of claims 7-10, wherein said neurodegenerative disorder is selected from the group consisting of Huntington's Disease, Parkinson's Disease, dementia and Alzheimer's Disease. 12. The method of claim 11 , wherein said neurodegenerative disorder is Alzheimer's Disease. 13. The method of claim 7, wherein said assay comprises: a yeast two-hybrid assay, or measuring in vitro a complex formed by combining the proteins of the protein complex, said proteins isolated from said animal, or mixing an antibody specific for said protein complex with a tissue extract from said animal and measuring the binding of said antibody. 14. The method of claim 13, wherein said complex is measured by binding with an antibody specific for said complex. 15. A method for determining whether a mutation in a gene encoding one of the proteins of a protein complex set forth in claim 1 is useful for diagnosing a neurodegenerative disorder, which comprises assaying for the ability of said protein with said mutation to form a complex with the other protein of said protein complex, wherein an inability to form said complex is indicative of said mutation being useful for diagnosing a neurodegenerative disorder. 16. The method of claim 15, wherein said gene is an animal gene or a human gene. 17. The method of claim 15 , wherein the diagnosis is for a predisposition to a neurodegenerative disorder. 18. The method of claim 15, wherein the diagnosis is for the existence of a neurodegenerative disorder. 19. The method of claim 15 , wherein said assay comprises : a yeast two-hybrid assay, or measuring in vitro a complex formed by combining the proteins of the protein complex, said proteins isolated from an animal. 20. The method of claim 19, wherein said complex is measured by binding with an antibody specific for said complex. 21. The method of any one of claims 15-20, wherein said neurodegenerative disorder is selected from the group consisting of Huntington's Disease, Parkinson's Disease, dementia and  Alzheimer's Disease. 22. The method of claim 21 , wherein said neurodegenerative disorder is Alzheimer's Disease. 23. A non-human animal model for a neurodegenerative disorder wherein the genome of said animal or an ancestor thereof has been modified such that the formation of a protein complex set forth in claim 1 has been altered. 24. The non-human animal model of claim 23, wherein the formation of said protein complex has been altered as a result of:  (a) over-expression of at least one of the proteins of said protein complex;  (b) replacement of a gene for at least one of the proteins of said protein complex with a gene from a second animal and expression of said protein;  (c) expression of a mutant form of at least one of the proteins of said protein complex;  (d) a lack of expression of at least one of the proteins of said protein complex; or  (e) reduced expression of at least one of the proteins of said protein complex. 25. The non-human animal model of claim 23 or 24, wherein said neurodegenerative disorder is selected from the group consisting of Huntington's Disease, Parkinson's Disease, dementia and Alzheimer's Disease. 26. The non-human animal model of claim 25, wherein said neurodegenerative disorder is Alzheimer's Disease. 27. A cell line obtained from the animal model of claim 26. 28. A non-human animal model for a neurodegenerative disorder, wherein the biological activity of a protein complex set forth in claim 1 has been altered. 29. The non-human animal model of claim 28, wherein said biological activity has been altered as a result of:  (a) disrupting the formation of said complex; or  (b) disrupting the action of said complex. 30. The non-human animal model of claim 29, wherein the formation of said complex is disrupted by binding an antibody to at least one of the proteins which form said protein complex. 31. The non-human animal model of claim 29, wherein the action of said complex is disrupted by binding an antibody to said complex. 32. The non-human animal model of claim 29, wherein the formation of said complex is disrupted by binding a small molecule to at least one of the proteins which form said protein complex. 33. The non-human animal model of claim 29, wherein the action of said complex is disrupted by binding a small molecule to said complex. 34. The non-human animal model of any one of claims 28-33, wherein said neurodegenerative disorder is selected from the group consisting of Huntington's Disease, Parkinson's Disease, dementia and Alzheimer's Disease. 35. The non-human animal model of claim 34, wherein said neurodegenerative disorder is Alzheimer's Disease. 36. A cell in which the genome of cells of said cell line has been modified to produce at least one protein complex set forth in claim 1. 37. A cell line in which the genome of the cells of said cell line has been modified to eliminate at least one protein of a protein complex set forth in claim 1. 38. A composition comprising : a first expression vector having a nucleic acid encoding a first protein or a homologue or derivative or fragment thereof; and a second expression vector having a nucleic acid encoding a second protein, or a homologue or derivative or fragment thereof, wherein said first and said second proteins are the proteins of claim 1. 39. A host cell comprising: a first expression vector having a nucleic acid encoding a first protein which is first protein or a homologue or derivative or fragment thereof; and a second expression vector having a nucleic acid encoding a second protein which is second protein, or a homologue or derivative or fragment thereof thereof, wherein said first and said second proteins are the proteins of claim 1. 40. The host cell of claim 39, wherein said host cell is a yeast cell. 41. The host cell of claim 39, wherein said first and second proteins are expressed in fusion proteins. 42. The host cell of claim 39, wherein one of said first and second nucleic acids is linked to a nucleic acid encoding a DNA binding domain, and the other of said first and second nucleic acids is linked to a nucleic acid encoding a transcription-activation domain, whereby two fusion proteins can be produced in said host cell. 42. The host cell of claim 39, further comprising a reporter gene, wherein the expression of the reporter gene is determined by the interaction between the first protein and the second protein. 43. A method for screening for drag candidates capable of modulating the interaction of the proteins of a protein complex, the protein complex selected from the group consisting of the protein complexes of claim 1, said method comprising  (i) combining the proteins of said protein complex in the presence of a drag to form a first complex;  (ii) combining the proteins in the absence of said drag to form a second complex; (iii) measuring the amount of said first complex and said second complex; and (iv) comparing the amount of said first complex with the amount of said second complex, wherein if the amount of said first complex is greater than, or less than the amount of said second complex, then the drug is a drug candidate for modulating the interaction of the proteins of said protein complex. 44. The method of claim 43, wherein said screening is an in vitro screening. 45. The method of claim 43, wherein said complex is measured by binding with an antibody specific for said protein complexes. 46. The method of claim 43, wherein if the amount of said first complex is greater than the amount of said second complex, then said drag is a drug candidate for promoting the interaction of said proteins. 47. The method of claim 43, wherein if the amount of said first complex is less than the amount of said second complex, then said drug is a drug candidate for inhibiting the interaction of said proteins. 48. A method of screening for drug candidates useful in treating a neurodegenerative disorder which comprises the steps of: . (a) measuring the activity of a protein selected from the group consisting of a first protein and a second protein in the presence of a drag, wherein said first and second proteins are selected from the group consisting of the proteins of claim 1,  (b) measuring the activity of said protein in the absence of said drag, and (c) comparing the activity measured in steps (1) and (2), wherein if there is a difference in activity, then said drug is a drag candidate for treating said neurodegenerative disorder. 49. A drug useful for treating a neurodegenerative disorder identified by the method of any one of claims 43-48. 50. The drag of claim 49, wherein said neurodegenerative disorder is selected from the group consisting of Huntington's Disease, Parkinson's Disease, dementia and Alzheimer's Disease. 51. The drug of claim 50, wherein said neurodegenerative disorder is Alzheimer's Disease. 52. A method for selecting modulators of a protein complex formed between a first protein or a homologue or derivative or fragment thereof and a second protein or a homologue or derivative or fragment thereof, wherein said first and second proteins are selected from the group consisting of the proteins of claim 1, said method comprising: providing the protein complex; contacting said protein complex with a test compound; and determining the presence or absence of binding of said test compound to said protein complex. 53. A method for selecting modulators of an interaction between a first protein and a second protein, said first protein or a homologue or derivative or fragment thereof and said second protein or a homologue or derivative or fragment thereof, wherein said first and second proteins are selected from the group consisting of the proteins of claim 1, said method comprising: contacting said first protein with said second protein in the presence of a test compound; and determining the interaction between said first protein and said second protein. 54. The method of claim 53, wherein at least one of said first and second proteins is a fusion protein having a detectable tag. 55. The method of claim 53, wherein said step of determining the interaction between said first protein and said second protein is conducted in a substantially cell free environment. 56. The method of claim 53, wherein the interaction between said first protein and said second protein is determined in a host cell. 57. The method of claim 56, wherein said host cell is a yeast cell. 58. The method of claim 53, wherein said test compound is provided in a phage display library. 59. The method of claim 53, wherein said test compound is provided in a combinatorial library. 60. A method for selecting modulators of a protein complex formed from a first protein or a homologue or derivative or fragment thereof, and a second protein or a homologue or derivative or fragment thereof, wherein said first and second proteins are selected from the group consisting of the proteins of claim 1, said method comprising: contacting said protein complex with a test compound; and determining the interaction between said first protein and said second protein. 61. A method for selecting modulators of an interaction between a first polypeptide and a second polypeptide, said first polypeptide being a first protein or a homologue or derivative or fragment thereof and said second polypeptide being a second protein or a homologue or derivative or fragment thereof, wherein said first and second proteins are selected from the group consisting of the proteins of claim 1, said method comprising: providing in a host cell a first fusion protein having said first polypeptide, and a second fusion protein having said second polypeptide, wherein a DNA binding domain is fused to one of said first and second polypeptides while a transcription-activating domain is fused to the other of said first and second polypeptides; providing in said host cell a reporter gene, wherein the transcription of the reporter gene is determined by the interaction between the first polypeptide and the second polypeptide; allowing said first and second fusion proteins to interact with each other within said host cell in the presence of a test compound; and determining the presence or absence of expression of said reporter gene. 62. The method of claim 61 , wherein said host cell is a yeast cell. 63. A method for selecting modulators of an interaction between a first polypeptide and a second polypeptide, said first polypeptide being a first protein or a homologue or derivative or fragment thereof and said second polypeptide being a second protein or a homologue or derivative or fragment thereof, wherein said first and second proteins are selected from the group consisting of the proteins of claim 1, said method comprising: providing atomic coordinates defining a three-dimensional structure of a protein complex formed by said first polypeptide and said second polypeptide; and designing or selecting compounds capable of modulating the interaction between a first polypeptide and a second polypeptide based on said atomic coordinates. 64. A method for selecting modulators of a protein, wherein said protein is selected from the group consisting of the proteins of claim 1, said method comprising: contacting said protein with a test compound; and determining binding of said test compound to said protein. 65. The method of claim 64, wherein said test compound is provided in a phage display library. 66. The method of claim 64, wherein said test compound is provided in a combinatorial library. 67. A modulator useful for treating a neurodegenerative disorder identified by the method of any one of claims 52-66. 68. The modulator of claim 67, wherein said neurodegenerative disorder is selected from the group consisting of Huntington's Disease, Parkinson's Disease, dementia and Alzheimer's Disease. 69. The modulator of claim 68, wherein said neurodegenerative disorder is Alzheimer's Disease. 70. A method for identifying a compound that binds to a protein in vitro, wherein said protein is selected from the group consisting of the proteins of claim 1, said method comprising: contacting a test compound with said protein for a time sufficient to form a complex and detecting for the formation of a complex by detecting said protein or the compound in the complex, so that if a complex is detected, a compound that binds to protein is identified. 71. A compound useful for treating a neurodegenerative disorder identified by the method of claim 70. 72. The compound of claim 71, wherein said neurodegenerative disorder is selected from the group consisting of Huntington's Disease, Parkinson's Disease, dementia and Alzheimer's Disease. 73. The compound of claim 72, wherein said neurodegenerative disorder is Alzheimer's Disease. 74. A method for providing inhibitors of an interaction between a first polypeptide and a second polypeptide, said first polypeptide being a first protein or a homologue or derivative or fragment thereof and said second polypeptide being a second protein or a homologue or derivative or fragment thereof, wherein said first and second proteins are selected from the group consisting of the proteins of claim 1, said method comprising: providing atomic coordinates defining a three-dimensional structure of a protein complex formed by said first polypeptide and said second polypeptide; and designing or selecting compounds capable of interfering with the interaction between a first polypeptide and a second polypeptide based on said atomic coordinates. 75. An inhibitor useful for treating a neurodegenerative disorder identified by the method of claim 74. 76. The inhibitor of claim 75 wherein said neurodegenerative disorder is selected from the group consisting of Huntington's Disease, Parkinson's Disease, dementia and Alzheimer's Disease. 77. The inhibitor of claim 76, wherein said neurodegenerative disorder is Alzheimer's Disease. 78. A method for modulating, in a cell, a protein complex having a first protein interacting with a second protein, wherein said first and second proteins are selected from the group consisting of the proteins of claim 1, said method comprising: administering to said cell a compound capable of modulating said protein complex. 79. The method of claim 78, wherein said compound is selected from the group consisting of: a compound which is capable of interfering with the interaction between said first protein and said second protein, a compound which is capable of binding at least one of said first protein and said second protein, a compound which comprises a peptide having a contiguous span of amino acids of at least 4 amino acids of said second protein and capable of binding said first protein, a compound which comprises a peptide capable of binding said first protein and having an amino acid sequence of from 4 to 30 amino acids that is at least 75% identical to a contiguous span of amino acids of said second protein of the same length, a compound which comprises a peptide having a contiguous span of amino acids of at least 4 amino acids of first protein and capable of binding said second protein, a compound which comprises a peptide capable of binding second protein and having an amino acid sequence of from 4 to 30 amino acids that is at least 75% identical to a contiguous span of amino acids of first protein of the same length, a compound which is an antibody immunoreactive with said first protein or said second protein, a compound which is a nucleic acid encoding an antibody immunoreactive with said first protem or said second protein, a compound which modulates the expression of said first protein or said second protein a which is an antisense compound or a ribozyme specifically hybridizing to a nucleic acid encoding said first protein or said second protein or complement thereof 80. The method of claim 79, wherein said nucleic acid encodes said first protein. 81. The method of claim 79, wherein said nucleic acid encodes said second protein. 82. A method for modulating, in a cell, a protein complex having a first protein interacting with a second protein, wherein said first and second proteins are selected from the group consisting of the proteins of claim 1, said method comprising: administering to said cell a peptide capable of interfering with the interaction between said first protein and said second protein, wherein said peptide is associated with a transporter capable of increasing cellular uptake of said peptide. 83. The method of claim 82, wherein said peptide is covalently linked to said transporter which is selected from the group consisting of penetratins, /-Tat49.57, d-Tat49_57, retro-inverso isomers of/- or ύ?-Tat49.57, L-arginine oligomers, D- arginine oligomers, L-lysine oligomers, D-lysine oligomers, L-histine oligomers, D-histine oligomers, L-ornithine oligomers, D-ornithine oligomers, short peptide sequences derived from fibroblast growth factor, Galparan, and HSN-1 structural protein NP22, and peptoid analogs thereof. 84. A method for modulating, in a cell, the interaction of a protein with a ligand, wherein said protein is selected from the group consisting of the first or second proteins of claim 1, said method comprising: administering to said cell a compound capable of modulating said interaction. 85. The method of claim 84, wherein said protein is one of said first or second proteins and said ligand is the other of said first or second proteins. 86. The method of claim 84 or 85, wherein said compound is selected from the group consisting of: a compound which interferes with said interaction, a compound which binds to said protein or said ligand, a compound which comprises a peptide having a contiguous span of amino acids of at least 4 amino acids of said protein and capable of binding said ligand, a compound which comprises a peptide capable of binding said ligand and having an amino acid sequence of from 4 to 30 amino acids that is at least 75% identical to a contiguous span of amino acids of said protein of the same length, a compound which is an antibody immunoreactive with said protein or said ligand, a compound which is a nucleic acid encoding an antibody immunoreactive with said ligand or said protein, a compound which modulates the expression of said protein or said ligand, a compound which is an antisense compound or a ribozyme specifically hybridizing to a nucleic acid encoding said ligand or complement thereof, and a compound which is an antisense compound or a ribozyme specifically hybridizing to a nucleic acid encoding said protein or complement thereof. 87. A method for modulating neuronal death in a patient having a neurodegenerative disorder comprising: modulating a protein complex having a first protein interacting with a second protein, wherein said first and second proteins are selected from the group consisting of the proteins of claim 1. 88. A method for modulating neuronal death in a patient having neurodegenerative disorder comprising: administering to the patient a compound capable of modulating a protein complex having a first protein interacting with a second protein, wherein said first and second proteins are selected from the group consisting of the proteins of claim 1. 89. The method of claim 88, wherein said compound is selected from the group consisting of: a compound which is capable of interfering with the interaction between said first protein and said second protein, a compound which is capable of binding at least one of said first protein and said second protein, a compound which comprises a peptide having a contiguous span of amino acids of at least 4 amino acids of a second protein and capable of binding a first protein, a compound which comprises a peptide capable of binding a first protein and having an amino acid sequence of from 4 to 30 amino acids that is at least 75% identical to a contiguous span of amino acids of a second protein of the same length, a compound which comprises a peptide having a contiguous span of amino acids of at least 4 amino acids of first protein and capable of binding a second protein, a compound which comprises a peptide capable of binding a second protein and having an amino acid sequence of from 4 to 30 amino acids that is at least 75% identical to a contiguous span of amino acids of a first protein of the same length, a compound which is an antibody immunoreactive with a first protein or a second protein, a compound which is a nucleic acid encoding an antibody immunoreactive with a first protein or a second protein, a compound which modulates the expression of a first protein or a second protein, a compound which is an antisense compound or a ribozyme specifically hybridizing to a nucleic acid encoding a first protein or complement thereof, and a compound which is an antisense compound or a ribozyme specifically hybridizing to a nucleic acid encoding a second protem or complement thereof.  A method for modulating neuronal death in a patient having neurodegenerative disorder comprising: administering to said cell a peptide capable of interfering with the interaction between a first protein and a second protein, wherein said first and second proteins are selected from the group consisting of the proteins of claim 1, wherein said peptide is associated with a transporter capable of increasing cellular uptake of said peptide. 91. The method of claim 90, wherein said peptide is covalently linked to said transporter which is selected from the group consisting of penetratins, /-Tat49.57, -i-Tat49.57, retro-inverso isomers of I- or -f-Tat49_57, L-arginine oligomers, D- argi-nine oligomers, L-lysine oligomers, D-lysine oligomers, L-histine oligomers, D-histine oligomers, L-ornithine oligomers, D-ornithine oligomers, short peptide sequences derived from fibroblast growth factor, Galparan, and  HSN-1 structural protein VP22, and peptoid analogs thereof. 92. A method for treating a neurodegenerative disorder comprising: administering to a patient in need of treatment a compound capable of modulating a protein complex having a first protein interacting with a second protein, wherein said first and second proteins are selected from the group consisting of the proteins of claim 1. 93. The method of claim 150, wherein said compound is selected from the group consisting of: a compound which capable of interfering with the interaction between said first protein and said second protein, a compound which compound is capable of binding at least one of said first protein and said second protein, a compound which comprises a peptide having a contiguous span of amino acids of at least 4 amino acids of said second protein and capable of binding said first protein, a compound which comprises a peptide capable of binding said first protein and having an amino acid sequence of from 4 to 30 amino acids that is at least 75% identical to a contiguous span of amino acids of said second protein of the same length, a compound which comprises a peptide having a contiguous span of amino acids of at least 4 amino acids of first protein and capable of binding said second protein, a compound which comprises a peptide capable of binding said second protein and having an amino acid sequence of from 4 to 30 amino acids that is at least 75% identical to a contiguous span of amino acids of said first protein of the same length, a compound which is an antibody immunoreactive with siad first protein or said second protein, a compound which is a nucleic acid encoding an antibody immunoreactive with said first protein or said second protein, a compound which modulates the expression of said first protein or said second protein, a compound which is an antisense compound or a ribozyme specifically hybridizing to a nucleic acid encoding a first protein or complement thereof, a compound which is an antisense compound or a ribozyme specifically hybridizing to a nucleic acid encoding a second protein or complement thereof, and a compound which is capable of strengthening the interaction between said first protein and said second protein. 94. A method for treating a neurodegenerative disorder comprising: administering to said cell a peptide capable of interfering with the interaction between a first protein and a second protein, wherein said first and second proteins are selected from the group consisting of the proteins of claim 1, wherein said peptide is associated with a transporter capable of increasing cellular uptake of said peptide. 95. The method of claim 94, wherein said peptide is covalently linked to said transporter which is selected from the group consisting of penetratins, /-Tat49.57, -Tat49.57, retro-inverso isomers of/- or -Tat49.57, L-arginine oligomers, D- arginine oligomers, L-lysrne oligomers, D-lysine oligomers, L-histine oligomers, D(...)
法律状态
(WO200233114) LEGAL DETAILS FOR WO200233114  Actual or expected expiration date=2004-04-17    Legal state=DEAD    Status=LAPSED     Event publication date=2001-10-16  Event code=WO/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=WO WOUS0132199  Application date=2001-10-16  Standardized application number=2001WO-US32199     Event publication date=2002-04-25  Event code=WO/A2  Event type=Examination events  International application published without international search report  Publication country=WO  Publication number=WO200233114  Publication stage Code=A2  Publication date=2002-04-25  Standardized publication number=WO200233114     Event publication date=2002-04-25  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 PH PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG UZ VN YU ZA ZW    Event publication date=2002-04-25  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 ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG    Event publication date=2003-02-13  Event code=WO/A3  Event indicator=Pos  Event type=Examination events  Later publication of ISR with revised front page  Publication country=WO  Publication number=WO200233114  Publication stage Code=A3  Publication date=2003-02-13  Standardized publication number=WO200233114     Event publication date=2004-04-17  Event code=WO/EETL  Event type=Event indicating Not In Force  PCT Application validity period expired. LEGAL DETAILS FOR DESIGNATED STATE AU1324102  Actual or expected expiration date=2007-04-29    Legal state=DEAD    Status=LAPSED   Corresponding cc:  Designated or member state=AU Corresponding appl: AU1324102  Application date in the designated or member state=2001-10-16   Application number in the designated or member state=2002AU-0013241 Corresponding cc:  Designated or member state=AU Corresponding pat: AU1324102  Publication stage code in the designated or member state=A  Publication date in the designated or member state=2002-04-29   Publication number in the designated or member state=AU200213241    Event publication date=2002-04-29  Event code=AU/STCHG  Patent Status changed by the national office Corresponding cc:  Designated or member state=AU  LEGAL DETAILS FOR DESIGNATED STATE DE  Actual or expected expiration date=2003-08-28    Legal state=DEAD    Status=LAPSED   Corresponding cc:  Designated or member state=DE     Event publication date=2003-08-28  Event code=WO/REG  Event code=DE/8642  Event indicator=Neg  Event type=Non-entry into national phase  Event type=Event indicating Not In Force  Reference to a national code Impact abolished for de - i.e. PCT appl. not ent. German phase Wirkung weggefallen fuer de Corresponding cc:  Designated or member state=DE  LEGAL DETAILS FOR DESIGNATED STATE JP  Actual or expected expiration date=2005-09-14    Legal state=DEAD    Status=LAPSED   Corresponding cc:  Designated or member state=JP     Event publication date=2005-09-14  Event code=WO/NENP  Event type=Event indicating Not In Force  Non-entry into the national phase in: Corresponding cc:  Designated or member state=JP
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