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
WO200233112 A2 2002-04-25 [WO200233112]WO200233112 A3 2002-08-29 [WO200233112] / 2002-04-252002-08-29
申请号/申请日
2001WO-US32196 / 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
(WO200233112) 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
(WO200233112) WHAT IS CLAIMED IS: 1. An isolated protein complex comprising two proteins, the protein complex selected from the group consisting of: (a) a complex of CIB and MLK2;  (b) a complex of a fragment of CIB and MLK2;  (c) a complex CIB and a fragment of MLK2; and  (d) a complex of a fragment of CIB and a fragment ofMLK2. 2. The protein complex of claim 1, wherein said protein complex comprises CIB and MLK2. 3. The protein complex of claim 1 , wherein said protein complex comprises a fragment of CIB and MLK2 or CIB and a fragment of MLK2. 4. The protein complex of claim 1 , wherein said protein complex comprises fragments of CIB and MLK2. 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 abilify 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 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. 12. The method of claim 11, wherein said complex is measured by binding with an antibody specific for said complex. 13. The method of any one of claims 7-12, wherein said neurodegenerative disorder is selected from the group consisting of Huntington's Disease, Parkinson's Disease, dementia and Alzheimer's Disease. 14. The method of claim 13, wherein said neurodegenerative disorder is Alzheimer's Disease. 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 CIB or a homologue or derivative or fragment thereof; and a second expression vector having a nucleic acid encoding MLK2 or a homologue or derivative or fragment thereof. 39. A host cell comprising: a first expression vector having a nucleic acid encoding a first protein which is CIB or a homologue or derivative or fragment thereof; and a second expression vector having a nucleic acid encoding a second protein which is MLK2, or a homologue or derivative or fragment thereof thereof. 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 drug 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 drug to form a first complex;  (ii) combining the proteins in the absence of said drug 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 drug 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 CIB and MLK2 in the presence of a drug,  (b) measuring the activity of said protein in the absence of said drug, and  (c) comparing the activity measured in steps (1) and (2), wherein if there is a difference in activity, then said drug is a drug 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 drug 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 which is CIB or a homologue or derivative or fragment thereof and a second protein which is MLK2 or a homologue or derivative or fragment thereof, 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 being CIB or a homologue or derivative or fragment thereof and said second protein being MLK2 or a homologue or derivative or fragment thereof, 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 which is CIB or a homologue or derivative or fragment thereof, and a second protein which is  MLK2 or a homologue or derivative or fragment thereof, said method comprising: contacting said protein complex with a test compound; and determining the mteraction 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 CIB or a homologue or derivative or fragment thereof and said second polypeptide being MLK2 or a homologue or derivative or fragment thereof, said method comprising: providing in a host cell a first fusion protem 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 CIB or a homologue or derivative or fragment thereof and said second polypeptide being MLK2 or a homologue or derivative or fragment thereof, 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 MLK2, said method comprising: contacting MLK2 with a test compound; and determining binding of said test compound to MLK2. 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 MLK2 in vitro, said method comprising: contacting a test compound with MLK2 for a time sufficient to form a complex and detecting for the formation of a complex by detecting MLK2 or the compound in the complex, so that if a complex is detected, a compound that binds to MLK2 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 CIB or a homologue or derivative or fragment thereof and said second polypeptide being MLK2 or a homologue or derivative or fragment thereof, 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 which is CIB interacting with a second protein which is MLK2, 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 said 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 said 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, and 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 CTB. 81. The method of claim 79, wherein said nucleic acid encodes MLK2. 82. A method for modulating, in a cell, a protein complex having a first protein which is CIB interacting with a second protein which is MLK2, 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, -Tat49.57, retro-inverso isomers of I- or -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 MLK2 with a ligand, said method comprising: administering to said cell a compound capable of modulating said interaction. 85. The method of claim 84, wherein said ligand is CIB. 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 MLK2 or said ligand, a compound which comprises a peptide having a contiguous span of amino acids of at least 4 amino acids of MLK2 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 MLK2 of the same length, a compound which is an antibody immunoreactive with MLK2 or said ligand, a compound which is a nucleic acid encoding an antibody immunoreactive with said ligand or MLK2, a compound which modulates the expression of MLK2 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 MLK2 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 which is CIB interacting with a second protein which is MLK2. 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 which is CIB interacting with a second protein which is MLK2. 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 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 said 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 said 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 said first protein or complement thereof, and a compound which is an antisense compound or a ribozyme specifically hybridizing to a nucleic acid encoding said second protein or complement thereof. 90. 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 being CIB and a second protein being MLK2, 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, c?-Tat49.57, retro-inverso isomers of/- or d-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 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 being CIB interacting with a second protein being  MLK2. 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 said 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 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 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 said first protein or complement thereof, a compound which is an antisense compound or a ribozyme specifically hybridizing to a nucleic acid encoding said second proten 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 being CIB and a second protein being MLK2, 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, refro-inverso isomers of I- or d-Tat4g_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. 96. A method for treating a neurodegenerative disorder comprising: administering to a patient in need of treatment a compound capable of modulating the activity of MLK2. 97. The method of claim 96, wherein the activity is the interaction of MLK2 with a ligand. 98. The method of claim 96, wherein said ligand is CIB . 99. The method of any one of claims 87-98, wherein said neurodegenerative disorder is selected from the group consisting of Huntington's Disease, Parkinson's Disease, dementia and Alzheimer's Disease. 100. The method of claim 99, wherein said neurodegenerative disorder is Alzheimer's Disease. 101. A method of modulating MLK2 activity in a cell, said method comprising: administering to said cell a compound capable of modulating MLK2. 102. The method of claim 101, wherein said compound is selected from the group consisting of: a compound which is capable of binding MLK2, a compound which comprises a peptide having a contiguous span of at least 4 amino acids of CIB and capable of binding MLK2, a compound which comprises a peptide capable of binding MLK2 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 CIB of the same length, a compound which is an antibody immunoreactive with MLK-2, a compound which is a nucleic acid encoding an antibody immunoreactive with MLK2, and a compound which is an antisense compound or a ribozyme specifically hybridizing to a nucleic acid encoding MLK2 or complement thereof. 103. A method for modulating MLK2 activities of a protein in a cell, said method comprising: administering to said cell a peptide having a contiguous span of at least 4 amino acids of CIB capable of binding MLK2, wherein said peptide is associated with a transporter capable of increasing cellular uptake of said peptide. 104. The method of claim 103, wherein said peptide is covalently linked to said fransporter which is selected from the group consisting of penetratins, /-Tat49.57, -Tat49.57, retro-inverso isomers of I- or c?-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 VP22, and peptoid analogs thereof.
法律状态
(WO200233112) LEGAL DETAILS FOR WO200233112  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 WOUS0132196  Application date=2001-10-16  Standardized application number=2001WO-US32196     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=WO200233112  Publication stage Code=A2  Publication date=2002-04-25  Standardized publication number=WO200233112     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=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=2002-08-29  Event code=WO/A3  Event indicator=Pos  Event type=Examination events  Later publication of ISR with revised front page  Publication country=WO  Publication number=WO200233112  Publication stage Code=A3  Publication date=2002-08-29  Standardized publication number=WO200233112     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 AU1323902  Actual or expected expiration date=2007-04-29    Legal state=DEAD    Status=LAPSED   Corresponding cc:  Designated or member state=AU Corresponding appl: AU1323902  Application date in the designated or member state=2001-10-16   Application number in the designated or member state=2002AU-0013239 Corresponding cc:  Designated or member state=AU Corresponding pat: AU1323902  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=AU200213239    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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