{"search_session":{},"preferences":{"l":"en","queryLanguage":"en"},"patentId":"WO_2019_145523_A1","frontPageModel":{"patentViewModel":{"ref":{"entityRefId":"061-782-497-903-83X","entityRefType":"PATENT"},"entityMetadata":{"linkedIds":{"empty":true},"tags":[],"collections":[{"id":182990,"type":"PATENT","title":"2","description":"","access":"OPEN_ACCESS","displayAvatar":true,"attested":false,"itemCount":49434,"tags":[],"user":{"id":320339875,"username":"tadro.abbott@csiro.au","firstName":"Tadro","lastName":"Abbott","created":"2019-06-27T07:11:33.000Z","displayName":"Tadro Abbott","preferences":"{\"usage\":\"public\"}","accountType":"PERSONAL","isOauthOnly":false},"notes":[],"sharedType":"PUBLISHED","hasLinkedSavedQueries":false,"savedQueries":[],"created":"2020-08-10T01:50:08Z","updated":"2020-08-10T01:54:38Z","lastEventDate":"2020-08-10T01:54:38Z"},{"id":185688,"type":"PATENT","title":"Food Safety","description":"","access":"OPEN_ACCESS","displayAvatar":true,"attested":false,"itemCount":50000,"tags":[],"user":{"id":379426745,"username":"guzmanbarcenas","firstName":"","lastName":"","created":"2020-11-27T23:02:26.000Z","displayName":"guzmanbarcenas","accountType":"PERSONAL","isOauthOnly":false},"notes":[],"sharedType":"PUBLISHED","hasLinkedSavedQueries":false,"savedQueries":[],"created":"2020-11-27T23:38:28Z","updated":"2020-11-27T23:40:39Z","lastEventDate":"2020-11-27T23:40:39Z"},{"id":185689,"type":"PATENT","title":"Food Safety and Management Systems","description":"","access":"OPEN_ACCESS","displayAvatar":true,"attested":false,"itemCount":50000,"tags":[],"user":{"id":379426745,"username":"guzmanbarcenas","firstName":"","lastName":"","created":"2020-11-27T23:02:26.000Z","displayName":"guzmanbarcenas","accountType":"PERSONAL","isOauthOnly":false},"notes":[],"sharedType":"PUBLISHED","hasLinkedSavedQueries":true,"savedQueries":[],"created":"2020-11-27T23:43:53Z","updated":"2020-11-27T23:45:31Z","lastEventDate":"2020-11-27T23:45:31Z"}],"notes":[],"inventorships":[],"privateCollections":[],"publicCollections":[{"id":182990,"type":"PATENT","title":"2","description":"","access":"OPEN_ACCESS","displayAvatar":true,"attested":false,"itemCount":49434,"tags":[],"user":{"id":320339875,"username":"tadro.abbott@csiro.au","firstName":"Tadro","lastName":"Abbott","created":"2019-06-27T07:11:33.000Z","displayName":"Tadro Abbott","preferences":"{\"usage\":\"public\"}","accountType":"PERSONAL","isOauthOnly":false},"notes":[],"sharedType":"PUBLISHED","hasLinkedSavedQueries":false,"savedQueries":[],"created":"2020-08-10T01:50:08Z","updated":"2020-08-10T01:54:38Z","lastEventDate":"2020-08-10T01:54:38Z"},{"id":185688,"type":"PATENT","title":"Food Safety","description":"","access":"OPEN_ACCESS","displayAvatar":true,"attested":false,"itemCount":50000,"tags":[],"user":{"id":379426745,"username":"guzmanbarcenas","firstName":"","lastName":"","created":"2020-11-27T23:02:26.000Z","displayName":"guzmanbarcenas","accountType":"PERSONAL","isOauthOnly":false},"notes":[],"sharedType":"PUBLISHED","hasLinkedSavedQueries":false,"savedQueries":[],"created":"2020-11-27T23:38:28Z","updated":"2020-11-27T23:40:39Z","lastEventDate":"2020-11-27T23:40:39Z"},{"id":185689,"type":"PATENT","title":"Food Safety and Management Systems","description":"","access":"OPEN_ACCESS","displayAvatar":true,"attested":false,"itemCount":50000,"tags":[],"user":{"id":379426745,"username":"guzmanbarcenas","firstName":"","lastName":"","created":"2020-11-27T23:02:26.000Z","displayName":"guzmanbarcenas","accountType":"PERSONAL","isOauthOnly":false},"notes":[],"sharedType":"PUBLISHED","hasLinkedSavedQueries":true,"savedQueries":[],"created":"2020-11-27T23:43:53Z","updated":"2020-11-27T23:45:31Z","lastEventDate":"2020-11-27T23:45:31Z"}],"privateNotes":[],"landscapeCollections":[],"landscapeNotes":[]},"document":{"record_lens_id":"061-782-497-903-83X","lens_id":["061-782-497-903-83X","138-171-469-822-708"],"doc_key":"WO_2019145523_A1_20190801","created":"2019-08-08T16:16:41.199","docdb_id":517182878,"lens_internal":{"earliest_lens_id_created_time":"2019-08-08T16:16:41.199","last_modified":"2024-03-25T06:22:59.758","legacy_pub_key":"WO_2019_145523_A1","has_doc_lang":true,"has_biblio_lang":true,"has_all_title_lang":true,"has_all_abstract_lang":true,"has_all_claims_lang":true,"has_description_lang":true},"jurisdiction":"WO","doc_number":"2019145523","kind":"A1","date_published":"2019-08-01","year_published":2019,"ids":["WO_2019_145523_A1","061-782-497-903-83X","138-171-469-822-708","WO_2019145523_A1_20190801","WO","2019145523","A1","WO2019145523A1","WO2019145523","2019145523A1"],"lang":"en","publication_type":"PATENT_APPLICATION","application_reference":{"jurisdiction":"EP","doc_number":"2019051951","kind":"W","date":"2019-01-28"},"priority_claim":[{"jurisdiction":"EP","doc_number":"18305081","kind":"A","date":"2018-01-29"},{"jurisdiction":"EP","doc_number":"18184726","kind":"A","date":"2018-07-20"}],"priority_claim.source":"DOCDB","earliest_priority_claim_date":"2018-01-29","title":{"en":[{"text":"BACLOFEN AND ACAMPROSATE BASED THERAPY OF ALZHEIMER'S DISEASE IN PATIENTS HAVING LOST RESPONSIVENESS TO ACETYLCHOLINESTERASE INHIBITOR THERAPY","lang":"en","source":"DOCDB","data_format":"DOCDBA"}],"fr":[{"text":"THÉRAPIE DE LA MALADIE D'ALZHEIMER À BASE DE BACLOFÈNE ET D'ACAMPROSATE CHEZ DES PATIENTS AYANT PERDU LA SENSIBILITÉ À UNE THÉRAPIE PAR UN INHIBITEUR DE L'ACÉTYLCHOLINESTÉRASE","lang":"fr","source":"DOCDB","data_format":"DOCDBA"}]},"title_lang":["en","fr"],"has_title":true,"applicant":[{"name":"PHARNEXT","residence":"FR","sequence":1,"app_type":"applicant"}],"applicant_count":1,"has_applicant":true,"inventor":[{"name":"BRUREAU ANTHONY","residence":"FR","sequence":1},{"name":"CHOLET NATHALIE","residence":"FR","sequence":2},{"name":"COHEN DANIEL","residence":"FR","sequence":3},{"name":"HAJJ RODOLPHE","residence":"FR","sequence":4},{"name":"NABIROCHKIN SERGUEI","residence":"FR","sequence":5}],"inventor_count":5,"has_inventor":true,"agent":[{"name":"CABINET BECKER ET ASSOCIES","address":"25, rue Louis le Grand, 75002 PARIS, 75002","country":"FR","sequence":1}],"agent_count":1,"has_agent":true,"owner":[],"owner_count":0,"owner_all":[],"owner_all_count":0,"has_owner":false,"has_examiner":false,"class_ipcr":[{"symbol":"A61K31/185","version_indicator":"2006-01-01","class_symbol_position":"F","class_value":"I","action_date":"2019-08-01","class_status":"B","class_data_source":"H","generating_office":"EP","sequence":1},{"symbol":"A61K31/197","version_indicator":"2006-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-08-01","class_status":"B","class_data_source":"H","generating_office":"EP","sequence":2},{"symbol":"A61K31/27","version_indicator":"2006-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-08-01","class_status":"B","class_data_source":"H","generating_office":"EP","sequence":3},{"symbol":"A61K31/445","version_indicator":"2006-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-08-01","class_status":"B","class_data_source":"H","generating_office":"EP","sequence":4},{"symbol":"A61K31/55","version_indicator":"2006-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-08-01","class_status":"B","class_data_source":"H","generating_office":"EP","sequence":5},{"symbol":"A61K45/06","version_indicator":"2006-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-08-01","class_status":"B","class_data_source":"H","generating_office":"EP","sequence":6},{"symbol":"A61P25/28","version_indicator":"2006-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-08-01","class_status":"B","class_data_source":"H","generating_office":"EP","sequence":7}],"class_ipcr.first_symbol":"A61K31/185","class_ipcr.later_symbol":["A61K31/197","A61K31/27","A61K31/445","A61K31/55","A61K45/06","A61P25/28"],"class_ipcr.inv_symbol":["A61K31/185","A61K31/197","A61K31/27","A61K31/445","A61K31/55","A61K45/06","A61P25/28"],"class_ipcr.add_symbol":[],"class_ipcr.source":"DOCDB","class_cpc":[{"symbol":"A61K45/06","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP","sequence":1},{"symbol":"A61K31/185","version_indicator":"2013-01-01","class_symbol_position":"F","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP","sequence":2},{"symbol":"A61K31/197","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP","sequence":3},{"symbol":"A61K31/27","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP","sequence":4},{"symbol":"A61K31/445","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP","sequence":5},{"symbol":"A61K31/55","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP","sequence":6},{"symbol":"A61P25/28","version_indicator":"2018-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP","sequence":7},{"symbol":"A61P25/28","version_indicator":"2018-01-01","class_symbol_position":"L","class_value":"I","action_date":"2021-08-06","class_status":"B","class_data_source":"H","generating_office":"US","sequence":13},{"symbol":"A61K31/16","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2021-08-06","class_status":"B","class_data_source":"H","generating_office":"US","sequence":14},{"symbol":"A61K31/197","version_indicator":"2013-01-01","class_symbol_position":"F","class_value":"I","action_date":"2021-08-06","class_status":"B","class_data_source":"H","generating_office":"US","sequence":15},{"symbol":"A61K31/445","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2021-08-06","class_status":"B","class_data_source":"H","generating_office":"US","sequence":16}],"class_cpc_cset":[{"class":[{"symbol":"A61K31/185","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP"},{"symbol":"A61K2300/00","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP"}],"sequence":8},{"class":[{"symbol":"A61K31/197","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP"},{"symbol":"A61K2300/00","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP"}],"sequence":9},{"class":[{"symbol":"A61K31/445","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP"},{"symbol":"A61K2300/00","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP"}],"sequence":10},{"class":[{"symbol":"A61K31/27","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP"},{"symbol":"A61K2300/00","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP"}],"sequence":11},{"class":[{"symbol":"A61K31/55","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP"},{"symbol":"A61K2300/00","version_indicator":"2013-01-01","class_symbol_position":"L","class_value":"I","action_date":"2019-03-28","class_status":"B","class_data_source":"H","generating_office":"EP"}],"sequence":12}],"class_cpc.first_symbol":"A61K31/185","class_cpc.later_symbol":["A61K45/06","A61K31/197","A61K31/27","A61K31/445","A61K31/55","A61P25/28","A61P25/28","A61K31/16","A61K31/445"],"class_cpc.inv_symbol":["A61K45/06","A61K31/185","A61K31/197","A61K31/27","A61K31/445","A61K31/55","A61P25/28","A61P25/28","A61K31/16","A61K31/197","A61K31/445"],"class_cpc.add_symbol":[],"class_cpc.source":"DOCDB","class_national":[],"class_national.later_symbol":[],"reference_cited":[{"npl":{"num":1,"text":"CHOLET NATHALIE ET AL: \"A COMBINATION OF ACAMPROSATE AND BACLOFEN (PXT864) SYNERGIZES WITH STANDARDS OF CARE FOR THE TREATMENT OF ALZHEIMER'S DISEASE\", ALZHEIMER'S & DEMENTIA: THE JOURNAL OF THE ALZHEIMER'SASSOCIATION, vol. 13, no. 7, 18 July 2017 (2017-07-18), XP085217620, ISSN: 1552-5260, DOI: 10.1016/J.JALZ.2017.06.1860","npl_type":"s","xp_number":"085217620","external_id":["10.1016/j.jalz.2017.06.1860"],"record_lens_id":"101-016-356-288-34X","lens_id":["165-067-639-007-669","101-016-356-288-34X"],"sequence":1,"category":["Y"],"us_category":[],"cited_phase":"ISR","cited_date":"2019-03-28","rel_claims":[],"srep_office":"EP"}},{"npl":{"num":2,"text":"TOUCHON J: \"Treatment with PXT-864 showed stabilisation of cognitive disability in mild Alzheimer's disease after 36 weeks\", ALZHEIMER'S AND DEMENTIA 20170701 ELSEVIER INC. NLD, vol. 13, no. 7, 1 July 2017 (2017-07-01), XP002782798, ISSN: 1552-5279","npl_type":"s","xp_number":"002782798","external_id":["10.1016/j.jalz.2017.06.653"],"record_lens_id":"026-063-113-765-766","lens_id":["138-125-121-907-850","026-063-113-765-766"],"sequence":2,"category":["Y"],"us_category":[],"cited_phase":"ISR","cited_date":"2019-03-28","rel_claims":[],"srep_office":"EP"}},{"patent":{"num":1,"document_id":{"jurisdiction":"EP","doc_number":"2796132","kind":"A1","date":"2014-10-29","name":"PHARNEXT [FR]"},"lens_id":"127-284-380-442-866","srep_office":"EP","category":["Y","D"],"us_category":[],"cited_phase":"ISR","cited_date":"2019-03-28","rel_claims":[],"sequence":3}},{"npl":{"num":3,"text":"ILYA CHUMAKOV ET AL: \"Combining two repurposed drugs as a promising approach for Alzheimer's disease therapy\", SCIENTIFIC REPORTS, vol. 5, 8 January 2015 (2015-01-08), pages 7608, XP055252147, DOI: 10.1038/srep07608","npl_type":"s","xp_number":"055252147","external_id":["pmc5378993","10.1038/srep07608","25566747"],"record_lens_id":"060-193-488-802-429","lens_id":["094-467-470-144-199","155-259-505-581-108","060-193-488-802-429"],"sequence":4,"category":["Y"],"us_category":[],"cited_phase":"ISR","cited_date":"2019-03-28","rel_claims":[],"srep_office":"EP"}},{"npl":{"num":4,"text":"S.L ROGERS ET AL: \"Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: final analysis of a US multicentre open-label study\", EUROPEAN NEUROPSYCHOPHARMACOLOGY., vol. 10, no. 3, 1 May 2000 (2000-05-01), NL, pages 195 - 203, XP055490093, ISSN: 0924-977X, DOI: 10.1016/S0924-977X(00)00067-5","npl_type":"s","xp_number":"055490093","external_id":["10793322","10.1016/s0924-977x(00)00067-5"],"record_lens_id":"103-727-806-980-194","lens_id":["109-044-854-483-737","103-727-806-980-194","109-259-394-593-596"],"sequence":5,"category":["A"],"us_category":[],"cited_phase":"ISR","cited_date":"2019-03-28","rel_claims":[],"srep_office":"EP"}},{"patent":{"num":1,"document_id":{"jurisdiction":"WO","doc_number":"2012117076","kind":"A2","date":"2012-09-07","name":"PHARNEXT [FR], et al"},"lens_id":"168-066-517-290-560","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":1}},{"patent":{"num":2,"document_id":{"jurisdiction":"WO","doc_number":"2010102071","kind":"A1","date":"2010-09-10","name":"XENOPORT INC [US], et al"},"lens_id":"161-796-631-857-700","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":2}},{"patent":{"num":3,"document_id":{"jurisdiction":"US","doc_number":"2009197958","kind":"A1","date":"2009-08-06","name":"SASTRY SRIKONSDA [US], et al"},"lens_id":"014-663-027-793-035","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":3}},{"patent":{"num":4,"document_id":{"jurisdiction":"WO","doc_number":"2009096985","kind":"A1","date":"2009-08-06","name":"XENOPORT INC [US], et al"},"lens_id":"018-534-569-680-371","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":4}},{"patent":{"num":5,"document_id":{"jurisdiction":"WO","doc_number":"2009061934","kind":"A1","date":"2009-05-14","name":"XENOPORT INC [US], et al"},"lens_id":"125-159-012-113-430","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":5}},{"patent":{"num":6,"document_id":{"jurisdiction":"WO","doc_number":"2008086492","kind":"A1","date":"2008-07-17","name":"XENOPORT INC [US], et al"},"lens_id":"176-052-066-620-243","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":6}},{"patent":{"num":7,"document_id":{"jurisdiction":"US","doc_number":"2009216037","kind":"A1","date":"2009-08-27","name":"GALLOP MARK A [US], et al"},"lens_id":"194-476-119-570-828","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":7}},{"patent":{"num":8,"document_id":{"jurisdiction":"WO","doc_number":"2005066122","kind":"A2","date":"2005-07-21","name":"XENOPORT INC [US], et al"},"lens_id":"174-523-674-771-163","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":8}},{"patent":{"num":9,"document_id":{"jurisdiction":"US","doc_number":"2011021571","kind":"A1","date":"2011-01-27","name":"GALLOP MARK A [US], et al"},"lens_id":"062-819-291-025-94X","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":9}},{"patent":{"num":10,"document_id":{"jurisdiction":"WO","doc_number":"03077902","kind":"A1","date":"2003-09-25","name":"XENOPORT INC [US]"},"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":10}},{"patent":{"num":11,"document_id":{"jurisdiction":"WO","doc_number":"2010120370","kind":"A2","date":"2010-10-21","name":"XENOPORT INC [US], et al"},"lens_id":"001-908-418-067-613","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":11}},{"patent":{"num":12,"document_id":{"jurisdiction":"WO","doc_number":"2009033069","kind":"A1","date":"2009-03-12","name":"XENOPORT INC [US], et al"},"lens_id":"181-598-748-721-020","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":12}},{"patent":{"num":13,"document_id":{"jurisdiction":"WO","doc_number":"2009033061","kind":"A1","date":"2009-03-12","name":"XENOPORT INC [US], et al"},"lens_id":"115-949-784-360-697","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":13}},{"patent":{"num":14,"document_id":{"jurisdiction":"WO","doc_number":"2009033054","kind":"A1","date":"2009-03-12","name":"XENOPORT INC [US], et al"},"lens_id":"170-203-670-241-992","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":14}},{"patent":{"num":15,"document_id":{"jurisdiction":"WO","doc_number":"2009052191","kind":"A1","date":"2009-04-23","name":"XENOPORT INC [US], et al"},"lens_id":"164-945-758-671-642","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":15}},{"patent":{"num":16,"document_id":{"jurisdiction":"WO","doc_number":"2009033079","kind":"A1","date":"2009-03-12","name":"XENOPORT INC [US], et al"},"lens_id":"143-146-146-709-627","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":16}},{"patent":{"num":17,"document_id":{"jurisdiction":"US","doc_number":"2009099253","kind":"A1","date":"2009-04-16","name":"LI YUNXIAO [US], et al"},"lens_id":"137-237-224-275-876","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":17}},{"patent":{"num":18,"document_id":{"jurisdiction":"US","doc_number":"2009069419","kind":"A1","date":"2009-03-12","name":"JANDELEIT BERND [US], et al"},"lens_id":"136-995-805-862-266","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":18}},{"patent":{"num":19,"document_id":{"jurisdiction":"US","doc_number":"2009082464","kind":"A1","date":"2009-03-26","name":"JANDELEIT BERND [US], et al"},"lens_id":"121-052-416-598-424","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":19}},{"patent":{"num":20,"document_id":{"jurisdiction":"US","doc_number":"2009082440","kind":"A1","date":"2009-03-26","name":"JANDELEIT BERND [US], et al"},"lens_id":"126-471-108-945-269","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":20}},{"patent":{"num":21,"document_id":{"jurisdiction":"US","doc_number":"2009076147","kind":"A1","date":"2009-03-19","name":"JANDELEIT BERND [US], et al"},"lens_id":"176-012-156-424-223","category":[],"us_category":[],"cited_phase":"APP","rel_claims":[],"sequence":21}},{"npl":{"num":1,"text":"CROOK R; VERKKONIEMI A; PEREZ-TUR J; MEHTA N; BAKER M; HOULDEN H; FARRER M; HUTTON M; LINCOLN S; HARDY J: \"A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1\", NAT. MED., vol. 4, 1998, pages 452 - 5","npl_type":"s","external_id":["9546792","10.1038/nm0498-452"],"record_lens_id":"001-060-867-130-424","lens_id":["025-673-852-109-625","001-060-867-130-424","015-066-237-812-530"],"sequence":22,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":2,"text":"HOULDEN H; BAKER M; MCGOWAN E; LEWIS P; HUTTON M; CROOK R; WOOD NW; KUMAR-SINGH S; GEDDES J; SWASH M: \"Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations\", ANN. NEUROL., vol. 48, 2000, pages 806 - 8","npl_type":"s","external_id":["10.1002/1531-8249(200011)48:5<806::aid-ana18>3.0.co;2-f","10.1002/1531-8249(200011)48:5<806::aid-ana18>3.3.co;2-6","11079548"],"record_lens_id":"047-802-035-479-753","lens_id":["162-243-512-296-150","047-802-035-479-753","052-031-229-360-599","065-703-208-475-216","011-020-597-201-937"],"sequence":23,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":3,"text":"KWOK JB; TADDEI K; HALLUPP M; FISHER C; BROOKS WS; BROE GA; HARDY J; FULHAM MJ; NICHOLSON GA; STELL R: \"Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype\", NEUROREPORT, vol. 8, 1997, pages 1537 - 42","npl_type":"s","external_id":["9172170","10.1097/00001756-199704140-00043"],"record_lens_id":"053-602-673-604-943","lens_id":["095-432-358-733-037","053-602-673-604-943","081-900-466-232-885"],"sequence":24,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":4,"text":"VERKKONIEMI A; KALIMO H; PAETAU A; SOMER M; IWATSUBO T; HARDY J; HALTIA M: \"Variant Alzheimer disease with spastic paraparesis: neuropathological phenotype\", J. NEUROPATHOL. EXP. NEUROL., vol. 60, 2001, pages 483 - 92","npl_type":"s","external_id":["11379823","10.1093/jnen/60.5.483"],"record_lens_id":"073-145-062-332-859","lens_id":["073-646-255-115-637","073-145-062-332-859","168-545-338-005-590"],"sequence":25,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":5,"text":"CITRON M: \"Strategies for disease modification in Alzheimer's disease\", NAT. REV. NEUROSCI., vol. 5, 2004, pages 677 - 85, XP009065997, DOI: doi:10.1038/nrn1495","npl_type":"s","xp_number":"009065997","external_id":["15322526","10.1038/nrn1495"],"record_lens_id":"003-852-258-590-095","lens_id":["183-691-082-686-765","003-852-258-590-095","109-197-365-980-924"],"sequence":26,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":6,"text":"SUH Y-H; CHECLER F: \"Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease\", PHARMACOL. REV., vol. 54, 2002, pages 469 - 525, XP002476151, DOI: doi:10.1124/pr.54.3.469","npl_type":"s","xp_number":"002476151","external_id":["10.1124/pr.54.3.469","12223532"],"record_lens_id":"113-645-826-017-120","lens_id":["120-161-669-646-814","113-645-826-017-120","179-472-236-149-31X"],"sequence":27,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":7,"text":"BLACKER D; ALBERT MS; BASSETT SS; GO RC; HARRELL LE; FOLSTEIN MF: \"Reliability and validity of NINCDS-ADRDA criteria for Alzheimer's disease. The National Institute of Mental Health Genetics Initiative\", ARCH. NEUROL., vol. 51, 1994, pages 1198 - 204","npl_type":"s","external_id":["7986174","10.1001/archneur.1994.00540240042014"],"record_lens_id":"013-405-535-958-475","lens_id":["121-191-696-060-476","013-405-535-958-475","185-471-743-232-575"],"sequence":28,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":8,"text":"ROSSOR MN; FOX NC; FREEBOROUGH PA; HARVEY RJ: \"Clinical features of sporadic and familial Alzheimer's disease\", NEURODEGENERATION, vol. 5, 1996, pages 393 - 7","npl_type":"s","external_id":["9117552","10.1006/neur.1996.0052"],"record_lens_id":"033-031-652-911-416","lens_id":["089-139-550-911-999","033-031-652-911-416","061-731-017-726-097"],"sequence":29,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":9,"text":"GLENNER GG; WONG CW; QUARANTA V; EANES ED: \"The amyloid deposits in Alzheimer's disease: their nature and pathogenesis\", APPL. PATHOL., vol. 2, 1984, pages 357 - 69","npl_type":"s","external_id":["6242724"],"record_lens_id":"116-118-289-397-563","lens_id":["152-211-020-176-073","116-118-289-397-563"],"sequence":30,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":10,"text":"BALLATORE C; LEE VM-Y; TROJANOWSKI JQ: \"Tau-mediated neurodegeneration in Alzheimer's disease and related disorders\", NAT. REV. NEUROSCI., vol. 8, 2007, pages 663 - 72, XP009179485, DOI: doi:10.1038/nrn2194","npl_type":"s","xp_number":"009179485","external_id":["17684513","10.1038/nrn2194"],"record_lens_id":"064-433-923-907-707","lens_id":["169-312-589-321-511","064-433-923-907-707","126-161-800-701-179"],"sequence":31,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":11,"text":"DILUCA M; BELL KFS; CLAUDIO CUELLO A: \"Altered synaptic function in Alzheimer's disease\", EUR. J. PHARMACOL., vol. 545, 2006, pages 11 - 21","npl_type":"s","external_id":["10.1016/j.ejphar.2006.06.045","16887118"],"record_lens_id":"006-427-751-434-434","lens_id":["023-663-037-756-410","006-427-751-434-434","092-253-536-816-933"],"sequence":32,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":12,"text":"HARDY JA; HIGGINS GA: \"Alzheimer's disease: the amyloid cascade hypothesis\", SCIENCE, vol. 256, 1992, pages 184 - 5","npl_type":"s","external_id":["1566067","10.1126/science.1566067"],"record_lens_id":"019-147-450-716-329","lens_id":["183-553-407-970-276","019-147-450-716-329","168-557-615-786-70X"],"sequence":33,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":13,"text":"BRAAK H; BRAAK E: \"Neuropathological stageing of Alzheimer-related changes\", ACTA NEUROPATHOL, vol. 82, 1991, pages 239 - 59","npl_type":"s","external_id":["10.1007/bf00308809","1759558"],"record_lens_id":"020-798-450-711-581","lens_id":["096-926-146-745-040","020-798-450-711-581","080-495-359-043-322"],"sequence":34,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":14,"text":"MACCIONI RB; FARIAS G; MORALES I; NAVARRETE L: \"The revitalized tau hypothesis on Alzheimer's disease\", ARCH MED RES., vol. 41, no. 3, April 2010 (2010-04-01), pages 226 - 31, XP027078889, DOI: doi:10.1016/j.arcmed.2010.03.007","npl_type":"s","xp_number":"027078889","external_id":["20682182","10.1016/j.arcmed.2010.03.007"],"record_lens_id":"129-001-035-968-103","lens_id":["191-170-868-137-81X","166-028-437-141-311","129-001-035-968-103"],"sequence":35,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":15,"text":"GOLDE TE: \"The Abeta hypothesis: leading us to rationally-designed therapeutic strategies for the treatment or prevention of Alzheimer disease\", BRAIN PATHOL, vol. 15, 2005, pages 84 - 7","npl_type":"s","external_id":["10.1111/j.1750-3639.2005.tb00104.x","15779241","pmc8095797"],"record_lens_id":"091-408-670-399-082","lens_id":["098-031-149-299-715","091-408-670-399-082","134-258-502-529-092"],"sequence":36,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":16,"text":"HARDY J; SELKOE DJ: \"The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics\", SCIENCE, vol. 297, 2002, pages 353 - 6, XP055310378, DOI: doi:10.1126/science.1072994","npl_type":"s","xp_number":"055310378","external_id":["10.1126/science.1072994","12130773"],"record_lens_id":"079-004-710-947-368","lens_id":["138-562-012-809-798","079-004-710-947-368","085-495-874-119-485"],"sequence":37,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":17,"text":"SELKOE DJ: \"The genetics and molecular pathology of Alzheimer's disease: roles of amyloid and the presenilins\", NEUROL. CLIN., vol. 18, 2000, pages 903 - 22","npl_type":"s","external_id":["10.1016/s0733-8619(05)70232-2","11072267"],"record_lens_id":"025-529-582-760-090","lens_id":["044-138-612-643-508","025-529-582-760-090","189-819-058-438-380"],"sequence":38,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":18,"text":"ZLOKOVIC B V: \"The blood-brain barrier in health and chronic neurodegenerative disorders\", NEURON, vol. 57, 2008, pages 178 - 201, XP055475126, DOI: doi:10.1016/j.neuron.2008.01.003","npl_type":"s","xp_number":"055475126","external_id":["10.1016/j.neuron.2008.01.003","18215617"],"record_lens_id":"011-686-034-873-378","lens_id":["155-089-327-516-629","033-594-573-436-484","011-686-034-873-378"],"sequence":39,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":19,"text":"BUDD HAEBERLEIN SL; LIPTON SA: \"Encyclopedia of neuroscience\", 2009, ELSEVIER, article \"Excitotoxicity in neurodegenerative disease\", pages: 77 - 86","npl_type":"b","external_id":["10.1016/b978-008045046-9.00498-8"],"record_lens_id":"136-156-590-934-703","lens_id":["197-617-571-161-110","136-156-590-934-703"],"sequence":40,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":20,"text":"BURNS A; ROSSOR M; HECKER J; GAUTHIER S; PETIT H; MOLLER H J; ROGERS S L: \"Friedhoff L T and the International Donepezil Study Group. The Effects of Donepezil in Alzheimer's Disease - Results from a Multinational Trial\", DEMENT GERIATR COGN DISORD, vol. 10, 1999, pages 237 - 244","npl_type":"s","external_id":["10.1159/000017126","10325453"],"record_lens_id":"017-747-901-080-144","lens_id":["143-252-364-971-585","017-747-901-080-144","122-697-529-445-525"],"sequence":41,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":21,"text":"ROGERS S L; FARLOW M R; DOODY R S; MOHS R; FRIEDHOFF L T: \"Donepezil Study Group. A 24-week, double -blind, placebo controlled trial of donepezil in patients with Alzheimer's disease\", NEUROLOGY, vol. 50, January 1998 (1998-01-01)","npl_type":"s","external_id":["10.1212/wnl.50.1.136","9443470"],"record_lens_id":"025-926-941-609-819","lens_id":["049-780-384-165-195","025-926-941-609-819","039-774-302-311-491"],"sequence":42,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":22,"text":"ROGERS S L; DOODY R S; PRATT R D; IENI J R: \"Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: a final analysis of a US multicenter open-label study\", EUROPEAN NEUROPSYCHOPHARMACOLOGY, vol. 10, 2000, pages 195 - 203, XP055490093, DOI: doi:10.1016/S0924-977X(00)00067-5","npl_type":"s","xp_number":"055490093","external_id":["10793322","10.1016/s0924-977x(00)00067-5"],"record_lens_id":"103-727-806-980-194","lens_id":["109-044-854-483-737","103-727-806-980-194","109-259-394-593-596"],"sequence":43,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":23,"text":"ROCCA P; COCUZZA E; MARCHIARO L; BOGETTO F: \"Donepezil in the treatment of Alzheimer's disease Long-term efficacy and safety\", PROGRESS IN NEUROPSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, vol. 26, 2002, pages 369 - 373, XP002442170, DOI: doi:10.1016/S0278-5846(01)00283-4","npl_type":"s","xp_number":"002442170","external_id":["10.1016/s0278-5846(01)00283-4","11817515"],"record_lens_id":"044-631-046-449-08X","lens_id":["166-391-650-109-43X","044-631-046-449-08X","054-120-490-211-789"],"sequence":44,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":24,"text":"FELDMAN H H; LANE R: \"Rivastigmine: a placebo controlled trial of twice daily and three times daily regimens in patients with Alzheimer's disease\", J NEUROL NEUROSURG PSYCHIATRY, vol. 78, 2007, pages 1056 - 1063","npl_type":"s","external_id":["pmc2117538","17353259","10.1136/jnnp.2006.099424"],"record_lens_id":"066-798-495-397-695","lens_id":["068-601-511-424-851","066-798-495-397-695","121-201-555-016-910"],"sequence":45,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":25,"text":"RASKIND M A: \"Update on Alzheimer Drugs (Galantamine\", THE NEUROLOGIST, vol. 9, no. 5, September 2003 (2003-09-01)","npl_type":"s","external_id":["10.1097/01.nrl.0000087722.46430.c4","12971834"],"record_lens_id":"007-335-147-560-061","lens_id":["121-148-348-254-246","007-335-147-560-061","167-541-942-833-507"],"sequence":46,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":26,"text":"ROSEN WG; MOHS RC; DAVIS KL: \"A new rating scale for Alzheimer's disease\", AM J PSYCHIATRY, vol. 141, 1984, pages 1356 - 64","npl_type":"s","external_id":["10.1176/ajp.141.11.1356","6496779"],"record_lens_id":"018-622-691-667-330","lens_id":["169-338-371-892-472","018-622-691-667-330","149-203-214-151-626"],"sequence":47,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":27,"text":"FOLSTEIN MF; FOLSTEIN SE; MCHUGH PR: \"Mini-mental state''. A practical method for grading the cognitive state of patients for the clinician\", J PSYCHIATR RES, vol. 12, 1975, pages 189 - 98","npl_type":"s","external_id":["1202204","0001202204","10.1016/0022-3956(75)90026-6"],"record_lens_id":"022-988-712-445-94X","lens_id":["058-156-659-186-006","022-988-712-445-94X","138-399-180-525-72X"],"sequence":48,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":28,"text":"HUGHES CP; BERG L; DANZIGER WL; COBEN LA; MARTIN RL: \"A new clinical scale for the staging of dementia\", BR J PSYCHIATRY, vol. 140, 1982, pages 566 - 572","npl_type":"s","external_id":["7104545","10.1192/bjp.140.6.566"],"record_lens_id":"025-921-219-887-720","lens_id":["192-433-389-711-026","025-921-219-887-720","076-245-491-189-242"],"sequence":49,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":29,"text":"HUGHES C P: \"A new clinical scale for the staging of dementia\", BR J PSYCHIATRY, vol. 140, June 1982 (1982-06-01), pages 566 - 72","npl_type":"s","external_id":["7104545","10.1192/bjp.140.6.566"],"record_lens_id":"025-921-219-887-720","lens_id":["192-433-389-711-026","025-921-219-887-720","076-245-491-189-242"],"sequence":50,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":30,"text":"KNOPMAN DS: \"The Clinician Interview-Based Impression (CIBI): a clinician's global change rating scale in Alzheimer's disease\", NEUROLOGY, vol. 44, no. 12, December 1994 (1994-12-01), pages 2315 - 21","npl_type":"s","external_id":["10.1212/wnl.44.12.2315","7991118"],"record_lens_id":"005-954-967-439-726","lens_id":["119-449-364-418-738","005-954-967-439-726","104-947-521-289-51X"],"sequence":51,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":31,"text":"TEUNISSE S: \"The interview for deterioration in daily living activities in dementia: agreement between primary and secondary caregivers\", INT PSYCHOGERIATR, vol. 9, no. 1, 1997, pages 155 - 62","npl_type":"s","external_id":["10.1017/s1041610297004845","9447438"],"record_lens_id":"034-503-012-456-936","lens_id":["142-523-972-198-675","034-503-012-456-936","106-888-017-740-979"],"sequence":52,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":32,"text":"LAWTON: \"Assessment of Older People: Self-Maintaining and Instrumental Activities of Daily Living\", GERONTOLOGIST, vol. 9, no. 3, 1969, pages 179 - 86","npl_type":"s","external_id":["5349366","10.1093/geront/9.3_part_1.179"],"record_lens_id":"099-150-317-608-133","lens_id":["153-958-648-588-489","099-150-317-608-133","100-699-307-024-742"],"sequence":53,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":33,"text":"ISAACS B; KENNIE A: \"The Set test as an aid to the detection of dementia in old people\", THE BRITISH JOURNAL OF PSYCHIATRY, vol. 123, 1973, pages 467 - 470","npl_type":"s","external_id":["4748864","10.1192/bjp.123.4.467"],"record_lens_id":"005-242-991-509-821","lens_id":["057-452-659-023-987","005-242-991-509-821","130-654-135-557-620"],"sequence":54,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":34,"text":"JINPING WANG: \"ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials\", J NEUROL NEUROSURG PSYCHIATRY, vol. 87, no. 9, September 2016 (2016-09-01), pages 993 - 999","npl_type":"s","external_id":["27010616","10.1136/jnnp-2015-312383","pmc5013117"],"record_lens_id":"080-371-898-554-127","lens_id":["155-861-342-565-227","173-327-384-858-100","080-371-898-554-127"],"sequence":55,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":35,"text":"STELLA VJ: \"Prodrugs: challenges and rewards\", 2007, SPRINGER SINGAPORE PTE. LIMITED","npl_type":"b","external_id":[],"lens_id":[],"sequence":56,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":36,"text":"WERMUTH CG: \"The Practice of Medicinal Chemistry\", 2011, ELSEVIER SCIENCE","npl_type":"b","external_id":[],"lens_id":[],"sequence":57,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":37,"text":"PEZRON I; MITRA AK; DUWURI S; TIRUCHERAI GS: \"Prodrug strategies in nasal drug delivery\", EXPERT OPIN. THER. PAT., vol. 12, 2002, pages 331 - 340","npl_type":"s","external_id":["10.1517/13543776.12.3.331"],"record_lens_id":"183-090-975-387-259","lens_id":["194-506-796-091-669","183-090-975-387-259"],"sequence":58,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":38,"text":"STELLA VJ: \"Prodrugs as therapeutics\", EXPERT OPIN. THER. PAT., vol. 14, 2004, pages 277 - 280","npl_type":"s","external_id":["10.1517/eotp.14.3.277.27479"],"record_lens_id":"009-853-330-679-071","lens_id":["009-853-330-679-071","106-598-245-011-932"],"sequence":59,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":39,"text":"STELLA VJ; NTI-ADDAE KW: \"Prodrug strategies to overcome poor water solubility\", ADV. DRUG DELIV. REV., vol. 59, 2007, pages 677 - 94, XP022211987, DOI: doi:10.1016/j.addr.2007.05.013","npl_type":"s","xp_number":"022211987","external_id":["17628203","10.1016/j.addr.2007.05.013"],"record_lens_id":"008-832-184-332-184","lens_id":["117-524-053-926-203","008-832-184-332-184","056-125-331-629-411"],"sequence":60,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":40,"text":"BEAUMONT K; WEBSTER R; GARDNER I; DACK K: \"Design of ester prodrugs to enhance oral absorption of poorly permeable compounds: challenges to the discovery scientist\", CURR. DRUG METAB., vol. 4, 2003, pages 461 - 85, XP008058352, DOI: doi:10.2174/1389200033489253","npl_type":"s","xp_number":"008058352","external_id":["10.2174/1389200033489253","14683475"],"record_lens_id":"036-809-620-727-642","lens_id":["156-850-243-624-036","036-809-620-727-642","142-867-460-987-637"],"sequence":61,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":41,"text":"HIGUCHI T; STELLA VJ: \"Pro-drugs as Novel Drug Delivery System\", 1975, ACS SYMPOS AMERICAN CHEMICAL SOCIETY","npl_type":"b","external_id":[],"lens_id":[],"sequence":62,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":42,"text":"ROCHE EB: \"Design of biopharmaceutical properties through prodrugs and analogs: a symposium\", 1977, AMERICAN P THE ACADEMY","npl_type":"b","external_id":[],"lens_id":[],"sequence":63,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":43,"text":"LAL R; SUKBUNTHERNG J; TAI EHL; UPADHYAY S; YAO F; WARREN MS; LUO W; BU L; NGUYEN S; ZAMORA J: \"Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R-baclofen\", J. PHARMACOL. EXP. THER., vol. 330, 2009, pages 911 - 21, XP002639644, DOI: doi:10.1124/JPET.108.149773","npl_type":"s","xp_number":"002639644","external_id":["10.1124/jpet.108.149773","19502531"],"record_lens_id":"064-197-831-157-070","lens_id":["167-325-030-262-987","085-704-863-082-54X","064-197-831-157-070"],"sequence":64,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":44,"text":"XU F; PENG G; PHAN T; DILIP U; CHEN JL; CHERNOV-ROGAN T; ZHANG X; GRINDSTAFF K; ANNAMALAI T; KOLLER K: \"Discovery of a novel potent GABA(B) receptor agonist\", BIOORG. MED. CHEM. LETT., vol. 21, 2011, pages 6582 - 5","npl_type":"s","external_id":["21920749","10.1016/j.bmcl.2011.08.006"],"record_lens_id":"016-660-015-049-902","lens_id":["069-875-065-636-428","055-615-343-277-455","016-660-015-049-902"],"sequence":65,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":45,"text":"WISHART DS; KNOX C; GUO AC; CHENG D; SHRIVASTAVA S; TZUR D; GAUTAM B; HASSANALI M: \"DrugBank: a knowledgebase for drugs, drug actions and drug targets\", NUCLEIC ACIDS RES., vol. 36, 2008, pages D901 - 6","npl_type":"s","external_id":["10.1093/nar/gkm958","18048412","pmc2238889"],"record_lens_id":"030-069-949-925-776","lens_id":["079-457-389-597-497","163-079-375-280-615","030-069-949-925-776"],"sequence":66,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":46,"text":"LEACH AR; GILLET VJ: \"An Introduction to Chemoinformatics\", SPRINGER- VERLAG","npl_type":"b","external_id":["10.1007/978-1-4020-6291-9"],"record_lens_id":"153-120-132-598-337","lens_id":["153-120-132-598-337"],"sequence":67,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":47,"text":"RAHMAN SA; BASHTON M; HOLLIDAY GL; SCHRADER R; THORNTON JM: \"Small Molecule Subgraph Detector (SMSD) toolkit\", J. CHEMINFORM., vol. 1, 2009, pages 12, XP021061076, DOI: doi:10.1186/1758-2946-1-12","npl_type":"s","xp_number":"021061076","external_id":["10.1186/1758-2946-1-12","pmc2820491","20298518"],"record_lens_id":"144-957-377-114-925","lens_id":["169-841-449-030-900","150-324-685-583-675","144-957-377-114-925"],"sequence":68,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":48,"text":"STAHL H; WERMUTH CG: \"Pharmaceutical salts: Properties, selection, and use\", 2011","npl_type":"b","external_id":[],"lens_id":[],"sequence":69,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":49,"text":"HANAFI R; MOSAD S; ABOUZID K; NIESS R; SPAHN-LANGGUTH H: \"Baclofen ester and carbamate prodrug candidates: a simultaneous chromatographic assay, resolution optimized with DryLab\", J. PHARM. BIOMED. ANAL., vol. 56, 2011, pages 569 - 76, XP028256802, DOI: doi:10.1016/j.jpba.2011.06.023","npl_type":"s","xp_number":"028256802","external_id":["21782368","10.1016/j.jpba.2011.06.023"],"record_lens_id":"060-111-838-107-37X","lens_id":["184-839-205-705-546","169-930-638-253-104","060-111-838-107-37X"],"sequence":70,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":50,"text":"GENNARO AR: \"Remington: The Science and Practice of Pharmacy\", 2000, LIPPINCOTT WILLIAMS & WILKINS","npl_type":"b","external_id":[],"lens_id":[],"sequence":71,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":51,"text":"\"Encyclopedia of Pharmaceutical Technology Dekker\", MARCEL","npl_type":"b","external_id":[],"lens_id":[],"sequence":72,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":52,"text":"MAURICE T; LOCKHART BP; PRIVAT A: \"Brain Res\", vol. 706, 1996, article \"Amnesia induced in mice by centrally administered 0-amyloid peptides involves cholinergic dysfunction\", pages: 181 - 193","npl_type":"b","external_id":["8822355","10.1016/0006-8993(95)01032-7"],"record_lens_id":"002-938-723-939-100","lens_id":["072-589-685-292-719","002-938-723-939-100","026-319-673-428-22X"],"sequence":73,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":53,"text":"MAURICE T; SU TP; PRIVAT A: \"Sigmai ( ) receptor agonists and neurosteroids attenuate 0 - -amyloid peptide-induced amnesia in mice through a common mechanism\", NEUROSCIENCE, vol. 83, 1998, pages 413 - 428, XP025993098, DOI: doi:10.1016/S0306-4522(97)00405-3","npl_type":"s","xp_number":"025993098","external_id":["10.1016/s0306-4522(97)00405-3","9460750"],"record_lens_id":"039-834-540-216-758","lens_id":["114-236-891-926-178","039-834-540-216-758","162-916-359-780-117"],"sequence":74,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":54,"text":"MEUNIER J; IENI J; MAURICE T: \"The anti-amnesic and neuroprotective effects of donepezil against amyloid P - peptide-induced toxicity in mice involve an interaction with the i receptor\", BR J PHARMACOL, vol. 149, 2006, pages 998 - 1012","npl_type":"s","external_id":["17057756","pmc2014636","10.1038/sj.bjp.0706927"],"record_lens_id":"007-567-633-234-969","lens_id":["071-227-997-653-822","007-567-633-234-969","023-609-295-317-464"],"sequence":75,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":55,"text":"VILLARD V; ESPALLERGUES J; KELLER E; ALKAM T; NITTA A; YAMADA K; NABESHIMA T; VAMVAKIDES A; MAURICE T: \"Anti-amnesic and neuroprotective effects of the aminotetrahydrofuran derivative ANAVEX1-41 against amyloid 0 - -induced toxicity in mice\", NEUROPSYCHOPHARMACOLOGY, vol. 34, 2009, pages 1552 - 66","npl_type":"s","external_id":["10.1038/npp.2008.212","19052542"],"record_lens_id":"036-976-225-978-343","lens_id":["159-150-092-280-02X","157-667-256-605-265","036-976-225-978-343"],"sequence":76,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":56,"text":"VILLARD V; ESPALLERGUES J; KELLER E; VAMVAKIDES A; MAURICE T: \"Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigmai ( ) ligand ANAVEX2-73, a novel aminotetrahydrofuran derivative\", J PSYCHOPHARMACOL, vol. 25, 2011, pages 1101 - 17, XP009169910, DOI: doi:10.1177/0269881110379286","npl_type":"s","xp_number":"009169910","external_id":["20829307","10.1177/0269881110379286"],"record_lens_id":"054-028-627-502-201","lens_id":["113-540-013-411-453","188-404-182-477-968","054-028-627-502-201"],"sequence":77,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":57,"text":"ITOH, J; UKAI, M; KAMEYAMA, T: \"Dynorphin A-(1-13) markedly improves scopolamine-induced impairment of spontaneous alternation performance in mice\", EUROPEANJOURNAL OF PHARMACOLOGY, vol. 236, 1993, pages 341 - 345","npl_type":"s","external_id":["8102969","10.1016/0014-2999(93)90469-x"],"record_lens_id":"004-451-185-362-786","lens_id":["134-703-234-642-20X","004-451-185-362-786","026-936-774-830-596"],"sequence":78,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":58,"text":"HIRAMATSU, M; INOUE, K: \"Nociceptin/orphanin FQ and nocistatin on learning and memory impairment induced by scopolamine in mice\", BRITISH JOURNAL OF PHARMACOLOGY, vol. 127, 1999, pages 655 - 660","npl_type":"s","external_id":["10.1038/sj.bjp.0702595","10401555","pmc1566063"],"record_lens_id":"069-738-564-081-307","lens_id":["104-674-497-148-512","069-738-564-081-307","115-006-265-638-93X"],"sequence":79,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}},{"npl":{"num":59,"text":"HALEY, TJ; MCCORMICK, WG: \"Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse\", BRITISH JOURNAL OF PHARMACOLOGY AND CHEMOTHERAPY, vol. 12, 1957, pages 12 - 15","npl_type":"s","external_id":["10.1111/j.1476-5381.1957.tb01354.x","13413144","pmc1509635"],"record_lens_id":"030-973-944-156-117","lens_id":["086-611-967-412-623","092-233-020-575-974","030-973-944-156-117"],"sequence":80,"category":[],"us_category":[],"cited_phase":"APP","rel_claims":[]}}],"reference_cited.source":"DOCDB","reference_cited.patent_count":22,"cites_patent":true,"reference_cited.npl_count":63,"reference_cited.npl_resolved_count":56,"cites_npl":true,"cites_resolved_npl":true,"cited_by":{"patent_count":0,"patent":[]},"cited_by_patent":false,"family":{"simple":{"size":8,"id":194309364,"member":[{"lens_id":"147-635-925-988-568","document_id":{"jurisdiction":"EP","doc_number":"3746062","kind":"A1","date":"2020-12-09"}},{"lens_id":"139-596-462-810-069","document_id":{"jurisdiction":"AU","doc_number":"2019211135","kind":"A1","date":"2020-08-06"}},{"lens_id":"125-505-939-216-899","document_id":{"jurisdiction":"JP","doc_number":"2021512174","kind":"A","date":"2021-05-13"}},{"lens_id":"118-277-118-309-179","document_id":{"jurisdiction":"AU","doc_number":"2019211135","kind":"A8","date":"2020-09-03"}},{"lens_id":"066-289-516-903-572","document_id":{"jurisdiction":"CN","doc_number":"111902138","kind":"A","date":"2020-11-06"}},{"lens_id":"130-813-217-414-303","document_id":{"jurisdiction":"CA","doc_number":"3088715","kind":"A1","date":"2019-08-01"}},{"lens_id":"145-037-877-936-196","document_id":{"jurisdiction":"US","doc_number":"20210236445","kind":"A1","date":"2021-08-05"}},{"lens_id":"061-782-497-903-83X","document_id":{"jurisdiction":"WO","doc_number":"2019145523","kind":"A1","date":"2019-08-01"}}]},"extended":{"size":8,"id":194109053,"member":[{"lens_id":"147-635-925-988-568","document_id":{"jurisdiction":"EP","doc_number":"3746062","kind":"A1","date":"2020-12-09"}},{"lens_id":"125-505-939-216-899","document_id":{"jurisdiction":"JP","doc_number":"2021512174","kind":"A","date":"2021-05-13"}},{"lens_id":"139-596-462-810-069","document_id":{"jurisdiction":"AU","doc_number":"2019211135","kind":"A1","date":"2020-08-06"}},{"lens_id":"118-277-118-309-179","document_id":{"jurisdiction":"AU","doc_number":"2019211135","kind":"A8","date":"2020-09-03"}},{"lens_id":"066-289-516-903-572","document_id":{"jurisdiction":"CN","doc_number":"111902138","kind":"A","date":"2020-11-06"}},{"lens_id":"130-813-217-414-303","document_id":{"jurisdiction":"CA","doc_number":"3088715","kind":"A1","date":"2019-08-01"}},{"lens_id":"145-037-877-936-196","document_id":{"jurisdiction":"US","doc_number":"20210236445","kind":"A1","date":"2021-08-05"}},{"lens_id":"061-782-497-903-83X","document_id":{"jurisdiction":"WO","doc_number":"2019145523","kind":"A1","date":"2019-08-01"}}]}},"has_sequence":false,"legal_status":{"ipr_type":"patent for invention","granted":false,"earliest_filing_date":"2018-07-20","has_disclaimer":false,"patent_status":"PENDING","publication_count":1,"has_spc":false,"has_grant_event":false,"has_entry_into_national_phase":false},"abstract":{"en":[{"text":"The present invention relates to combinations and methods based on Baclofen and Acamprosate for the treatment of Alzheimer's disease or Alzheimer's related disorders in patients who do not respond to an inhibitor of acetylcholinesterase, typically in patients treated with an inhibitor of acetylcholinesterase and who have lost responsiveness to said 5 inhibitor of acetylcholinesterase.","lang":"en","source":"WIPO_FULLTEXT","data_format":"ORIGINAL"}],"fr":[{"text":"La présente invention concerne des combinaisons et des méthodes basées sur le baclofène et l'acamprosate pour le traitement de la maladie d'Alzheimer ou de troubles associés à la maladie d'Alzheimer chez des patients qui ne sont pas sensibles à un inhibiteur de l'acétylcholinestérase, typiquement chez des patients traités par un inhibiteur de l'acétylcholinestérase et qui ont perdu la sensibilité audit inhibiteur de l'acétylcholinestérase.","lang":"fr","source":"WIPO_FULLTEXT","data_format":"ORIGINAL"}]},"abstract_lang":["en","fr"],"has_abstract":true,"claim":{"en":[{"text":"CLAIMS 1. A composition comprising Baclofen and Acamprosate, or pharmaceutically acceptable salts or derivatives thereof, for use in the treatment of Alzheimer’s disease or an Alzheimer’s disease related disorder in a subject not responding to an inhibitor of acetylcholinesterase. 2. The composition for use according to claim 1 , wherein the subject is not-responding to said inhibitor of acetylcholinesterase when his/her performance in a cognitive test after treatment with said inhibitor is suboptimal. 3. The composition for use according to claim 1 , wherein the subj ect is not-responding to said inhibitor of acetylcholinesterase when his/her performance in a cognitive test is not improved by said inhibitor. 4. The composition for use according to claim 2 or 3, wherein the cognitive test is selected from ADAS-Cog, MMSE and CDR-SB. 5. The composition for use according to anyone of claims 1 to 4, wherein the subject is a patient under treatment with therapeutic doses of said inhibitor of acetylcholinesterase and who has lost optimal responsiveness to said inhibitor. 6. The composition for use according to claim 1, wherein the subject is a patient who has been under treatment with the inhibitor of acetylcholinesterase for a period of at least 12 weeks. 7. The composition for use according to claim 5, wherein the subject is a patient who has been under treatment with the inhibitor of acetylcholinesterase for a period of at least 6 months. 8. The composition for use according to any one of claims 1 to 7, wherein said inhibitor of acetylcholinesterase is selected from the group consisting of donepezil, rivastigmine and galantamine. 9. The composition for use according to claim 8, wherein said inhibitor of acetylcholinesterase is donepezil. 10. The composition for use according to any of the preceding claims, further comprising said inhibitor of acetylcholinesterase. 11. The composition for use according to claim 10, wherein said inhibitor is donepezil at a dose between 1 and 20 mg per day. 12. The composition for use according to claim 10, wherein said inhibitor is rivastigmine at a dose between 1 and 30 mg per day. 13. The composition for use according to claim 10, wherein said inhibitor is galantamine at a dose between 8 and 40 mg per day. 14. A composition comprising Baclofen and Acamprosate, or pharmaceutically acceptable salts or derivatives thereof, for use in the treatment of Alzheimer’s disease or an Alzheimer’s disease related disorder in a subject under treatment with an inhibitor of acetylcholinesterase, wherein said composition is administered to the subject when the subject has lost responsiveness to said inhibitor of acety lcho linesterase . 15. The composition for use according to anyone of claims 1 to 14, comprising baclofen and acamprosate as the only active agent. 16. The composition for use of any one of the preceding claims, which further comprises a pharmaceutically acceptable carrier or excipient 17. The composition for use of any one of the preceding claims, wherein the compounds in said composition are formulated or administered together, separately or sequentially. 18. The composition for use of any one of the preceding claims, wherein the ratio Acamprosate/Baclofen (W:W) is comprised between 0.05 and 1000. 19. The composition for use of any one of the preceding claims, wherein the dose of Baclofen is less than 100 mg/day. 20. The composition for use of any one of the preceding claims, wherein the dose of Acamprosate is less than 1000 mg/day. 21. Baclofen and Acamprosate, or pharmaceutically acceptable salts or derivatives thereof, for use in the treatment of Alzheimer’s disease or an Alzheimer’s disease related disorder in a subject not responding to an inhibitor of acetylcholinesterase.","lang":"en","source":"WIPO_FULLTEXT","data_format":"ORIGINAL"}]},"claim_lang":["en"],"has_claim":true,"description":{"en":{"text":"BACLOFEN AND ACAMPROSATE BASED THERAPY OF ALZHEIMER’S DISEASE IN PATIENTS HAVING LOST RESPONSIVENESS TO ACETYLCHOLINESTERASE INHIBITOR THERAPY FIELD OF THE INVENTION The present invention relates to combinations and methods for the treatment of Alzheimer’s disease or Alzheimer’s related disorders in patients who do not respond to an inhibitor of acetylcholinesterase, typically in patients treated with an inhibitor of acetylcholinesterase and who have lost responsiveness to said inhibitor of acetylcholinesterase. More specifically, the present invention relates to novel combinatorial therapy, based on Baclofen and Acamprosate combination, for Alzheimer’s or Alzheimer’s related disorders patients already treated with an inhibitor of acetylcholinesterase and who have lost responsiveness to said inhibitor of acety lcho linesterase . BACKGROUND OF THE INVENTION Alzheimer’s disease (AD) is the prototypic cortical dementia characterized by memory deficit together with dysphasia (language disorder in which there is an impairment of speech and of comprehension of speech), dyspraxia (disability to coordinate and perform certain purposeful movements and gestures in the absence of motor or sensory impairments) and agnosia (ability to recognize objects, persons, sounds, shapes, or smells) attributable to involvement of the cortical association areas. Special symptoms such as spastic paraparesis (weakness affecting the lower extremities) can also be involved (1-4). Incidence of Alzheimer disease increases dramatically with the age. AD is at present the most common cause of dementia. It is clinically characterized by a global decline of cognitive function that progresses slowly and leaves end-stage patients bound to bed, incontinent and dependent on custodial care. Death occurs, on average, 9 years after diagnosis (5). The incidence rate of AD increases dramatically with age. United Nation population projections estimate that the number of people older than 80 years will approach 370 million by the year 2050. Currently, it is estimated that 50% of people older than age 85 years are afflicted with AD. Therefore, more than 100 million people worldwide will suffer from dementia in 50 years. The vast number of people requiring constant care and other services will severely affect medical, monetary and human resources (6). Memory impairment is the early feature of the disease and involves episodic memory (memory for day-to-day events). Semantic memory (memory for verbal and visual meaning) is involved later in the disease. By contrast, working memory (short-term memory involving structures and processes used for temporarily storing and manipulating information) and procedural memory (unconscious memory that is long-term memory of skills and procedure) are preserved until late. As the disease progresses, the additional features of language impairment, visual perceptual and spatial deficits, agnosias and apraxias emerge. The classic picture of Alzheimer’s disease is sufficiently characteristic to allow identification in approximately 80% of cases (7). Nevertheless, clinical heterogeneity does occur and not only is this important for clinical management but provides further implication of specific medication treatments for functionally different forms (8). The pathological hallmarks of AD include deposition of extracellular amyloid plaques containing beta-amyloid peptides (Abeta), intracellular neurofibrillary tangles (NFT) composed of Tau protein and progressive neuronal and synaptic dysfunction and loss (9-11). The etiology of AD remains elusive and for the last decades, several main hypotheses on the cause of AD have been proposed: the “cholinergic hypothesis” attributing a particular role for decrease acetylcholinergic signalling in development of AD, “amyloid cascade hypothesis”, which states that the neurodegenerative process is a series of events provoked by the abnormal processing of the Amyloid Precursor Protein (APP) (12), the revised“Tau hypothesis” (13), which proposes that cytoskeletal changes are the triggering pathological events, and recently, neuroimmomodulation hypothesis prioritizing changes in immune signalling in AD etiology and progression (14). The most widely accepted theory explaining AD progression remains the amyloid cascade hypothesis (15- 17) and AD researchers have mainly focused on determining the mechanisms underlying the toxicity associated with amyloidogenic Abeta peptides. Importantly, changes in microvascular permeability and vessels remodeling, manifested as aberrant angiogenesis and blood brain barrier breakdown in course of AD, have been identified as key events implicated in the APP toxicity (18). Synaptic density change is a pathological lesion that correlates better with cognitive impairment than the deposition of APP and Tau aggregates. Studies have revealed that the amyloid pathology appears to progress in a neurotransmitter-specific manner where the cholinergic terminals appear most vulnerable, followed by the glutamatergic terminals and finally by the GABAergic terminals (11). Glutamate is the most abundant excitatory neurotransmitter in the mammalian nervous system, and its functional effects are finely contra-balanced by GABAergic inhibitory neuronal receptors. Under pathological conditions, abnormal accumulation of glutamate in the synaptic cleft leads to glutamate receptors overactivation (19), that results in cognitive dysfunction and finally in neuronal cell death. This process, named excitotoxicity, is commonly observed in neuronal tissues during acute and chronic neurological disorders and is recognized now as one of the major pathological triggers in AD. Moreover, dysfunction in inhibitory GABA-mediated neuronal circuits observed in AD could increase negative consequences of dysregulated glutamate signaling in neuronal cells Patients diagnosed with mild-to-moderate AD are commonly treated with acetylcholinesterase inhibitors (19), such as Donepezil (DNPz), Galantamine, or Rivastigmine, considered standards of care. However, some patients do not respond to such therapy. Also, in responding patients, it appears the efficacy of acetylcholinesterase inhibitors decreases fast over time with disease progression, few months after initiation of treatment, leaving the patients without any treatment alternative. For example, studies on donepezil showed that the treatment improved the patient’s cognitive function for the first 12 weeks, then the patient’s cognitive function starts declining to reach its baseline level only 30 weeks after initiation of treatment (20, 21, 22 and 23-). The same limited efficacy is described for rivastigmine (24) and galantamine (25). It results therefore that inhibitors of acetylcholinesterase only improve patients’ cognitive functions during the first 12 weeks. After that period, the patients’ cognitive functions start declining again. After only 6 months to 12 months of treatment, most patients will have regained the level of cognitive impairment suffered prior to treatment with their cognitive function further declining inexorably. Thus, such patients lose their responsiveness to acetylcholinesterase inhibitors. WO2012/117076 discloses drug combinations for use in the treatment of AD, in particular the combination of baclofen and acamprosate. It also discloses that said combination can be further combined with existing treatment of AD such as donepezil, galantamine, rivastigmine and tacrine. SUMMARY OF INVENTION It has now been found that baclofen and acamprosate may be used as an effective combination therapy of AD in patients who either do not respond to acetylcholinesterase inhibitors or have lost responsiveness to acetylcholinesterase inhibitors. The combination therapy is effective in such patients and can also restore responsiveness to acetylcholinesterase inhibitors. It is thus an object of the present invention to provide new therapeutic methods and compositions for treating Alzheimer’s disease in patients who do not respond to a treatment with an acetylcholinesterase inhibitor, comprising administering to the patient a combination of baclofen and acamprosate, or salts or derivatives thereof. It is a further object of the present invention to provide methods and compositions for restoring responsiveness to a treatment with an acetylcholinesterase inhibitor in patients who do not respond to said treatment, comprising administering to the patient a combination of baclofen and acamprosate, or salts or derivatives thereof. It is another object of the present invention to provide new therapeutic methods and compositions for treating Alzheimer’s disease in patients treated with an inhibitor of acetylcholinesterase and who have lost responsiveness to said inhibitor of acetylcholinesterase, comprising administering to the patient a combination of baclofen and acamprosate, or salts or derivatives thereof. The invention stems, inter alia, from the unexpected discovery, by the inventors, that the combination of Baclofen and Acamprosate provides substantial and unexpected benefit to patients with Alzheimer’s disease under therapy with an inhibitor of acetylcholinesterase and who have lost optimal responsiveness to said inhibitor of acety lcho linesterase . The invention also relates to compositions comprising Baclofen and Acamprosate, or pharmaceutically acceptable salts or derivatives thereof, for use in the treatment of Alzheimer’s disease or an Alzheimer’s disease related disorder in a subject not responding to an inhibitor of acetylcholinesterase. A further object of this invention relates to compositions comprising a combination of Baclofen and Acamprosate, for use in the treatment of AD or an AD related disorder in patients suffering from such disease, wherein said patients are under treatment with an inhibitor of acetylcholinesterase and have lost responsiveness to said inhibitor of acety lcho linesterase . Another object of this invention also relates to compositions comprising a combination of Baclofen and Acamprosate, for use in the treatment of AD or an AD related disorder in patients suffering from such disease, wherein said patients have been treated with an inhibitor of acetylcholinesterase for a period of at least 12 weeks, preferably 6 months, and have lost responsiveness to said inhibitor of acetylcholinesterase. The composition of the invention may contain Baclofen and Acamprosate as the only active ingredients. Alternatively, the compositions may comprise additional active ingredient(s) such as, in particular, an inhibitor of acetylcholinesterase. In this regard, a further object of this invention relates to a composition comprising a combination of Baclofen, Acamprosate and an inhibitor of acetylcholinesterase for use in the treatment of AD and related disorders in a subject in need thereof, wherein said subject was initially under therapy with said inhibitor of acetylcholinesterase and has lost responsiveness to said acetylcholinesterase inhibitor. In a particular embodiment, the inhibitor of acetylcholinesterase is selected from donepezil, galantamine and rivastigmine. More particularly, the inhibitor of acetylcholinesterase is donepezil. As it will be further disclosed in the present application, the compounds in a combinatorial therapy of the invention may be administered simultaneously, separately, sequentially and/or repeatedly to the subject. The compositions of the invention typically further comprise one or several pharmaceutically acceptable excipients or carriers. Also, the compounds as used in the present invention may be in the form of a salt, hydrate, ester, ether, acid, amide, racemate, or isomer. They may also be in the form of sustained-release formulations. Prodrugs or derivatives of the compounds may be used as well. In a preferred embodiment, the compound is used as such or in the form a salt, hydrate, ester, ether or sustained release form thereof. A particularly preferred salt for use in the present invention is Acamprosate calcium. In another preferred embodiment, a prodrug or derivative is used. The subject or patient may be any mammal, particularly a human, at any stage of the disease. A preferred object of this invention relates to a method for treating Alzheimer disease in a human subject in need thereof, and wherein said subject is under treatment with an inhibitor of acetylcholinesterase and has lost responsiveness to said inhibitor of acetylcholinesterase, the method comprising simultaneously, separately or sequentially administering to said subject an effective amount of at least Baclofen and Acamprosate or salts or derivatives thereof. In a preferred embodiment, the method further comprises administering to the subject said inhibitor of acetylcholinesterase. BRIEF DESCRIPTION OF THE FIGURES Figure 1: Rescue effect of acamprosate and baclofen alone or as add-on therapy to declining donepezil on Ap 2 5-35-induced spontaneous alternation deficits in mice. (A) Mice are injected ICV at Day 1 (D01) with amyloid b-peptide (25-35) or Scrambled. Ab. Nineteen days later (D20), animals received the treatment (vehicle or donepezil (DNPz) (lmg/Kg)) per os by gavage once a day (treatment with vehicle not represented in figure 1). At D30 one group with donepezil treatment was maintained on donepezil treatment alone (group 3), another group with donepezil treatment was administered, in addition to donepezil treatment, with acamprosate (ACP) and baclofen (BCL) (0.2 mg/Kg; 3mg/Kg respectively) (group 4). At D30 and D38, animal cognitive performances in each group were tested by the Y-maze test. At Day D39/40 animal cognitive performances in each group were tested by Passive avoidance test. (B) Mice are injected ICV at Day 1 (D01) with amyloid b-peptide (25-35) or Scrambled. Ab (Xe.Ab). Nineteen days later (D20), animals received the treatment (vehicle, donepezil (DNPz) (lmg/Kg) or a combination of acamprosate (ACP) and baclofen (BCL) (0.2 mg/Kg; 3mg/Kg respectively)) per os by gavage once a day (treatment with vehicle not represented in figure 1). At D30 one group with donepezil treatment (lmg/Kg) was maintained on donepezil treatment alone (group 5). In another group, treatment with donepezil (lmg/Kg) was stopped at D30 and replaced with the administration of acamprosate and baclofen (0.2 mg/Kg; 3mg/Kg respectively) (group 6). At last, at D30 one group with acamprosate and baclofen treatment (0.2 mg/Kg; 3mg/Kg respectively) was maintained on acamprosate and baclofen treatment alone (group 7). At D30 and D40, animal cognitive performances in each group were tested by the Y- maze test. At Day D41/42, animal cognitive performances in each group were tested by Passive avoidance test. Figure 2: Rescue effect of acamprosate and baclofen alone or as add-on therapy to declining donepezil on Ab^^-pkEioeά spontaneous alternation deficits in mice. (A) and (B) Spontaneous alternation performances assessed by Y-maze was performed at D30 after 11 days of treatment respectively for the groups tested according to figure 1.A protocol or figure 1.B protocol. (C) and (D) Spontaneous alternation performances assessed by Y-maze was performed at D38 after 19 days of treatment and D41 after 22 days of treatment respectively for the group of animals tested according to the protocol of figure l .A. or figure l .B. 1. Sc-Ab injected animal group + vehicle treatment. 2. Ab 25 -35 injected animal group + vehicle treatment. 3 (Group 3). Ab 25 -35 injected animal group + Donepezil (lmg/Kg) between D20 and D40. 4 (Group 4). Ab 25 -35 injected animal group + Donepezil (lmg/Kg) between D20 and D40 + acamprosate and baclofen (0.2mg/Kg and 3mg/Kg; respectively) between D30 to D40. 5 (Group 5). Ab 25 -35 injected animal group + Donepezil (lmg/Kg) between D20 and D42. 6 (Group 6). Ab 25 -35 injected animal group + Donepezil (lmg/Kg) between D20 and D29 and then acamprosate and baclofen (0.2mg/Kg and 3mg/Kg; respectively) between D30 to D42. 7 (Group 7). Ab 25 -35 injected animal group + acamprosate and baclofen (0.2mg/Kg and 3mg/Kg; respectively) between D20 and D42. Data are represented as mean and SEM. n = 8 per group; *** p < 0.001 vs. the Ab 25 -35 / Veh group; ## p < 0.01 ; ### p < 0.001 vs. the Sc-Ab / Veh group ANOVA followed by a Dunnetf s test was performed. Figure 3: Rescue effect of acamprosate and baclofen alone or as add-on therapy to declining donepezil on Ap 2 5-35-mduced step-through passive avoidance deficits in mice. (A) and (B) Step-through latency assessed by passive avoidance test was performed at D40 after 21 days of treatment or D42 after 23 days of treatment respectively for the groups tested according to figure 1.A protocol or figure 1.B protocol. (C) and (D) Escape latency assessed by passive avoidance was performed at D40 after 21 days of treatment or D42 after 23 days of treatment respectively for the groups tested according to figure l .A protocol or figure 1.B protocol. 1. Sc-Ab injected animal group + vehicle treatment. 2. Ab 25- 35 injected animal group + vehicle treatment. 3. Ab 25 -35 injected animal group + Donepezil (lmg/Kg) between D20 and D40. 4. Ab 25 -35 injected animal group + Donepezil (lmg/Kg) between D20 and D40 + acamprosate and baclofen (0.2mg/Kg and 3mg/Kg; respectively) between D30 to D40. 5. Ab 25 -35 injected animal group + Donepezil (lmg/Kg) between D20 and D42. 6. Ab 25 -35 injected animal group + Donepezil (lmg/Kg) between D20 and D29 and then acamprosate and baclofen (0.2mg/Kg and 3mg/Kg; respectively) between D30 to D42. 7. Ab 25- 3 5 injected animal group + acamprosate and baclofen (0.2mg/Kg and 3mg/Kg; respectively) between D20 and D42. Data are represented as mean and SEM. n = 8 per group; *** p < 0.001 vs. the Ab 25 -35 / Veh group; # p < 0.05; ## p < 0.01; ### p < 0.001 vs. the Sc-Ab / Veh group Kruskall- Wallis followed by a Dunns test was performed. Figure 4: Three independent studies were used to demonstrate that donepezil efficacy declines when the treatment is initiated at later stages of the disease in an AD mouse model. Mice were intracerebroventricularly injected at Day 1 (D01) with amyloid b-peptide (25- 35) or 8e¾ihM6ά.Ab. Vehicle or donepezil were administered per os by gavage once a day starting at (A) D8 for a period of 10 days or (B) D20 for a period of 11 days or (C) D20 for a period of 21 days. At (A) D15, (B) D28, (C) D30 and D38, animal cognitive performances were tested by the Y-maze test. At (A) D16-17, (B) 29-30, (C) D39-40, animal cognitive performances were tested by passive avoidance test. Figure 5: Effect of DNPz on Ab 25- 35- induced cognitive deficits in mice at different timepoints of disease. 1. Sc-Ab injected animal group + vehicle treatment. 2. Ab 25 -35 injected animal group + vehicle treatment. 3. Ab 25 -35 injected animal group + Donepezil between (A) D08 to D17, (B) D20 to D30 and (C) D20 to D40. At (A) D15, (B) D28, animal cognitive performances were tested by the Y-maze test, data are represented as mean and SEM. At (A) D16-17, (B) D29-30, animal cognitive performances were tested by passive avoidance test, data are represented as mean and SEM. (C) The animal cognitive performances were tested at D30 and D38, data are represented as mean of percentage drug effect and SEM. n is at least 8 per groups; *p<0,05; ** p<0,0l; *** p < 0.001 vs. the Ab 25- 35 / Veh group; # p < 0.05; ##
90% or number of arm entries < 8) were discarded. In the first set of experiments (figure 1 A), animals were tested after the beginning of the treatment at D30 and D38. In the second set of experiments (figure 1B), animals were tested after the beginning of the treatment, at D30 and D40. Passive avoidance test (STPA) All animals were tested for passive avoidance performance, an index of contextual long term memory. The apparatus is a two-compartment (15 x 20 x 15 cm high) box with one illuminated with white polyvinylchloride walls and the other darkened with black polyvinylchloride walls and a grid floor. A guillotine door separates each compartment. A 60 W lamp positioned 40 cm above the apparatus lights up the white compartment during the experiment. Scrambled footshocks (0.3 mA for 3 s) can be delivered to the grid floor using a shock generator scrambler (MedAssociates, USA). The guillotine door was initially closed during the training session. Each mouse was placed into the white compartment. After 5 s, the door was raised. When the mouse was entered in the darkened compartment and placed all its paws on the grid floor, the door was closed and the footshocks delivered for 3 s. The step-through latency, that is, the latency spent to enter the darkened compartment, and the number of vocalizations were recorded. The retention test was carried out 24 h after training. Each mouse was placed again into the white compartment. After 5 s, the door was raised. The step-through latency was recorded up to a cut-off time of 300 s (52-56). In the first set of experiments (figure 1 A), animals were tested after the beginning of the treatment at D39 and D40. In the second set of experiments (figure 1B), animals were tested after the beginning of the treatment, at D41 and D42. Statistical analyses All values were expressed as mean ± S.E.M. Statistical analyses were performed on the different conditions using one-way ANOVA (F value), followed by the Dunnett’s post-hoc multiple comparison test. Passive avoidance latencies do not follow a Gaussian distribution, since upper cut-off times are set. They were therefore be analyzed using a Kruskal- Wallis non-parametric ANOVA (H value), followed by a Dunn's multiple comparison test p < 0.05 will be considered as statistically significant. Results On day 1, all animals received an ICV injection whether with Ab or Sc.Ap. The treatments with donepezil, with a combination of acamprosate and baclofen, or with the vehicle started 19 days after the ICV (D20) to D40, when the pathology was already manifested. At D30 one group of animals treated with donepezil were supplemented with Acamprosate and baclofen for at least 11 days (D30 to D40 or D42). At D30 another group of animals also treated with donepezil stopped treatment with donepezil and instead was administered a combination of acamprosate and baclofen. The cognitive performances of animals were tested at D30 and D38 or D40 by the spontaneous alternation performance test, and at D39- 40 or D41-42 for the passive avoidance test (Figure 1A and 1B). The spontaneous alternation performance assessed by Y-maze is a readout of the spatial working memory of animals. It has been shown that one ICV injection of Ab 25 -35 is able to induce cognitive impairment compared to Sc-Ab ICV injection. Eleven days of treatment, started at D20 with donepezil (1 mg/Kg), or a combination of acamprosate and baclofen (0.2 mg/Kg and 3 mg/Kg, respectively), partially alleviated Ab25-35-ύkEieeά cognitive impairment (Figures 2A-2B). The activity of donepezil was totally lost after a longer treatment period (D20 to D38 or D40) (Figures 2C-2D). The activity of the combination of acamprosate and baclofen (0.2 mg/Kg and 3 mg/Kg, respectively) improved after a longer treatment period (Figures 2B-2D). Remarkably, 10 days of donepezil treatment followed with up to 11 days period of Acamprosate and baclofen (0.2 mg/kg; 3 mg/Kg, respectively), alone (figure 2D) or as a supplement to donepezil (figure 2C), allowed to fully rescue the loss of cognitive impairment induced by Ab 2 5-35. The passive avoidance test is a readout of the fear conditioning memory and implicated also in long-term memory. It has been shown that one ICV injection of Ab 25 -35 is able to induce cognitive impairment compared to Sc-Ab ICV injection. The step-through latency and the escape latency of animals treated with donepezil (1 mg/Kg) or a combination of acamprosate and baclofen (0.2 mg/Kg and 3 mg/Kg, respectively) (D20 to D40 or D42) were significantly smaller than Sc-Ab injected animal group + vehicle. This data suggested that donepezil (1 mg/Kg) alone or a combination of baclofen and acamprosate (0.2 mg/Kg and 3 mg/Kg, respectively) alone partially restored long-term memory when administered at D20 under the tested conditions (Figure 3). Remarkably, animals initially treated with donepezil (1 mg/Kg) and administered with acamprosate and baclofen (0.2 mg/Kg and 3 mg/Kg, respectively) (D30 to D40-D42) alone (Figure 3B-3D) or as a supplementation to donepezil treatment (Figure 3A-3C), showed comparable performances on fear conditioning memory assessed by passive avoidance test than Sc-Ab injected animal group + vehicle. Conclusion DNPz (1 mg/Kg) administered between D20 to D30 showed a partial activity to rescue Ap 2 5-35-induced cognitive impairment assessed by Y-maze. At D38-D40, this effect was not sustained. The combination of acamprosate and baclofen (0.2 mg/Kg and 3 mg/Kg, respectively) administered between D20 to D30 was able to partially rescue AP25-35-induced cognitive impairment assessed by Y-maze. This effect was substantially improved at D40. When animals were treated with donepezil (1 mg/Kg) for 10 days (D20 to D29) and then with acamprosate and baclofen (0.2 mg/Kg and 3 mg/Kg, respectively) for 13 other days (D30 to D42), the treatment with acamprosate and baclofen was able to fully rescue Ab 25- 35-induced cognitive impairment assessed by Y-maze and passive avoidance test. Likewise, when animals were treated with donepezil (1 mg/Kg) for 21 days (D20 to D40) and supplemented with acamprosate and baclofen (0.2 mg/Kg and 3 mg/Kg, respectively) for 11 subsequent days (D30 to D40), the combinational treatment was able to fully rescue Ab 2 5-35-ΐhάueeά cognitive impairment assessed by Y-maze and passive avoidance test. These data demonstrated that administration of acamprosate and baclofen, alone or as an add-on therapy to donepezil treatment, was able to fully rescue cognitive impairments in mice who lost their responsiveness to donepezil treatment. This result was especially surprising considering that in the same model of Ab 25-35 -pk1ho6ά cognitive impairment, the sole administration of a combination of baclofen and acamprosate at the same dose and during the same period of treatment was not able to fully rescue cognitive impairments of the mice. B) DONEPEZIL TREATMENT OF DISEASES RELATED TO Ab TOXICITY IN IN VIVO MODEL Protocol Animals Male Swiss mice weighing 30-35 g, were purchased at JANVIER (Saint Berthevin, France). Housing and experiments were performed within AMYLGEN's animal facility (Direction Regionale de fAlimentation, de l'Agriculturc et de la Foret du Languedoc- Roussillon, agreement #A 34-169-002 from May 02, 2014). Animals were housed in groups with access to food and water ad libitum, except during behavioral experiments. The temperature and humidity were controlled, and the animal facility on a 12 h/l2 h light/dark cycle (lights off at 07:00 pm). Mice were numbered by marking their tail using permanent markers. All animal procedures will be conducted in strict adherence to the European Union Directive of September 22, 2010 (2010/63/UE). Health of animals, general aspect of animals and activity were checked daily. Weight was monitored 3 times per week. Acute or delayed mortality were checked. Amyloid peptide injection (by ICV) Male Swiss mice were anesthetized 5 minutes with isoflurane 2.5%. At day 01 (D01), animals were injected intracerebroventricularly (ICV) through a 28-gauge stainless-steel needle, 4 mm long. An injection volume of 3 mΐ was delivered gradually within 30 s and the needle left in place for an additional 30 s before being removed. Animals were injected with amyloid peptide 25-35 (Ab 25- 35) peptide (9 nmol/mouse) or Scrambled Ab peptide (Sc-Ab) (9 nmol/mo use), in a final volume of 3 mΐ/mousc, according to the previously described method (52-56). Homogeneous preparation of the Ab 25 -35 peptide were performed according to the AMYLGEN's owned procedure. Treatment All animals received a per os gavage using an inox steel cannula. Vehicle or Donepezil (lmg/kg) were administered at D8 until D17; or at D20 until D30 or at D20 to D40 once a day. All the treatments were administered under a volume calculated according to the individual body weight of each mouse (5mL/Kg). Spontaneous alternation performance (Y-maze) Mice were tested for spontaneous alternation performance in the Y-maze, an index of spatial working memory. The Y-maze was designed according to Itoh et al.,1993 (57) and Hiramatsu and Inoue, 1999 (58), and is made of grey polyvinylchloride. Each arm is 40 cm long, 13 cm high, 3 cm wide at the bottom, 10 cm wide at the top, and converging at an equal angle. Each mouse was placed at the end of one arm and allowed to move freely through the maze during an 8min session. The series of arm entries, including possible returns into the same arm, were checked visually by an experimenter blind to treatment. An alternation is defined as entries into all three arms on consecutive occasions. The number of maximum alternations were therefore the total number of arm entries minus two and the percentage of alternation were calculated as (actual alternations / maximum alternations) x 100. Calculated parameters consisted in the percentage of alternation (memory index) and the total number of arm entries (exploration index)(52-56). Mice that showed an extreme behavior (Alternation percentage < 20% or > 90% or number of arm entries < 8) were discarded. Animals were tested every week after the beginning of the treatment, at D15 D28; D30 and D38. Passive avoidance test (STPA) All animals were tested for passive avoidance performance, an index of contextual long term memory. The apparatus is a two-compartment (15 x 20 x 15 cm high) box with one illuminated with white polyvinylchloride walls and the other darkened with black polyvinylchloride walls and a grid floor. A guillotine door separates each compartment. A 60 W lamp positioned 40 cm above the apparatus lights up the white compartment during the experiment. Scrambled footshocks (0.3 mA for 3 s) can be delivered to the grid floor using a shock generator scrambler (MedAssociates, USA). The guillotine door was initially closed during the training session. Each mouse was placed into the white compartment. After 5 s, the door was raised. When the mouse was entered in the dark compartment and placed all its paws on the grid floor, the door was closed and the footshocks delivered for 3 s. The step-through latency, that is, the latency spent to enter the darkened compartment, and the number of vocalizations were recorded. The retention test was carried out 24 h after training. Each mouse was placed again into the white compartment. After 5 s, the door was raised. The step-through latency was recorded up to a cut-off time of 300 s (52-56). Animals were tested every week after the beginning of the treatment, at D 16/17 and D29/30 and D39/40. Statistical analyses All values were expressed as mean ± S.E.M. Statistical analyses were performed on the different conditions using one-way ANOVA (F value), followed by the Dunnett’s post-hoc multiple comparison test. Passive avoidance latencies do not follow a Gaussian distribution, since upper cut-off times are set. They were therefore analyzed using a Kruskal- Wallis non-parametric ANOVA (H value), followed by a Dunn's multiple comparison test. . p < 0.05 will be considered as statistically significant. Results On day 1, all animals received an ICV injection either with Ab or Sc.Ap. The treatments with donepezil or with the vehicle started at D8 for 10 days; D20 for 11 (B) or 21 days (C) (Figure 4). When the treatment started at D08 the dose of 1 mg/Kg of donepezil was able to fully recover Ab 25 -35 -induced cognitive impairment assessed by Y-maze. Donepezil administered between D20 to D30 was partially active (44% of optimal activity) (Figure 5A and B top graphs). Such a response is suboptimal. The passive avoidance test is a readout of the fear conditioning memory and implicated also in long-term memory. It has been shown that one ICV injection of Ab 25 -35 is able to induce cognitive impairment compared to Sc-Ab ICV injection. When the treatment started at D08 the dose of 1 mg/Kg of donepezil was able to fully recover Ab 25 -35 -induced cognitive impairment assessed passive avoidance test. Donepezil administered between D20 to D30 was partially active (Figure 5A and B bottom graphs). In the last experiment, the treatment of Donepezil was initiated at D20 until D40 (21 days of treatment). The cognitive performances of animals were tested at D30 and D38 by Y- maze test. At D30, Donepezil effect (lmg/Kg) was partially active (43% of activity - therefore further reproducing the abovementioned results following administration of donepezil between D20 to D30), and at D38 the drug effect was much lower, not statistically significant, only 25%. These data suggest that donepezil effect clearly decreases with time. Conclusion This data demonstrated that donepezil at this therapeutic dose (1 mg/kg) was able to provide a full therapeutic effect. Indeed, when administered for eleven days starting 7 days after the induction of the pathology, this dose of donepezil resulted in a full recovery of the mice cognitive impairment induced by Ab 2 5-35. When the initiation of the treatment was delayed, (D20), the response to donepezil was less optimal despite the effective therapeutic dose used. This design was able to mimic the loss of responsiveness of donepezil seen in the clinical context. As previously emphasized, studies with donepezil showed that the treatment improved the patient’s cognitive function for the first 12 weeks, then the patient’s cognitive function started declining to reach its baseline level only 30 weeks after initiation of treatment (20-23). The same limited efficacy was also described for rivastigmine (24) and galantamine (25). Therefore, it appears that patients lose their responsiveness to acetylcholinesterase inhibitors with time. C) BACLOFEN AND ACAMPROSATE TREATMENT OF DISEASES RELATED TO Ab TOXICITY IN AN IN VIVO MODEL THAT LOST RESPONSIVENESS TO THERAPEUTIC EFFECTIVE DOSE OF DONEPEZIL Protocol Animals Male Swiss mice weighing 30-35 g, from JANVIER (Saint Berthevin, France), were housed and experiments were performed within AMYLGEN's animal facility (Direction Regionale de l'Alimentation, de l'Agriculture et de la Foret du Languedoc-Roussillon, agreement #A 34-169-002 from May 02, 2014). Animals were housed in groups with access to food and water ad libitum, except during behavioral experiments. The temperature and humidity were controlled, and the animal facility on a 12 h/l2 h light/dark cycle (lights off at 07:00 pm). Mice were numbered by marking their tail using permanent markers. All animal procedures were conducted in strict adherence to the European Union Directive of September 22, 2010 (2010/63/UE). Health of animals, general aspect of animals and activity were checked daily. Weight were monitored 3 times per week. Acute or delayed mortality were checked. Amyloid peptide injection (by ICV) Male Swiss mice were anesthetized 5 minutes with isoflurane 2.5%, were restrained and the head immobilized, then the peptide was injected intracerebroventricularly (ICV) through a 28-gauge stainless-steel needle, 4 mm long. An injection volume of 3 mΐ was delivered gradually within 30 s and the needle was left in place for an additional 30 s before being removed (59). Animals were treated with amyloid peptide 25-35 (Ab 2 5-35) peptide (9 nmol/mouse) or Scrambled Ab peptide (Sc-Ab) (9 nmol/mo use), in a final volume of 3 m 1/mo use, according to the previously described method (52-56). Homogeneous preparation of the Ab 25 -35 peptide was performed according to the AMYLGEN's procedure. Treatment All animals received a per os gavage using an inox steel cannula. All the treatments were administered under a volume calculated according to the individual body weight of each mouse (5mL/Kg). Vehicle and donepezil (lmg/Kg) administration were done once a day, and the mix acamprosate/baclofen twice a day (0,2 mg/Kg and 3 mg/Kg, respectively). Two groups of animals were administered with donepezil (lmg/kg) from D7 until D100, the end of the study. In a first group of animals, only donepezil was administered during the whole study (group 3). In a second group of animals, at D48 when the activity of donepezil was lost as assessed by Y-maze, a combination of acamprosate and baclofen (0,2 mg/Kg and 3 mg/Kg respectively) was administered in addition of donepezil treatment (Group 4). Spontaneous alternation performance (Y-maze) Mice were tested at D7, D14, D21, D28, D35, D42, D49, D56, D63, D70, D77, D91 and D98 for spontaneous alternation performance in the Y-maze, an index of spatial working memory. The Y-maze is designed according to Itoh et al.,1993 (57) and Hiramatsu and Inoue, 1999 (58), and is made of grey polyvinylchloride. Each arm is 40 cm long, 13 cm high, 3 cm wide at the bottom, 10 cm wide at the top, and converging at an equal angle. Each mouse is placed at the end of one arm and is allowed to move freely through the maze during an 8 min session. The series of arm entries, including possible returns into the same arm, are checked visually by an experimenter blind to treatment. An alternation is defined as entries into all three arms on consecutive occasions. The number of maximum alternations are therefore the total number of arm entries minus two and the percentage of alternation are calculated as (actual alternations / maximum alternations) x 100. Parameters are included the percentage of alternation (memory index) and total number of arm entries (exploration index) (52-56). Mice that showed an extreme behavior (Alternation percentage < 20% or > 90% or number of arm entries < 8) are discarded. Passive avoidance test (STPA) At the end of the experiment (D99/D100), all animals were tested for passive avoidance performance, an index of contextual long-term memory. The apparatus is a two- compartment (15 x 20 x 15 cm high) box with one illuminated with white polyvinylchloride walls and the other darkened with black polyvinylchloride walls and a grid floor. A guillotine door separates each compartment. A 60 W lamp positioned 40 cm above the apparatus lights up the white compartment during the experiment. Scrambled footshocks (0.3 mA for 3 s) can be delivered to the grid floor using a shock generator scrambler (MedAssociates, USA). The guillotine door is initially closed during the training session. Each mouse is placed into the white compartment. After 5 s, the door is raised. When the mouse enters in the darkened compartment and places all its paws on the grid floor, the door closes and the footshocks delivers for 3 s. The step-through latency, that is, the latency spent to enter the darkened compartment, and the number of vocalizations is recorded. The retention test is carried out 24 h after training. Each mouse is placed again into the white compartment. After 5 s, the door is raised. The step-through latency is recorded up to a cut-off time of 300 s (52-56). Statistical analyses All values are expressed as mean ± S.E.M. Statistical analyses are performed on the different conditions using one-way ANOVA (F value), followed by the Dunnett’s post-hoc multiple comparison test. Passive avoidance latencies do not follow a Gaussian distribution, since upper cut-off times are set. They are therefore analyzed using a Kruskal- Wallis non-parametric ANOVA (//value), followed by a Dunn's multiple comparison test. p < 0.05 will be considered as statistically significant. Results DNPz treatment initiated at D7 showed a maximal effect between D21 and D28. This effect was not significantly different from Sc-Ab (70 to73% of alternation for DNPz treated animals, 76% of alternation for Sc.AP-vehicle treated animals) (Figure 8A). At D42, DNPz efficacy decreased, and cognitive performances of animals became similar to those of Ab 25- 35 injected animals treated ivith the vehicle (47 /o of alternation for AP25-35— DNPz treated animals against 51% of alternation for AP2 5- 3s-vehicle treated animals) (Figure 8A). After D48, donepezil inactivity was sustained until D100 in the group of animals treated only with donepezil, and their cognitive impairment was similar to that of animals injected with Ab 25 -35 and treated with the vehicle. At D48, when the activity of donepezil (lmg/kg) was lost as assessed by Y-maze, one group of animals (Group 4) was supplemented at D49 until D100 with a combination of acamprosate and baclofen (0,2 mg/Kg and 3 mg/Kg respectively). One week after supplementation with the combination of acamprosate and baclofen, the animals displayed a significant improvement of cognitive performances. In fact, at D56, no statistical difference was observed between animals supplemented with a combination acamprosate and baclofen and those injected with the scrambled Ab peptides. The full recovery was reached only two weeks after initiation of the supplementation with the combination of acamprosate and baclofen (Figure 8A). In the same manner, at the end of the experiment (D99/D100), fear conditioning memory assessed by STPA was altered for the animals treated only with donepezil (Figure 8B). By contrast, in the group of animals supplemented with the combination of acamprosate and baclofen, cognitive impairments was fully restored (274 s of STL vs 251 secs for Sc-Ab vehicle treated) (Figure 8B). This data demonstrated that the addition of a combination of acamprosate and baclofen after the loss of donepezil efficacy fully and quickly restored cognitive performances as spatial working memory and long-term memory in mice model of cognitive impairment induced by Ab 25-35 . Conclusion This data further confirmed that a therapeutic effective dose of donepezil resulted in an improvement, positive significant effect, of the mice cognitive impairment in a mice model of Alzheimer’s disease. It also further demonstrated that this effect then diminished with the mice becoming non- responsive to the therapeutic effective dose of donepezil. Most importantly, it demonstrated that further treating the mice at this stage with a combination of acamprosate and baclofen resulted in full recovery of the mice cognitive functions. The full recovery was achieved only two weeks after administration of the combination of acamprosate and baclofen. This result is especially surprising considering that in the same model of Ab25-35-ΐhάueeά cognitive impairment, the sole administration of a combination of baclofen and acamprosate at the same dose, for a period of 11 days (D20 to D30) and up to 21-23 days (D20 to D40, D41/D42), alleviated cognitive impairments of the mice but was not able to fully rescue it (see figure 2D and 3D). REFERENCES 1. Crook R, Verkkoniemi A, Perez-Tur J, Mehta N, Baker M, Houlden H, Farrer M, Hutton M, Lincoln S, Hardy J, Gwinn K, Somer M, Paetau A, Kalimo H, Ylikoski R, Poyhonen M, Kucera S & Haltia M (1998) A variant of Alzheimer’s disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat. Med. 4, 452-5. 2. Houlden H, Baker M, McGowan E, Lewis P, Hutton M, Crook R, Wood NW, Kumar- Singh S, Geddes J, Swash M, Scaravilli F, Holton JL, Lashley T, Tomita T, Hashimoto T, Verkkoniemi A, Kalimo H, Somer M, Paetau A, Martin JJ, Van Broeckhoven C, Golde T, Hardy J, Haltia M & Revesz T (2000) Variant Alzheimer’s disease with spastic paraparesis and cotton wool plaques is caused by PS-l mutations that lead to exceptionally high amyloid-beta concentrations. Ann. Neurol. 48, 806-8. 3. Kwok JB, Taddei K, Hallupp M, Fisher C, Brooks WS, Broe GA, Hardy J, Fulham MJ, Nicholson GA, Stell R, St George Hyslop PH, Fraser PE, Kakulas B, Clarnette R, Relkin N, Gandy SE, Schofield PR & Martins RN (1997) Two novel (M233T and R278T) presenilin- 1 mutations in early-onset Alzheimer’s disease pedigrees and preliminary evidence for association of presenilin- 1 mutations with a novel phenotype. Neuroreport 8, 1537-42. 4. Verkkoniemi A, Kalimo H, Paetau A, Somer M, Iwatsubo T, Hardy J & Haltia M (2001) Variant Alzheimer disease with spastic paraparesis: neuropathological phenotype. J. Neuropathol. Exp. Neurol. 60, 483-92. 5. Citron M (2004) Strategies for disease modification in Alzheimer’s disease. Nat. Rev. Neurosci. 5, 677-85. 6. Suh Y-H & Checler F (2002) Amyloid precursor protein, presenilins, and alpha- synuclein: molecular pathogenesis and pharmacological applications in Alzheimer’s disease. Pharmacol. Rev. 54, 469-525. 7. Blacker D, Albert MS, Bassett SS, Go RC, Harrell LE & Folstein MF (1994) Reliability and validity of NINCDS-ADRDA criteria for Alzheimer’s disease. The National Institute of Mental Health Genetics Initiative. Arch. Neurol. 51, 1 198-204. 8. Rossor MN, Fox NC, Freeborough PA & Harvey RJ (1996) Clinical features of sporadic and familial Alzheimer’s disease. Neurodegeneration 5, 393-7. 9. Glenner GG, Wong CW, Quaranta V & Eanes ED (1984) The amyloid deposits in Alzheimer’s disease: their nature and pathogenesis. Appl. Pathol. 2, 357-69. 10. Ballatore C, Lee VM-Y & Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat. Rev. Neurosci. 8, 663-72. 11. DiLuca M, Bell KFS & Claudio Cuello A (2006) Altered synaptic function in Alzheimer’s disease. Eur. J. Pharmacol. 545, 11-21. 12. Hardy JA & Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184-5. 13. Braak H & Braak E (1991) Neuropatho logical stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239-59. 14. Maccioni RB, Farias G, Morales I, Navarrete L (2010 Apr.) The revitalized tau hypothesis on Alzheimer's disease. Arch Med Res. 41(3): 226-31 15. Golde TE (2005) The Abeta hypothesis: leading us to rationally-designed therapeutic strategies for the treatment or prevention of Alzheimer disease. Brain Pathol. 15, 84- 7. 16. Hardy J & Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353-6. 17. Selkoe DJ (2000) The genetics and molecular pathology of Alzheimer’s disease: roles of amyloid and the presenilins. Neurol. Clin. 18, 903-22. 18. Zlokovic B V (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178-201. 19. Budd Haeberlein SL & Lipton SA (2009) Excitotoxicity in neurodegenerative disease. In Encyclopedia of neuroscience (Squire LR, ed), pp. 77-86. Elsevier. 20. Bums A, Rossor M, Hecker J, Gauthier S, Petit H, Moller H J, Rogers S L, Friedhoff L T and the International Donepezil Study Group. The Effects of Donepezil in Alzheimer’s Disease - Results from a Multinational Trial. Dement Geriatr Cogn Disord 1999; 10: 237-244 21. Rogers S L, Farlow M R, Doody R S, Mohs R, Friedhoff L T, and the Donepezil Study Group. A 24-week, double -blind, placebo controlled trial of donepezil in patients with Alzheimer’s disease. Neurology 50, January 1998. 22. Rogers S L, Doody R S, Pratt R D, Ieni J R. Long-term efficacy and safety of donepezil in the treatment of Alzheimer’s disease: a final analysis of a US multicenter open- label study. European Neuropsychopharmacology 10 (2000) 195-203. 23. Rocca P, Cocuzza E, Marchiaro L, Bogetto F. Donepezil in the treatment of Alzheimer’s disease Long-term efficacy and safety. Progress in Neuro- Psychopharmacology & Biological Psychiatry 26 (2002) 369-373. 24. Feldman H H, Lane R. Rivastigmine: a placebo controlled trial of twice daily and three times daily regimens in patients with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2007; 78: 1056-1063. 25. Raskind M A. Update on Alzheimer Drugs (Galantamine). The Neurologist, Vol 9 Number 5, September 2003. 26. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141: 1356-64. 27. Folstein MF, Folstein SE, McHugh PR.“Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res l975;12: 189— 98. 28. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatry. 1982;140:566-572. 29. Hughes C P. A new clinical scale for the staging of dementia. Br J Psychiatry. 1982 Jun;140:566-72 . 30. Knopman DS. The Clinician Interview-Based Impression (CIBI): a clinician's global change rating scale in Alzheimer's disease. Neurology. 1994 Dec;44(l2):23 l5-2l. 31. Teunisse S. The interview for deterioration in daily living activities in dementia: agreement between primary and secondary caregivers. Int Psychogeriatr. l997;9 Suppl 1 : 155-62. 32. Lawton. Assessment of Older People: Self-Maintaining and Instrumental Activities of Daily Living. Gerontologist 1969 ; 9 (3) : 179-86. 33. Isaacs B, Kennie A. The Set test as an aid to the detection of dementia in old people. The British Journal of Psychiatry, 1973, 123, 467-470. 34. Jinping Wang. ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials. J Neurol Neurosurg Psychiatry. 2016 Sep; 87(9): 993-999. 35. Stella VJ (2007) Prodrugs: challenges and rewards. (A. Press and Springer, cds.J. Springer Singapore Pte. Limited, New-York. 36. Wermuth CG (2011) The Practice of Medicinal Chemistry. Elsevier Science. 37. Pezron I, Mitra AK, Duwuri S & Tirucherai GS (2002) Prodrug strategies in nasal drug delivery. Expert Opin. Ther. Pat. 12, 331-340. 38. Stella VJ (2004) Prodrugs as therapeutics. Expert Opin. Ther. Pat. 14, 277-280. 39. Stella VJ & Nti-Addae KW (2007) Prodrug strategies to overcome poor water solubility. Adv. Drug Deliv. Rev. 59, 677-94 40. Beaumont K, Webster R, Gardner I & Dack K (2003) Design of ester prodrugs to enhance oral absorption of poorly permeable compounds: challenges to the discovery scientist. Curr. Drug Metab. 4, 461-85. 41. Higuchi T & Stella VJ (1975) Pro-drugs as Novel Drug Delivery System, ACS Sympos American Chemical Society, Washington, DC. 42. Roche EB (1977) Design of biopharmaceutical properties through prodrugs and analogs: a symposium, American P The Academy, Washington, DC 43. Lal R, Sukbunthemg J, Tai EHL, Upadhyay S, Yao F, Warren MS, Luo W, Bu L, Nguyen S, Zamora J, Peng G, Dias T, Bao Y, Ludwikow M, Phan T, Scheuerman RA, Yan H, Gao M, Wu QQ, Annamalai T, Raillard SP, Roller K, Gallop MA & Cundy KC (2009) Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R- baclofen. J. Pharmacol. Exp. Ther. 330, 911-21. 44. Xu F, Peng G, Phan T, Dilip U, Chen JL, Chemov-Rogan T, Zhang X, Grindstaff K, Annamalai T, Roller R, Gallop MA & Wustrow DJ (2011) Discovery of a novel potent GABA(B) receptor agonist. Bioorg. Med. Chem. Lett. 21, 6582-5. 45. Wishart DS, Rnox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B & Hassanali M (2008) DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 36, D901-6. 46. Leach AR & Gillet VJ An Introduction to Chemoinformatics (Springer- Verlag New York Inc, ed. ). 47. Rahman SA, Bashton M, Holliday GL, Schrader R & Thornton JM (2009) Small Molecule Subgraph Detector (SMSD) toolkit. J. Cheminform. 1, 12. 48. Stahl H & Wermuth CG (2011) Pharmaceutical salts: Properties, selection, and use, 2nd ed. (Wiley-VCH, ed.) 49. Hanafi R, Mosad S, Abouzid R, Niess R & Spahn-Langguth H (2011) Baclofen ester and carbamate prodrug candidates: a simultaneous chromatographic assay, resolution optimized with DryLab. J. Pharm. Biomed. Anal. 56, 569-76 50. Gennaro AR (2000) Remington: The Science and Practice of Pharmacy, 20th ed. (A. D. Gennaro, W. Lippincott, and Wilkins, eds.) Lippincott Williams & Wilkins. 51. Swarbrick J & Boylan JC (eds.) Encyclopedia of Pharmaceutical Technology Dekker, Marcel, New-York. 52. Maurice T, Lockhart BP, Privat A. Amnesia induced in mice by centrally administered b-amyloid peptides involves cholinergic dysfunction. Brain Res 706, 181-193, 1996 53. Maurice T, Su TP, Privat A. Sigmai (si) receptor agonists and neurosteroids attenuate P25-35-amyloid peptide-induced amnesia in mice through a common mechanism. Neuroscience, 83, 413-428, 1998 54. Meunier J, Ieni J, Maurice T. The anti-amnesic and neuroprotective effects of donepezil against amyloid b 25 -35 peptide-induced toxicity in mice involve an interaction with the si receptor. Br J Pharmacol, 149, 998-1012, 2006 55. Villard V, Espallergues J, Reller E, Alkam T, Nitta A, Yamada R, Nabeshima T, Vamvakides A, Maurice T. Anti-amnesic and neuroprotective effects of the aminotetrahydrofuran derivative ANAVEX1-41 against amyloid b25-25- induced toxicity in mice. Neuropsychopharmacology, 34, 1552-66, 2009 56. Villard V, Espallergues J, Keller E, Vamvakides A, Maurice T. Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigmai (si) ligand ANAVEX2-73, a novel aminotetrahydrofuran derivative. J Psychopharmacol, 25, 1101-17, 2011 57. Itoh, J, Ukai, M & Kameyama, T Dynorphin A-(l-l3) markedly improves scopolamine-induced impairment of spontaneous alternation performance in mice. European journal of pharmacology, 236, 341-345, 1993. 58. Hiramatsu, M & Inoue, K. Nociceptin/orphanin FQ and nocistatin on learning and memory impairment induced by scopolamine in mice. British journal of pharmacology, 127, 655-660, 1999. 59. Haley, TJ & McCormick, WG. Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse. British journal of pharmacology and chemotherapy, 12, 12-15, 1957.","lang":"en","source":"WIPO_FULLTEXT","data_format":"ORIGINAL"}},"description_lang":["en"],"has_description":true,"has_docdb":true,"has_inpadoc":true,"has_full_text":true,"biblio_lang":"en"},"jurisdiction":"WO","collections":[],"usersTags":[],"lensId":"061-782-497-903-83X","publicationKey":"WO_2019_145523_A1","displayKey":"WO 2019/145523 A1","docAssets":{"lensId":"061-782-497-903-83X","pdfUrl":"https://www.lens.org/images/patent/WO/2019145523/A1/WO_2019_145523_A1.pdf","images":[{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000001.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000001.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000002.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000002.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000003.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000003.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000004.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000004.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000005.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000005.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000006.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000006.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000007.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000007.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000008.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000008.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000009.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000009.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000010.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000010.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000011.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000011.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000012.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000012.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000013.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000013.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000014.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000014.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000015.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000015.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000016.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000016.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000017.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000017.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000018.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000018.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000019.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000019.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000020.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000020.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000021.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000021.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000022.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000022.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000023.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000023.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000024.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000024.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000025.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000025.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000026.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000026.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000027.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000027.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000028.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000028.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000029.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000029.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000030.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000030.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000031.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000031.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000032.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000032.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000033.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000033.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000034.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000034.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000035.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000035.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000036.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000036.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000037.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000037.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000038.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000038.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000039.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000039.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000040.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000040.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000041.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000041.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000042.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000042.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000043.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000043.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000044.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000044.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000045.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000045.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000046.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000046.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000047.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000047.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000048.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000048.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000049.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000049.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000050.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000050.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000051.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000051.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000052.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000052.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000053.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000053.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000054.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000054.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000055.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000055.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000056.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000056.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000057.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000057.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000058.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000058.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000059.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000059.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000060.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000060.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000061.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000061.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000062.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000062.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000063.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000063.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000064.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000064.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000065.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000065.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000066.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000066.png"},{"thumb":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/10pc/00000067.png","full":"https://s3-us-west-2.amazonaws.com/lens-resource/patent/WO/A1/2019145/2019145523/image/page/full/00000067.png"}],"fallover":false},"countryName":"WIPO (P.C.T.)","inventorModel":{"inventors":[{"name":{"value":"BRUREAU ANTHONY","valueNormalised":"Brureau Anthony"},"inventorship":null},{"name":{"value":"CHOLET NATHALIE","valueNormalised":"Cholet Nathalie"},"inventorship":null},{"name":{"value":"COHEN DANIEL","valueNormalised":"Cohen Daniel"},"inventorship":null},{"name":{"value":"HAJJ RODOLPHE","valueNormalised":"Hajj Rodolphe"},"inventorship":null},{"name":{"value":"NABIROCHKIN SERGUEI","valueNormalised":"Nabirochkin Serguei"},"inventorship":null}],"inventorships":[],"unmatchedInventorships":[],"activeUserHasInventorship":false},"simpleFamilyId":194309364,"citesPatentCount":22,"countrySpec":{"countryName":"WIPO (P.C.T.)","description":"INTERNATIONAL APPLICATION PUBLISHED WITH INTERNATIONAL Search Report","rule":"","docType":"PATENT_APPLICATION"},"pageTitle":"WO 2019/145523 A1 - Baclofen And Acamprosate Based Therapy Of Alzheimer's Disease In Patients Having Lost Responsiveness To Acetylcholinesterase Inhibitor Therapy","documentTitle":"Baclofen And Acamprosate Based Therapy Of Alzheimer's Disease In Patients Having Lost Responsiveness To Acetylcholinesterase Inhibitor Therapy"},"claims":{"source":"xml_claims","claims":[{"lines":["CLAIMS"],"number":-1,"annotation":true,"claim":false,"title":false},{"lines":["A composition comprising Baclofen and Acamprosate, or pharmaceutically acceptable salts or derivatives thereof, for use in the treatment of Alzheimer’s disease or an Alzheimer’s disease related disorder in a subject not responding to an inhibitor of acetylcholinesterase."],"number":1,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use according to claim 1 , wherein the subject is not-responding to said inhibitor of acetylcholinesterase when his/her performance in a cognitive test after treatment with said inhibitor is suboptimal."],"number":2,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use according to claim 1 , wherein the subj ect is not-responding to said inhibitor of acetylcholinesterase when his/her performance in a cognitive test is not improved by said inhibitor."],"number":3,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use according to claim 2 or 3, wherein the cognitive test is selected from ADAS-Cog, MMSE and CDR-SB."],"number":4,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use according to anyone of claims 1 to 4, wherein the subject is a patient under treatment with therapeutic doses of said inhibitor of acetylcholinesterase and who has lost optimal responsiveness to said inhibitor."],"number":5,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use according to claim 1, wherein the subject is a patient who has been under treatment with the inhibitor of acetylcholinesterase for a period of at least 12 weeks."],"number":6,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use according to claim 5, wherein the subject is a patient who has been under treatment with the inhibitor of acetylcholinesterase for a period of at least 6 months."],"number":7,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use according to any one of claims 1 to 7, wherein said inhibitor of acetylcholinesterase is selected from the group consisting of donepezil, rivastigmine and galantamine."],"number":8,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use according to claim 8, wherein said inhibitor of acetylcholinesterase is donepezil."],"number":9,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use according to any of the preceding claims, further comprising said inhibitor of acetylcholinesterase."],"number":10,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use according to claim 10, wherein said inhibitor is donepezil at a dose between 1 and 20 mg per day."],"number":11,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use according to claim 10, wherein said inhibitor is rivastigmine at a dose between 1 and 30 mg per day."],"number":12,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use according to claim 10, wherein said inhibitor is galantamine at a dose between 8 and 40 mg per day."],"number":13,"annotation":false,"claim":true,"title":false},{"lines":["A composition comprising Baclofen and Acamprosate, or pharmaceutically acceptable salts or derivatives thereof, for use in the treatment of Alzheimer’s disease or an Alzheimer’s disease related disorder in a subject under treatment with an inhibitor of acetylcholinesterase, wherein said composition is administered to the subject when the subject has lost responsiveness to said inhibitor of acety lcho linesterase ."],"number":14,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use according to anyone of claims 1 to 14, comprising baclofen and acamprosate as the only active agent."],"number":15,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use of any one of the preceding claims, which further comprises a pharmaceutically acceptable carrier or excipient"],"number":16,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use of any one of the preceding claims, wherein the compounds in said composition are formulated or administered together, separately or sequentially."],"number":17,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use of any one of the preceding claims, wherein the ratio Acamprosate/Baclofen (W:W) is comprised between 0.05 and 1000."],"number":18,"annotation":false,"claim":true,"title":false},{"lines":["The composition for use of any one of the preceding claims, wherein the dose of"],"number":19,"annotation":false,"claim":true,"title":false},{"lines":["Baclofen is less than 100 mg/day."],"number":-1,"annotation":true,"claim":false,"title":false},{"lines":["The composition for use of any one of the preceding claims, wherein the dose of Acamprosate is less than 1000 mg/day."],"number":20,"annotation":false,"claim":true,"title":false},{"lines":["Baclofen and Acamprosate, or pharmaceutically acceptable salts or derivatives thereof, for use in the treatment of Alzheimer’s disease or an Alzheimer’s disease related disorder in a subject not responding to an inhibitor of acetylcholinesterase."],"number":21,"annotation":false,"claim":true,"title":false}]}},"filters":{"npl":[],"notNpl":[],"applicant":[],"notApplicant":[],"inventor":[],"notInventor":[],"owner":[],"notOwner":[],"tags":[],"dates":[],"types":[],"notTypes":[],"j":[],"notJ":[],"fj":[],"notFj":[],"classIpcr":[],"notClassIpcr":[],"classNat":[],"notClassNat":[],"classCpc":[],"notClassCpc":[],"so":[],"notSo":[],"sat":[]},"sequenceFilters":{"s":"SEQIDNO","d":"ASCENDING","p":0,"n":10,"sp":[],"si":[],"len":[],"t":[],"loc":[]}}