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United States Patent (10 ) Patent No.: US 10,660,887 B2 Javitt (45 ) Date of Patent: *May 26 , 2020

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United States Patent (10 ) Patent No.: US 10,660,887 B2 Javitt (45 ) Date of Patent: *May 26 , 2020 US010660887B2 United States Patent (10 ) Patent No.: US 10,660,887 B2 Javitt (45 ) Date of Patent : *May 26 , 2020 (54 ) COMPOSITION AND METHOD FOR (56 ) References Cited TREATMENT OF DEPRESSION AND PSYCHOSIS IN HUMANS U.S. PATENT DOCUMENTS 6,228,875 B1 5/2001 Tsai et al. ( 71 ) Applicant : Glytech , LLC , Ft. Lee , NJ (US ) 2004/0157926 A1 * 8/2004 Heresco - Levy A61K 31/198 514/561 (72 ) Inventor: Daniel C. Javitt , Ft. Lee , NJ (US ) 2005/0261340 Al 11/2005 Weiner 2006/0204486 Al 9/2006 Pyke et al . 2008/0194631 Al 8/2008 Trovero et al. ( 73 ) Assignee : GLYTECH , LLC , Ft. Lee , NJ (US ) 2008/0194698 A1 8/2008 Hermanussen et al . 2010/0069399 A1 * 3/2010 Gant CO7D 401/12 ( * ) Notice : Subject to any disclaimer, the term of this 514 / 253.07 patent is extended or adjusted under 35 2010/0216805 Al 8/2010 Barlow 2011/0207776 Al 8/2011 Buntinx U.S.C. 154 ( b ) by 95 days . 2011/0237602 A1 9/2011 Meltzer This patent is subject to a terminal dis 2011/0306586 Al 12/2011 Khan claimer . 2012/0041026 A1 2/2012 Waizumi ( 21 ) Appl. No.: 15 /650,912 FOREIGN PATENT DOCUMENTS CN 101090721 12/2007 ( 22 ) Filed : Jul. 16 , 17 KR 2007 0017136 2/2007 WO 2005/065308 7/2005 (65 ) Prior Publication Data WO 2005/079756 9/2005 WO 2011044089 4/2011 US 2017/0312275 A1 Nov. 2 , 2017 WO 2012/104852 8/2012 WO 2005/000216 9/2013 WO 2013138322 9/2013 Related U.S. Application Data (63 ) Continuation of application No. 13/ 936,198 , filed on OTHER PUBLICATIONS Jul. 7 , 2013 , now Pat . No. 9,737,531 . Ceglia et al. , “ The 5 -HT2A receptor antagonist M100,907 prevents extracellular glutamate rising in response to NMDA receptor block ade in the mPFC , ” Journal of Neurochemistry, 2004, 91, 189-199 . (60 ) Provisional application No. 61/ 741,114 , filed on Jul. Mony et al. , “ Identification of a novel NR2B -selective NMDA 12 , 2012 , provisional application No. 61/ 741,115 , receptor antagonist using a virtual screening approach ,” Bioorganic & Medicinal Chemistry Letters 20 ( 2010 ) 5552-5558 . filed on Jul. 12 , 2012 . Rogoz, Z. et al. “ Synergistic effect of uncompetitive NMDA recep tor antagonists and antidepressant drugs in the forced swimming test (51 ) Int. Cl. in rats ” Neuropharmacology , Pergamon Press , Oxford , GB , 42 ( 8 ) : AOIN 43/00 (2006.01 ) 1024-1030 , ( Jun . 2002 ) . A61K 31/553 ( 2006.01 ) Heresco -Levy , U. et al. “ Controlled trial of d -cycloserine adjuvant A61K 31/554 (2006.01 ) therapy for treatment- resistant major depressive disorder” Journal A61K 31/496 of Affective Disorders, Elsevier Biochemical Press, Amsterdam , ( 2006.01 ) NL , 93 ( 1-3 ) : 239-243 , ( Jul. 2006 ) . A61K 3142 (2006.01 ) Crane , G.E. “ Cycloserine as an antidepressant agent” American A61K 31/06 ( 2006.01 ) journal of Psychiatry , American Psychiatric Publishing, Inc., US , A61K 31/381 ( 2006.01 ) 115 ( 11 ) : 1025-1026 , (May 1 , 1959 ) . A61K 31/55 ( 2006.01 ) Oliver et al . “ Quetiapine augmentation in depressed patients with A61K 31/138 partial response to antidepressants ” Human Psychopharm Clin Exp , ( 2006.01) 23 :653-660 , 2008 . A61K 45/06 ( 2006.01) Poleszak et al “ A complex interaction between glycine /NMDA A61K 31/431 ( 2006.01 ) receptors and serotonergic /noradrenergic antidepressants in the forced A61K 31/4525 (2006.01 ) swim test in mice ” Journal of Neural Transmission , 118 : 1535-1546 , A61K 31/519 ( 2006.01 ) 2011 . A61K 31/551 ( 2006.01 ) (Continued ) A61K 31/135 (2006.01 ) (52 ) U.S. CI. Primary Examiner Jared Barsky CPC A61K 31/496 ( 2013.01 ) ; A61K 31/06 (74 ) Attorney, Agent, or Firm — JMB Davis Ben - David (2013.01 ) ; A61K 31/135 (2013.01 ) ; A6IK ( 57 ) ABSTRACT 31/138 (2013.01 ) ; A61K 31/381 ( 2013.01 ) ; Compositions and methods for the treatment of depression A61K 31/42 ( 2013.01) ; A61K 31/431 and psychoses in humans are disclosed . More particularly , ( 2013.01) ; A61K 31/4525 ( 2013.01) ; A61K the invention is directed to formulations containing antip 31/519 (2013.01 ) ; A61K 31/55 ( 2013.01) ; sychotic and / or antidepressant medications and also con A61K 31/551 ( 2013.01 ) ; A61K 31/553 taining an NMDAR antagonist. The present Invention Is also ( 2013.01 ) ; A61K 31/554 (2013.01 ) ; A61K ecto to methods tor the treatment humans suffering 45/06 (2013.01 ) from depression and other psychoses , including, schizophre (58 ) Field of Classification Search nia , by administration of the inventive compositions in None antidepressant and / or antipsychotic effective amounts . See application file for complete search history . 16 Claims, 1 Drawing Sheet US 10,660,887 B2 Page 2 ( 56 ) References Cited OTHER PUBLICATIONS Ishibashi et al “ Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5 -Hydroxytryptamine 7 ( 5 -HT7 ) and 5 -HT1A Receptor Activity ” Journal of Pharmacology and Experimental Therapeutics, 334 : 171-181 , 2010 . Marek et al, “ The Selective 5 -HT2A Receptor Antagonist M100907 Enhances Antidepressant- Like Behavioral Effects of the SSRI Fluoxetine ” Neuropsychopharmacology 30 : 2205-2215 , 2005 . Letter to Dr. Daniel Javitt from Dr. Yehezkel Caine , CEO of Herzog Hospital , Apr. 12 , 2017 ( redacted ) ( 1 page) . Letter to Dr. Yehezkel Caine, CEO of Herzog Hospital from Dr. Daniel Javitt, May 15 , 2017 ( redacted ) . Ardayfio et al ., J. Pharm and Exp Ther , 327: 891-897, 2008. Gaisler- Salomon et al. , Psychopharm 196 :255-267 , 2008 . Carlsson et al ., J. Neuraltrans. 106 : 123-129 , 1999 . De Paulis , Curr Opin in Invest Drugs 2 : 123-132 , 2001. Fenton , “ Depression , Suicide and Suicide Prevention in Schizo phrenia ,” American Foundation for Suicide Prevention Education section , http://www.afsp.org/education/fenton.htm (date accessed Dec. 3 , 2015 ) . Jamison , “ Suicide and bipolar disorder, ” J Clin Psychiatry . 2000 ;61 Suppl 9 : 47-51 . * cited by examiner U.S. Patent May 26 , 2020 US 10,660,887 B2 ## los 5. *** 4 IN MDL100907(0.3mg/kg,1.P.)+DCS30-DOI2 MDL100907(0.3mg/kg,1.P.)+DCS300-DOI2 MDL100907(0.3mg/kg,1.P.)+DOI2 3.DCS(300mg/kg,1.P.)+2 PTSDOI(1.P.2mg/kg,) 2:DCS(30mg/kg,1.P.)+ = 1. 3 6 :5 80 60 40 20 ARMS OPEN IN SPENT TIME % US 10,660,887 B2 1 2 COMPOSITION AND METHOD FOR disorder, dissociative disorders, personality disorders or TREATMENT OF DEPRESSION AND adjustment disorders with depressed mood (DSM - IV ) . PSYCHOSIS IN HUMANS Current treatments for major depression consist primarily of older antidepressants , such as monoamine oxidase inhibi CROSS REFERENCE TO RELATED 5 tors (MAOI ) and tricyclic antidepressants ( TCAs ) (e.g. APPLICATIONS imipramine, amitryptiline, desipramine , clomipramine) that were first developed in the 1960's , and newer agents such as This is a continuation of co -pending U.S. patent applica tetracyclic antidepressants ( TeCAs) , e.g. amoxapine, setip tion Ser . No. 13 / 936,198 , filed Jul. 7 , 2013 , which claims the tiline , maprotiline , mianserin , mirtazapine ) , serotonin benefit of provisional application No.61 / 741,114 , filed Jul. 10 (SSRI ) and serotonin /norephinephrine (SNRT ) reuptake 12 , 2012 , and provisional application No. 61/ 741,115 , filed inhibitors ( e.g., fluoxetine , fluvoxamine, paroxetine, citalo Jul. 12 , 2012 , the contents of each of which are hereby pram , escitalopram , duloxetine , venlafaxine , dapoxetine, incorporated by reference . indalpine , valzodone ). These agents work by modulating BACKGROUND OF THE INVENTION 15 brain levels of monoamines , in particular norepinephrine and serotonin , and /or by blocking 5 -HT2A receptors . Schizophrenia is a clinical syndrome associated with MAOls and TCAs are considered “ broader spectrum ” agents psychotic symptoms such as delusions and hallucinations, as than SSRIs ; SNRIs that were developed subsequently well as a decline in function in such areas as work , social MAGI, TCAs , TeCAs, SSRIs . and SNRIs may collectively relation or self care . 20 be considered traditional antidepressants . Diagnosis of schizophrenia may be determined using Antipsychotics may also be effective in treatment of standard textbooks of the art , such as the Diagnostic and depression . Potentially beneficial antipsychotic medications Statistical Manual of Mental Disorders -fourth edition include but are not limited to risperidone , olanzapine , que (DSM - IV ) published by the American Psychiatric Associa tiapine, aripiprazole , clozapine, iloperidone , sertindole , tion . Symptoms of schizophrenia are typically measured 25 asenapine, lurasidone , cariprazine . using rating scales such as the Positive and Negative Syn Other antipsychotics and antidepressants in development drome Scale (PANSS ) . include Valdoxan ( agomelatine , AG0178 ) ( Servier, Novar Symptoms of schizophrenia are treated with antipsychotic tis ), Lu AA21004 (Lundbeck , Takeda ), F2695 , levomil medications, which function primarily by blocking dop nacipran (Forest , Pierre Fabre) , SEP - 227162 (Sepracor ) , amine D2 receptors . 30 LUAA24530 (Lundbeck , Takeda ) . SEP - 225289 (Sepracor ) , Antipsychotics may be divided into typical ( e.g. chlorpro Epivanserine ( Sanofi - Aventis ), SR463 9 (Sanofi - Aventis ) . mazine, haloperidol. perphenazine) vs. atypical ( e.g. amisul LY12624803 , HY10275 (Lilly , Hypnion ) , TI- 301/ pride, aripiprazole , asenapine , bioanserin , bifeprunox , car LY156735 ( Tikvah Therapeutics) , Lonasen (bioanserin , iprazine, clotiapine , clozapine, iloperidone , lurasidone , Dainippon ) , LU -31-130 (Lundbeck ), SLV313 (Solvay ) .Edi mosaproamine , olanzapine, paliperidone, perospirone, que- 35 voxetine (LY2216684 , Lilly ) , OPC - 34712 (Otsuka / Lund tiapine , remoxipride , risperidone
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