`Attorney Docket No. 05273.0127-01000
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Prior Application Art Unit 1612 Prior Application Examiner: Snigdha MAEWELL
`
`Commissioner: This is a request for filing a
`l:gJ Continuation D Continuation-in-Part D Divisional Application under 37 C.F.R
`§ 1.53(b) of pending prior Application No. 10/525,021, filed February 18, 2005 of
`Mitsutaka Nakamura et al. AGENT FOR TREATMENT OF SCHIZOPHRENIA
`D
`
`Enclosed is a complete copy of the prior application as originally filed. I
`hereby verify that the attached papers are a true copy of prior Application
`No. 10/525,021 as filed on February 18, 2005, which is incorporated
`herein by reference.
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`D
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`rgJ
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`rgJ
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`[""]
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`rgJ
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`Enclosed is an AIA Transition Application Statement under 1.55U),
`1.78(a)(6), and/or 1.78(c)(6).
`
`Enclosed is a Request for Non-Publication of Application and Certification
`Under 35 U.S.C. § 122(b)(2)(B)(i).
`
`A Preliminary Amendment is enclosed.
`
`The filing fee is calculated on the basis of the claims existing in the prior
`application as amended in the Preliminary Amendment filed herewith.
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`A new oath or declaration is enclosed.
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`An Application Data Sheet is enclosed.
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`Page 1 of 216
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`Application No": To be assigned
`Attorney Docket No.: 05276.0127-01
`Page 2 of 3
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`~
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`The Commissioner is hereby authorized to charge any additional fees
`which may be required including fees due under 37 C.F.R § 1.16 and any
`other fees due under 37 C.F.R § 1.17, or credit any overpayment during
`the pendency of this application to Deposit Account No. 06-0916.
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`10.
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`LJ
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`New acceptable drawings are enclosed,
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`Page 2 of 216
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`Application No.: To be assigned
`Attorney Docket No,: 05276.0127-01
`Page 3 of 3
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`The prior application is assigned of record to: DA!NIPPON SUMITOMO
`PHARMA CO., LTD.
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`Small entity status is appropriate and applies to this application.
`
`The power of attorney in the prior application is to FINNEGAN,
`HENDERSON, FARABOW, GARRETT & DUNNER, LL.P., Customer No,
`22,852.
`
`A listing Under 37 C.F.R. § 1.32(c)(3} of Ten or Fewer Practitioners to
`be Recognized by the PTO as Being of Record is attached.
`
`The power appears in the original declaration of the prior application.
`
`Since the power does not appear in the original declaration, a copy of the
`power in the prior application is enclosed,
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`Please address al! correspondence to FINNEGAN, HENDERSON,
`FARABOW, GARRETT and DUNNER, L.L.P., Customer Number 22,852.
`
`A new power of attorney is enclosed,
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`Also enclosed is
`
`PETITION FOR EXTENSION. !f any extension of time is necessary for the filing of this
`application, including any extension in parent Application No. 10/525,021,
`filed February 18, 2005, for the purpose of maintaining copendency between the parent
`application and this application, and such extension has not otherwise been requested,
`such an extension is hereby requested, and the Commissioner is authorized to charge
`necessary fees for such an extension to Deposit Account 06-0916.
`
`Dated: August 28, 2014
`
`FINNEGAN, HENDERSON, FARABOW,
`GARRETT & DUNNER, LL.P.
`
`By:···-·t'<Lu>.<'.)~.·>L-;( Ct t:,Vi:'<•~ L~_.~r\"""~ .. _:~:._; __ _
`Kimberl{[). Braslow
`Reg. No. 63,219
`(202) 408-4000
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`Page 3 of 216
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`1
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`DESCRIPTION
`
`AGENT FOR TREATMENT OF SCHIZOPHRENIA
`
`5
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`TECHNICAL FIELD
`
`The present invention relates to a novel method for treatment of
`
`schizophrenia and a novel therapeutic a.gent used therein, More
`
`particularly, the present invention relates to a method for improving
`
`schizophrenia without being accompanied by extra.pyramidal symptoms
`
`l O
`
`by orally administering a prescribed dose of a specific bicycloheptane(cid:173)
`
`dicarboximide derivative once a day, and a therapeutic agent used in
`
`said method,
`
`BACKGROUND ART
`
`15
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`Schizophrenia (split personality) is a kind of endogenous
`
`psychosis, and it is developed mainly during adolescence, and after a
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`chronic course, the personality of patient is progressively decayed, and
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`some of patients may culminate in a mental decay. The symptoms of
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`this disease are, for example, positive symptoms often observed during
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`20
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`the early stage of the disease such as hallucination, delusion, etc., or
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`negative symptoms such as apathy and withdrawal, or cognitive
`
`dysfunction such as impairments of concentration and learning abilities,
`
`etc. Moreover, there are other syn1ptom:s such as depression, anxiety,
`
`etc. as related symptoms thereof.
`
`25
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`Medication is rnainly employed in the treatment of schizophrenia,
`
`but the treatment of schizophrenia should be continued for a long time,
`
`and even though schizophrenia is once healed, there is a large risk of
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`reoccurring of schizophrenia after drug withdrawal so that it is
`
`necessary to continue the medication forever. Therefore, any side
`
`30
`
`effects of medication may always be serious problems, and based on
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`this perspective, it has been desired to develop a medicine being
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`suitable for prolonged medicatio:no
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`The agents for treatment of schizophrenia are various
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`medicaments such as ones classified in the category of antipsychotic,
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`5
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`for exrunple, phenoth:iazine derivatives (e.g., chlorpromazine. metho,cy-(cid:173)
`
`promazine, etc.), thioxanthin derivatives having a similar structure to
`phenothiazine (e.g., chlorprothixene, flupentbml, etc,1;· benzamide
`derivatives (e.g., sulpiride, sultopride, etc.), thienodiazepine derivatives
`
`(e.g., clotiazepai11, etizolam, etc.), and further butyrophenone derivatives
`
`10
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`(e.g., haloperidol, triperidol, etc.), diphenylbutylamine derivatives (e.g.,
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`pimozide, etc.), etc.
`
`However, phenothiazine derivatives, phenothiazine ai1alogues,
`
`and butyrophenone de1ivatives may cause serious side effects of
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`extra.pyramidal symptoms showing park:insonism such as the stiff gait
`
`15
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`of skeletal muscles, tremor of muscles, lack of facial expression,
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`salivation, etc.
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`Further, diphenylbutylamine derivatives may cause
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`extra.pyramidal symptoms in addition to insomnia.
`In addition, these
`conventional antipsychotics may be effective on only some of symptoms
`among positive sym.ptoms, negative symptoms, cognitive dysfunctions of
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`20
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`schizophrenia, and there has been no drug being effective on all of these
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`symptoms.
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`Therefore, it has been desired to develop a safe medicament
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`which exhibits an excellent effect on various schizophrenia as an
`
`antipsychotic without causing side effects such as extrapyramidal
`
`25
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`symptoms.
`On the other hand 1 it has been known that the imide derivative
`of the following formula, which was found by the co-workers of the
`
`present inventors, may be useful as an antipsychotic (c.f,, neurnleptk
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`agent, antiaxiety, etc.}, especially as an agent for treatment of
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`30
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`schizophrenia, senile insanity, manic depressive psychoses, and
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`3
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`nervous breakdown (USP 5,532,372),
`
`;--\
`Z-D-N
`G""Ar
`,_.,,,,.j
`
`wherein Z is
`
`0
`(CH2)11~
`
`R'I
`
`Ri:\--1--·""" 8 N-
`
`Rj R4
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`5
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`D is a group of the formula: -{CH2)i:i-A-(CH2)q-,
`":cH-
`
`' N-
`
`Gl'i /
`
`o:r
`
`<""'
`
`, etc., and
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`Ar is an aromatic group, or an aromatic heterocydic group, etc.
`
`DISCLOSURE OF INVENTION
`
`10
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`The present inventor has intensively studied on a series of imide
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`derivatives with respect to many aspects including a use and a dose
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`thereof in order to find a novel agent for treatment of schizophrenia,
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`which may exhibit an excellent effect in the treatment of schizophrenia
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`and have no side effect such as extra.pyramidal symptoms, which are
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`15
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`often observed in many conventional antipsychotics, and can safely be
`
`administered for a long time. As a :result, the present inventors have
`
`found that ( 1 R,2S,3R,4S}-N-H l R,2R}-2-!4-( l ,2-benzoisothiazol-3-yl)-1-
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`piperazinylmethylj-1-cyclohexylmethylJ-2,3-bicyclo[2.2 .1 Jheptane(cid:173)
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`dicarboximide of the following formula:
`
`tr"'''\.
`
`\
`
`_____ /
`
`~ ~ 0
`-c" - , 7~
`r-\
`~ -~~· N ,...._-#,'f A'--· N
`... ,:--· = ·
`H H
`- H
`H o
`
`\_,J
`
`N1·f·' S
`.N,_
`J
`~\
`~-//
`~w,-~/
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`20
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`( 1)
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`or a pharmaceutically acceptable salt thereof such as a hydrochloride
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`4
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`thereof is effective for relieving the wide-ranging symptoms of
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`schizophrenia, and may treat schizophrenia quite safely without being
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`accompanied by extrapyramidal symptoms by orally administering a
`
`prescribed dose thereof once a day,
`
`5
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`Namely, the present invention provides a method for treatment
`
`of schizophrenia without being accompanied by extra.pyramidal
`
`symptoms by orally administration of a prescribed amount of
`
`( 1 R,2S,3R,4S)-N-H l R,2R)-2-[4-( l ,2-benzoisothiazol-3-yl)-1-piperazinyl(cid:173)
`
`methyl]-1-cydohe~-ylmethyl]-2 ,3-bicydo[2.2 .1 ]heptanedicarboximide of
`
`10
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`the above formula { 1) or a pharmaceutically acceptable salt thereof once
`
`a day, and further provides an agent for treatment of schizophrenia
`
`which is used in said method.
`
`BRIEF DESCRIPTION OF DRAWINGS
`
`15
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`Fig. 1 is a graph showing the change with time in scores of Brief
`
`Psychiatric Rating Scale: BPRS, which are indexes for the effects on
`
`schizophrenia, of the active compound of the present invention,
`
`( 1 R,2S,3R,4S)-N-[{ l R,2R}-2-[4-( 1,2-benzoisothiazol-3-yl)-1-piperazinyl(cid:173)
`
`methyl]-1-cyclohexylmethyl]-2 ,3-bicyclo[2 .2, 1 ]heptanedicarboximide
`
`20
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`hydrochloride and placebo in the double blind clinical trial.
`
`DETAILED DESCRIPTION OF INVENTION
`
`As shown in Examples as described hereinafter, when orally
`
`administering a prescribed dose of (1R,2S,3R,4S)-N-[( 1R,2R}-2-[4-{1,2-
`
`25
`
`benzoisothiazol-3-y1)-1-piperazinylmethy1J-1-cyclohexylmethyl]-2,3-
`
`bicydo[2.2o lJheptanedicarbox.imide hydrochloride once a day for 6
`
`weeks to the patients with schizophrenia in the acute exacerbation, the
`
`present inventors have found that the excellent effects on the wide(cid:173)
`
`ranging symptoms were obtained, and surprisingly, any extrapyramida.l
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`30
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`symptoms as observed in the conventional antipsychotics were hardly
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`5
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`observed, especially, abnormal electrocardiogram which. progresses to
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`sudden death is not recognized, and hence, that this compound may be
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`quite safely used in the treatment of schizophrenia,
`
`Namely, the present invention provides a novel method for
`
`5
`
`treatment of schizophrenia improving a wide-ranging schizophrenia
`
`including positive symptoms, negative symptoms, and cognitive
`
`dysfunction, especially positive symptoms and negative symptoms,
`
`without being accompanied by extrapyramidal symptoms which
`
`comprises orally administering a prescribed dose of ( 1R,2S,3R,4SJ-N-
`
`10
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`[{ 1R,2R)-2-[4-( 1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-l-cyclo(cid:173)
`
`hexylmethyl]-2,3-bicydo[2.2. l]heptanedicarboximide of the above
`
`formula ( 1) or a pharma.ceu tically acceptable salt thereof, especially a
`
`hydrochloride thereof, to a patient with schizophrenia once a day,
`
`The present invention also provides a novel agent for treatment
`
`15
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`of such schizophrenia.
`
`According to the present invention, excellent improving effects
`
`on the wide-ranging symptoms of schizophrenia may be obtained by
`
`orally administering (1R,2S,3R,4S)-N-[(1R/2R)-2-[4-(1,2-benzoisothiazol-
`
`3-yl)-1-piperazinylmethy1]-1-cydohexy1methylJ-2,3-bicyclo[2.2. l]-
`
`20
`
`heptanedicarboximide or a pharmaceutically acceptable salt thereof, for
`
`example, a hydrochloride, at a daily dose of 5 mg to 120 mg, preferably
`
`at a daily dose of 10 mg to 100 mg, more preferably at a daily dose of 20
`mg to 80 mg, once a day. Further, in the therapeutic method of the
`
`present invention, side effects such as extrapyramidal symptoms such
`
`25
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`as pa.rkinsrmism, dysk.inesia, akathisia, etc., abnormal electro(cid:173)
`
`cardiogram, hepatic dysfunction are hardly observed, and hence, the
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`present method may be quite safely used and suitable for a prolonged
`
`medication,
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`Besides, when the present method is applied to a patient with
`
`30
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`schizophrenia in chronic phase, the above active compound should
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`6
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`preferably be administered to said patient for a long time at a dose as
`
`low as possible, and in such a case, the daily dose of the active
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`compound is in the range of 5 mg to 80 mg, preferably in the range of 5
`
`mg to 60 mg, more preferably in the range of 10 mg to 40 mg, and it is
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`5
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`orally administered once a day,
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`The therapeutic agent used in the method for treatment of
`
`schizophrenia of the present invention is in the fom1 of an oral
`
`preparation, which contains the cm11pound of the above formula {1} or a
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`pharmaceutically acceptable salt thereof, especially {1R,2S,3R,4S}-N-
`
`10
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`[( l R,2R)-2-[4-( l ,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cydo(cid:173)
`
`hexyl:methylj-2,3-bicydo[2.2. l ]heptanedicarbox.imide hydrochloride in
`
`an amount of 5 mg to 120 mg, preferably in an amount of 10 mg to 100
`
`mg, more preferably in an amount of 20 mg to 80 mg per a ~ingle
`
`dosage unit, The oral preparation includes, for example, tablets,
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`15
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`granules, fine granules, powders, capsules, syrups, etc, These
`
`preparations should be in the form of a preparation for administration
`
`once a day.
`
`The above preparations may be prepared by a conventional
`
`method by using a conventional pharmaceutically acceptable carrier
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`20
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`which is usually used in the preparation of a conventional
`
`pharmaceutical formulation, for example, excipients such as lactose,
`
`white sugar, glucose, starch, calcium carbonate, kaolin, talc, crystalline
`
`cellulose, silicic acid, etc"' binders such as water, ethanol, gelatin,
`
`carboxymethylcellulose, shellac, methylcellulose, gum arabic,
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`25
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`tragacanth powder, polyvinylpyrrolidone, etc,, disintegrating agents
`
`such as sodium arginate, agar powder, laminaran powder, sodium
`
`hydrogen carbonate, polyoxyethylenesorbitan fatty acid esters, sodium
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`laurylsulfate, stearic acid monoglyceride, etc., lubricants such as
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`purified talc, stearate, boric add powder, polyethyleneglycol, etc.
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`7
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`EXPERIMENTS
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`The method for treatment of the present invention and the
`effects thereof are illustrated in more detail by Experiments as
`described hereinafter,
`
`5
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`The active compound SM-13496 used in Experiments means
`
`( 1R,2S,3R,4S)-N-[( 1R,2R}-2-[4-( l ,2-benzoisothiazol-3-yl)- l-piperazinyl(cid:173)
`
`methyl]-1-cycloheA'}'illlethyl1-2,3-bicydo[2.2. ljheptanedicarboximide
`
`hydrochloride, and the meanings of the abbreviations used in
`
`Experiments are as follows.
`
`10
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`DSM-IV:
`
`Diagnostic and Statistical Manual of Mental Disorders, 4th
`
`CGI-S:
`
`CGI-1:
`
`AIMS:
`
`EPS:
`LOCF:
`
`BAS:
`
`SAS:
`
`PANSS:
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`ed.
`
`Clinical Global Impressions scale-Severity of Illness
`
`Clinical Global Impressions scale-Improvement
`
`Abnormal Involuntary Movement Scale
`
`Extrapyramidal symptoms
`
`Last Observation Carried FonN"ard
`
`(LOCF Analysis: a method of using last not-missing data in
`
`cases of d.ropou ts)
`
`Barnes Akathisia Scale
`
`Simpson-Angust Rating Scale
`
`(Rating Scale Fo:r Extra.pyramidal Reactions)
`
`Positive and Negative Syndrome Scale
`(Rating Scale For Positive · Negative symptoms}
`
`Experiment 1
`First Stage Phase n Clinical Trial
`Test method
`( 1)
`
`15
`
`20
`
`25
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`According to the procedures as shown in Table 1 as described
`
`below, the placebo-controlled double blind experiment was done on 149
`
`30
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`patients \.vith schizophrenia in the acute exacerbation phase at 15
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`8
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`facilities in USA. The efficacy and :safeness were studied when SM-
`13496 at a dose of 40 mg or 120 mg, or a placebo was orally
`administered once a day for 6 weeks after placebo washout.
`
`Table 1
`Name of ------- A doubr;:'bifu:d':"r~do~"Tz~d. fmed dos(~, placebo-
`Clinical Trial
`controlled, parallel-group, 6-week, efficacy, safety, and
`tolerability study of two dose levels of SM-, 13496 in
`patients with schizophrenia by DSM-IV criteria who are
`____ ... """·~"" .Ell",periendng ~"-~~~-~~ .. ~xacerba~~E~_.?.t~yrnptom~~ ..................... .
`Purpose
`'l'hi~ efficacy and safety on patients with schizophrenia
`in the acute exacerbation phase {DSM-IV criterii:t) were
`studied in the placebo-controlled, para.llel-group,
`Subjects ----
`double-blind test,
`Selection criteria:
`1) Patients ·with scchizophrenia determined according to
`DSM-IV criteria who are experiencing an acute
`exacerbation of symptoms
`2) Patients having 42 or more of Extracted-BPRS Score
`as well as 4 or more of CGI-S Score
`3) Patients having less than 2 of Simpson-Angus Score
`as well as less than 3 of AIMS Score
`4) Patients suffering from schizophrenia for more than 1
`year
`5} Males and females aged 18-64 years
`
`Factors for patient exclusion:
`1) Patients with treatment-resistant schizophrenia
`2) Patients being taking depot injections before finishing
`the therapy cycle
`3) Pa.tknts having a strong m.dddal .ideation
`4) .Patit~nts \;>,tith Prn-kl.nson'a disease., Ahfbe.imer dbi:e~:i.s(:,
`drug addk:tim1., cnnvuh~ive disorders. epilep$y
`5) Pregnant ~~'mnen s:ind any 1,,vomen having n p<>ssihility
`of pregnancy, and lactating women
`6) Patients having drug hypersensitivity
`7) Any patients who are examined not to be suitable as
`tn~bj(.X;t$ !:!;LE_!_ri:ndpal $n:y~:~!i&ator
`...... .-......... ..,..---~
`Placebo-contn,Ued, n':l_:n.dcm:iized, comparison \Vith
`P~E§~g~!::~t'()ll p, d_?}!:!?..~.~.~.~.~d
`............... · - - - - -................ ..
`Oral administration of thr.: test compound at a. dose of
`40mg/day, 120mg/day or a placebo once a day for 6
`weeks
`Washout vv'ith placebo for one week {at least for 3 day)
`Hospitalization during the washout period and two
`weeks after medication
`
`Design of
`Clinical Trial
`Dosage and
`Administration
`route
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`9
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`Number of
`:subjects
`
`Combined
`Drug and
`Combination
`Therapy
`
`l} Another antipsychotic is not administered. When
`another antipsychotic is taken, then it is necessary
`to set up a washout period before the trial at least 3
`days for oral drug or for one therapy cycle for depot
`injection,
`2) In case of onset of extra.pyramidal symptoms, then
`the administration of an a.ntipa:rkinson agent is
`allowed.
`3) In case of onset of insomnia, lorazepa.m is used.
`In the planning :stages: 132 subjects (each 44 sub_j_e_c-ts--11
`for the placebo-treated group, the 40 mg-treated group
`and the 120 mg-treated group)
`After the completion of the trial: 149 subjects {50
`subjects for the placebo-treated group, 50 subjects for
`the 40 mg-treated group, and 49 subjects for the 120
`""""··----·--------a
`.. __ ,!?}ttreated g;roup)
`___._ ________
`Efficacy: PANSS, Ext:racted-BPRS, CGI-S/I
`Evaluation
`Safety: EPS Rating scale (Simpson-Angus, Barnes,
`Items
`AIMS), vital signs (body temperature, blood pressure,
`pulse}, 12-lead electn:.H.:;:.trdiog:rr;un., laJ:mratm:y test
`[hematologic test. biochemical test: of bkH)d. prolactin,
`urine test], psy(-:.hQson1at.k conditions, eyt:gnnlnd·sht--
`t-------~-lam_...:P ___ m_1_·c_r_o-s_co_py, adverse event
`Test results:
`· (2)
`
`1 J
`
`{i)
`
`Evaluation of efficacy:
`
`The data by BPRS and PANSS (LOCF), and CGI-S and CGI-I at
`
`the end of the trial are shown in Table 2 and Table 3, respectively. As
`
`5
`
`is shown in Table 2 and Table 3, the reductions in the scores at the end
`
`of the trial (6 weeks after the administration) from those prior to the
`
`administration in the groups treated by SM-13496 40 mg or 120 mg are
`
`statistically significant as compared to that in the placebo-treated group
`
`with respect to BPRS, CGI-! and CGI-S evaluations. With respect to
`
`10
`
`PANSS evaluation, the reduction in the score at the end of the
`
`experiment in the SM-13496 120 mg-treated group is statistically
`
`significant as compared to that in the placebo-treated group,. which
`
`means the psychotic manifestations are improved by SM-13496. ·
`
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`SLAYBACK EXHIBIT 1046
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`
`
`10
`
`' ' ' ' -~ -----. E ..
`
`,
`
`t
`
`Table 2
`----····
`Dose
`
`..-.-....
`
`....... .: ..................... ..? ...... ~~-
`
`__ ._.._._.._......_.._._._.._.._._._.,,,, .. •••n••....,.
`
`-4J) (8.45)
`
`.
`
`-508
`(14.06)
`
`--1
`!
`,:,,:~~,~-~-----L .... ~J-~~~ ~-:: __ :ru~-~-~-..
`
`SM-13496 120 mg
`(44}
`-------------------·····---·····-- -
`
`--
`
`I (No. of
`SM-13496 40 mg
`Placebo
`(45}
`(47)
`1 Subjects)
`._.._.._.._.._._..,..,-•••••••••n••n'n••'-'-"....,,_ --........................................... .., ........ .._ .. , ...... --------··-···-···-···----····-
`Average
`Rating
`Average (SD)
`(SD)
`scaje
`..
`w:-;n· ............... _.
`BPRS
`-10,0
`Total
`(12.79)
`Score
`.............. .__.._..._._._ ............. ,..
`PANSS
`-14.1
`-17.4
`Total
`(15.70)
`I Score
`(23.10)
`l
`........ ..................... ~ ....... •n••
`. ...............
`--··-··-········
`................
`#: Two-sided Dunnett's t-test (comparison between the groups treated by each
`dose and the placebo-treated group)
`Covariance analysis using faculty an.d Groups as factors and the values before
`administration as covariate
`Table 3
`~~e
`
`0.014
`
`-11.3 (8.89}
`
`00003
`
`.._._._.._._,._._._•_•_•••••••••n~
`
`0.€)63
`
`.
`I
`I
`
`o.01o ___ J
`
`SM-13496 40 mg
`
`SM-13496 120 mg
`
`- Placebo
`................. _.,_._._.._.._._.._ - - ,••'-, .......... ,,
`ting
`i Scale
`~ ................... -------------
`
`Average
`(SD)
`(n,..41)
`0,0 (0.77)
`
`1 CGI--S
`
`CGH
`
`{n=45)
`4.0 (1.41)
`
`(n""47)
`3.2 (1.56)
`
`00013
`
`(n=42)
`3.0 (L29)
`
`OJ)05
`
`~
`
`I.
`!
`#; Two-sided Dunnett's t-test (comparison between the groups treated by each
`dose and the placebo-treated. group)
`Covariance analysis using faculty ru.1.d Groups as factors and the values before
`administration as covariate
`Further, the appended Fig. 1 shows the changes in BPRS total
`(ii)
`
`score (LOCF). As is shown in Fig. l, the BPRS scores in the SM-13496-
`
`5
`
`treated groups are statistically significantly reduced from those of prior
`
`to the administration as compared to that in the placebo-treated group
`
`at the 2 weeks or later {p<0.05).
`
`The ratio of the patients of which the BPRS reduction at the end
`(iii)
`of the experiment is 20 '% or more, or the patients who showed 1 or 2 of
`
`10
`
`CGI-I, those patients are considered as responder, is shown in Table 4.
`
`As is apparent from Table 4, there was a statistically significant
`
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`
`
`
`11
`
`difference between the SM-13496 40 mg- or 120 mg-treated group and
`
`the placebo-treated group.
`
`Table 4
`
`Dose
`{No. of
`Subjects)
`
`Placebo
`(45)
`
`------------------
`
`SM-13496 40 mg
`(47)
`
`............... r
`
`-
`
`..... _.1
`
`SM-13496 120 mg
`{44}
`
`I
`Number r------;--~~~e:--.. -
`=-~e:s;~~d'er ...... r,-----1·~---.. , ..... -[ _2_6_ J -_0.002 ............ ···,~;; .. ,·w . ! 0.007
`
`Number
`
`Num.ber·--r p-value*
`
`(comparison
`faculties
`the
`test adjusting
`#: Cochran-Mantel-Haen:szel
`between the groups treated by each dose and the placebo-treated group)
`Evaluation of Safety:
`2)
`
`5
`
`(i)
`
`Adverse events observed in 10 % or more of the patients are
`
`shown in Table 5.
`
`Table 5
`
`Number of Subjects
`
`50
`
`50
`
`49
`
`Number of subjects :showing adverse
`38 (78)
`40 (80)
`36 (72)
`events(%)
`lf----------------.-.......... ww ........ , ____________ ............................. -------JI,
`Number of subjects sho\1vi.ng :serious
`3 (6)
`3 (6}
`3 (6)
`adverse events(%)
`8..---------------------·-.............. _________ - --·--------•-.n·.·-· .-------------'t---------·-----JR
`---- ------------------------.. ----- ..... __________ ,.____ __ _
`Number of subjects who drop out from
`2 (4)
`6 (12)
`6 (12)
`the trial due to adverse events(%)
`-------------------------·······----.. ,. .........
`! Occurrence of Adverse events ('Yo)
`
`~.. N"''l"';~;i"; ~:~~~:~~~~~~::~::::::::::.-.. -------.......-,,----------6--·(i2}-··----r .... _4_(8_} ___ 2_(4_) ....... j
`__ ~~~· I
`~ - _
`st1oi
`11 t22i i
`!
`l--H~~~-~:~~---·······----.... -~----
`-- -----·-~·--~-:0)
`3 (6)
`8 (16)
`! Akathlsia
`7 (14)
`4 (8)
`0 {OJ
`i-----------------------···········------------···--.. ··---------------------------··---------.... ·-----------------------····-·-
`1 Free-floating vertigo (excluding
`rotatory vertigo)
`3 (6)
`6 (12)
`5 (10)
`------------········--...... , ________________________________ ._, ................. -+,-----·-- ------------------------------·········.--.--• ....... ,_
`Suppression
`5 (10)
`9 (18)
`7 (14)
`Drowsiness
`
`"-'-•-•-•-•-••••••n•••·--------.-.,,,.._.._,..,..,.,,,_,...._-._-._._••-•-•••-••••••••m....,..•••••••WWW ____ ,,,..,..,..,..,..,..
`
`......_,..,..,..,...._.._ .... .._...._...._...._ ............ ,.,.,.,. .. n••••••n••n••••·---
`
`5 (10)
`4 (8)
`2 (4)
`Exacerbation of schizophrenia
`l (2)
`2 (4)
`5 (10)
`•·:-:-:••••••••t?'?'""?°~ -""-~===--;;;,;,·-... -... i:::»;.;";;;;:.,;,_••..;;•·• ...
`~ - -...... «=~ - . i f i .......
`•••,.;.•••;..,l::,w::...::::;ll""< ;;(;(;i;H$S;H(:;:;;; ~~;;.;~~:«::==·.saB-'
`.._.._
`Subject having multiple adverse events \1vas accounted as L
`As is shown in Table 5, 114 subjects among 149 subjects (77 ~la)
`
`1
`
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`SLAYBACK EXHIBIT 1046
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`
`12
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`showed adverse events, but most o.f them were mild or moderate ones,
`
`The number of subjects who dropped out from the trial due to the
`·······act:..,erse·e,;ents·was.higher·fri·bo1:h· or ·t:he.groiirs··frea.teaoy two·ctoses·or
`SM-13496 than in the placebo-treated group.
`
`5
`
`The main adverse events are suppression, nausea, headache,
`
`akathisia, and free-floating vertigo (excluding rotatory vertigo). The
`
`ratio of the subjects showing suppression was 10 %, 18 %, 14 % in the
`
`placebo-treated group, the SM-13496 40 mg-treated group, and the SM-
`
`13496 120 mg-treated group, respectively.
`
`In the SM-13496 120 mg-
`
`10
`
`treated group, nausea was more observed as compared to the other
`
`groups$ but digestive disturbance was less observed than in the
`
`placebo-treated group. Exacerbation of schizophrenia '1vas less
`
`observed in the SM-13496 40 mg- and 120 mg-treated groups (4 % and
`
`2 ~lo, respectively) than in the placebo-treated group (10 °/o). Akathisia
`
`15
`
`was observed only in the SM-13496 treated groups, Le,, 8 % and 14 %
`
`in the 40 mg-treated group and in the 120 mg-treated group,
`
`respectively, The occurrence of the adverse events in the groups
`
`treated by SM-13496 were the same as that in the placebo-treated
`
`group. Either body weight gain, bulimia, impotence, erectile
`
`20
`
`dysfunction or convulsion was not observed.
`
`(ii!
`
`The serious adverse events observed in the above phase II
`
`clinical trial are shown in Table 6 as described below.
`
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`
`13
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`Table 6
`
`Occurrence of Serious Adverse Events(%)
`~--------------·····.··---·
`Exacerbation of
`............... ·······-~o-{o_i __ -i---·----=---~~~ .................... ___ o_(o_)_.
`· ....... ~~~~~a
`O {O)
`1 (2)
`0 (0)
`Psychosis aggravated
`.................. ______ ......... «··-·····-------{-........ _____ .................... ----+----------........... ., .... .
`Exacerbation of
`4 {8)
`1 (2)
`1 {2)
`1 schizophrenia
`-------·--.. ----···--·~·· ················----------·----------------·-
`}············----·-
`0 (0)
`0 (0)
`.............. !.. ... .
`....... ...1
`1 (2)
`As is shown in Table 6~ the serious adverse events were observed
`
`l ...... =~~~~enia
`
`in 4 cases of the placebo-treated group, 3 cases of the SM-13496 40
`
`mg-treated group and 2 cases of the SM-13496 120 mg-treated group,
`
`5
`
`but the relationship to the tested medicament was denied.
`
`(iii)
`
`Further) the side effects observed in this clinical trial are listed
`
`in the following Table 7,
`
`Table 7
`
`11'=.,_-.---------t-~"---·---~---~---
`Placebo
`40 mg
`120 mg
`.................... :?.~ .. -------.... ~.? ..................... -;------4_9 __ ......... .l
`=·»----------=~--~~: _______ 33-(6--6) __ ·..,,[.,,,,,,_,, __ 3_s_r_11'_i __ -;J
`1*::::e~-;,;;~d+-¾;q~-~~q= i :~: . ·········
`
`Number of Subjects
`Occurrence of side
`effects(%)
`· ~llenta1 disturbance
`
`,....,...................................
`
`xw.:.:..,~~-
`
`~ .... Agitation
`
`........................ f ................ o,. (Ol ......... .,
`
`•
`
`ti..,-..,.,_ ....................... ~..__.__i
`
`,__ ...... ,. ........................... "'
`
`._._ .. ._._ .. __ • • • •nn • • · - - - - - - -1 - . - . ............. ,._.._ ...... .._._._._._ __ uu •nn • • • • • •~ _
`
`Agitation aggravated
`Anxiety aggravated
`
`O (0)
`O (O) _____
`
`.. ....., ......... .,,.,,.. ....... .._.._.
`
`.._._.._._._._._._._._.................
`
`_..,..,.. ......... .._.._.._.._.._._.._.._._._._._._._••••••n....
`
`.. ............... .._.._.._.._ .................... .._.._ ...... ,•••••••• ....... .
`
`lnso.mnia
`
`O (0)
`
`............... .._.._.._.._.._.._.._.._ .... .._._ .. ..._..._._ •• n•• .... , - - - - - . . . . . . . . . ; . - - , . ._ .. ._._._._ .. ••••n ................ -.,
`
`
`
`.......... ~ .. .._ .... .._.._..,,.. ..... ...,._ ................................ , ____ , ...... ...,...,.,,.,.............., ............... .._.._.._.._.._..._.._ .•
`
`1 (2)
`
`l (2)
`
`1 (2}
`
`__ :"'=--···········o··{·ol... ...............
`
`1
`
`....... i .. (.2i··········--~······ .
`2 (4)
`0 (0)
`_ ............ •n••••••• ...... ,+~ - - -...... ..,,.,,.,,.,,...._ .. ._._.._.._ . .._.._._._.._.
`1 (2)
`0 (0)
`
`Page 16 of 216
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`
`
`14
`
`1 (2}
`
`0 (0)
`
`0 (0)
`
`,--••••••••• . . . . •
`
`. . . . . w . . •--»»---•••• • · - - -~ -............. -
`
`.. --•.•·-•
`
`....... , ................. ,_ . . ._ . .__ ,_ . , . .__ , ................ ••• .... •
`
`II'<----------------------=---,.,,_ _____ ......,,
`Pruritus
`,.,,________ -"'t""""'------i-----------.---------41
`Infection and parasitosis
`Tinea pedis
`O (0)
`0 (0)
`1 (2)
`! External otiti~ ................... -. _____ o_(_O_) - -... ------,--... ___ .JJ~.L·----............ O. (Ol ................ .
`[-·Paroti_d_1_·ti_' s ___ ............................ __ 1_(_2_) - -...................... ~J~L .. ______ 0 JO)_ .. _.,w ...... ..
`O (0)
`1 (2)
`0 '0)
` Urinary tract
`.
`infection
`\
`
`11
`
`[ Vas~ular diseases
`
`Disturbanc