PATENT
`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:g] 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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`7.
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`D
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`[]
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`l:g]
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`l:g]
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`[""]
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`l:g]
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`Enclosed is an AlA Transition Application Statement under 1.55U),
`1.78(a)(6), and/or 1.78(c)(6).
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`Enclosed is a Request for Non-Publication of Application and Certification
`Under 35 U.S.C. § 122(b)(2)(B)(i).
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`A Preliminary Amendment is enclosed.
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`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 26
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`Application No.: To be assigned
`Attorney Docket No.: 05276.0127-01
`Page 2 of 3
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`0
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`0 1
`1
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`1111
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`280.00
`$
`$280
`Basic Utility Application Filing Fee
`f--.::----.......-.w:-=---------------~--------------------------------------------------------------------------------------------~-
`Search Fee
`$600
`600.00
`~----------~-----.......................................................................... ------------------------------------------------ ---------~~
`Examination Fee
`$720
`720.00
`1-------------------------------------------------------------------------------------------------------
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`P-::~~~~-----+-N-um_b_e_r _of_C_Ia_im-=s· _I
`Extra
`Basic
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`7 I-
`20
`Total Claims
`0 x $ 80
`0.00
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`---~----------------------------------+------- ...................... ....~ _________________________________ .............. ---~-
`1 1-
`0.00
`!Independent Claims
`3
`0 x $420
`r·o··-Prese·n-iatfo·n--ofiVi li'itfpie--oe·p·:--cTaTm-(8)'
`...................... ..
`+ $780
`l
`""""""' ------------------------------------------
`1 Size Fee: Paper Filing
`1 T otai Application Pages
`l (specification, drawings, printed
`! sequence or computer listing,
`*Rounded up to next whoie number
`[J?E~!Lill.!!:l.§E~ .. 'E!.Ill.~t!.9.li!~D.tL ______________________ .......................................................... ~~-------+----~-----------------
`! Additional Fee for Paper Filing New Application $400
`j (DELETE if filing new application via EFS Web -fee not required for EFS new application
`0
`~--~-~!-~.ll1.!~-~!.? .. 11~.L-------------------------------------------------- ----------------------------------------------------------------~---------+------
`Size Fee: EFS-Web Filing
`Total Application Pages
`(specification, drawings, printed
`sequence or computer listing,
`"Rounded up to next whoie number
`1, preliminary ?meQ.~!J:l.~lltL ............ _. '------------------------------------------------------------------------------------------------------------------~+------.............-j
`140.00 I
`de-~c~l_a_ra-:-t-io_n_l __________________ ~--··----------------------------------------------J
`1,740.00 I
`$
`Subtotal
`--~-:-~-~~~~~~~-:j;_~~=-~~z_m:.~~--:.:~~~~--~~-:~ __ :_~gf-il-in_g_o_N_L_v_: _s_m_a_n_e_n_t_it_y_fe_e~fo--~r- _________________ j
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`1---------·---~~------~--------------------------------------------------------------------------------------------------------------------------------------~---------l
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`1
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`[Total] - 100 +50 = [number]* x $400
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`23 X .75- 100 +50= 0* x $400
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`[Surcharge under§ 1.16(f) $140 for postponing filing of oath or
`
`$
`1,740.00 I
`TOTAL FEES DUE
`------------------~-~-...... ...,.,.,._ ................................................................................ .._.._.._.._ ........ _.._.,_._.,_.,_.,_.,_.,_.._.._._.._._._._._._._ ...... .._.._.._.._.._.._ ............. ,. .... ,.,. ........ !
`
`Authorization to charge a credit card for the fee of $1,740.00 is submitted
`herewith.
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`9..
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`[gJ
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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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`Application No.: To be assigned
`Attorney Docket No.: 05276.0127-01
`Page 3 of 3
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`11'
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`The prior application is assigned of record to: DA!NIPPON SUMITOMO
`PHARMA CO., L TO.
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`D
`~
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`D
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`D
`D
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`D
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`16.
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`18.
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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.
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`The power appears in the original declaration of the prior application.
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`Since the power does not appear in the original declaration, a copy of the
`power in the prior application is enclosed.
`
`Please address all 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
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`PETITION FOR EXTENSION. If 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''\~:.u>.<:!L1Li~ __ (:Lti~L::~.~.L:E~=~ .. =:~) __ _
`Kimber!{[). Braslow
`Reg. No. 63,219
`(202) 408-4000
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`1
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`DESCRIPTION
`
`AGENT FOR TREATMENT OF SCHIZOPHRENIA
`
`5
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`TECHNICAL FIELD
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`The present invention relates to a novel method for treatment of
`
`schizophrenia and a novel therapeutic agent used therein, More
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`particularly, the present invention relates to a method for improving
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`schizophrenia without being accompanied by extrapyramidal symptoms
`
`10
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`by orally administering a prescribed dose of a specific bicydoheptane(cid:173)
`
`dicarboximide derivative once a day, and a therapeutic agent used in
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`said method.
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`BACKGROUND ART
`
`15
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`Schizophrenia (split personality) is a kind of endogenous
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`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
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`dysfunction such as impairments of concentration and learning abilities,
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`etc. Moreover, there are other s;.rmptoms such as depression, anxiety,
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`etc. as related symptoms thereof.
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`25
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`Medication is rnainly employed in the treatment of schizophrenia,
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`but the treatment of schizophrenia should be continued for a long time,
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`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
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`necessary to continue the medication forever. Therefore, any side
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`30
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`effects of medication may always be serious problems, and based on
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`2
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`this perspective, it has been desired to develop a medicine being
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`suitable for prolonged medication"
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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 example, phenothiazine derivatives (e.g., chlorpromazine. methozy(cid:173)
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`promazine, etc.), thioxanthin derivatives having a similar structure to
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`phenothiazine (e.g., chlorprothixene, flupentbml, etc.);· benzamide
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`derivatives (e.g., sulpiride, sultopride, etc.), thienodiazepine derivatives
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`(e.g., clotiazeprun, etizolam, etc.), and further butyrophenone derivatives
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`10
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`(e.g., haloperidol, triperidol, etc.), diphenylbutylamine derivatives (e.g.,
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`pimozide, etc.), etc.
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`However, phenothiazine derivatives, phenothiazine a11alogues,
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`and butyrophenone de:tivatives may cause serious side effects of
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`extrapyramidal symptoms showing parltinsonism such as the stiff gait
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`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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`extrapyramidal symptoms in addition to insomnia.
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`In addition, these
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`conventional antipsychotics may be effective on only some of symptoms
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`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
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`antipsychotic without causing side effects such as extrapyTamidal
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`25
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`symptoms.
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`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
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`present inventors, may be useful as an antipsychotic (c.f, neuroleptic
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`agent, antiax:iety, etc.} 1 especially as an agent for treatment of
`schizophrenia, senile insanity, manic depressive psychoses, and
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`30
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`3
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`nervous breakdown (USP 5,532~372),
`r-\
`Z-D-N
`G""Ar
`, __ ,_j
`
`wherein Z is
`
`0
`R'~ (CH2ln~
`Ri:\--1~--------B N-
`
`R~ R4
`
`5
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`o:r
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`<""'
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`• etc., and
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`D is a group of the formula: -{CH2)p-A-(CHz)q-,
`":cH-
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`' N-
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`GI'i /
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`Ar is an aromatic group, or an aromatic heterocyclic group, etc.
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`DISCLOSURE OF INVENTION
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`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 t.o 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 extrapyramidal symptoms, which are
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`15
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`often observed in many conventional antipsychotics, and can safely be
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`administered for a long time. As a result, the present inventors have
`found that ( 1 R,2S,3R,4S}-N-H 1 R,2R}-2-!4-( 1,2-benzoisothiazol-3-yl)-1-
`piperazinylmethylj-1-cydohexylmethylj-2,3-bicyclo[2.2. 1Jheptane(cid:173)
`
`dicarboximide of the following formula:
`
`;r"'''\.
`
`\
`
`___ /
`
`~ ~ 0
`~c--,7~
`r-\
`.N._
`N,.;:;-· S
`~ -~~· N,...._-#·'f A'--·N
`J
`H H
`... :--·:·
`- H
`~\
`H o
`~-~/
`~---~/
`
`\.,_,_!
`
`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
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`prescribed dose thereof once a day,
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`5
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`Namely, the present invention provides a method for treatment
`
`of schizophrenia without being accompanied by extrapyramidal
`
`symptoms by orally administration of a prescribed amount of
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`( 1 R~2S~3R~4S) -N-H 1 R,2R)-2-[4-( 1 ,2-benzoisothiazol-3-yl) -1-piperazinyl(cid:173)
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`methyl]-1-cydohe~'Ylmethyl]-2,3-bicydo[2.2.1jheptanedica:rboximide of
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`10
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`the above formula { 1) or a pharmaceutiCally acceptable salt thereof once
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`a day, and further provides an agent for treatment of schizophrenia
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`which is used in said method.
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`BRIEF DESCRIPTION OF DRAWINGS
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`15
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`Fig. 1 is a graph showing the change with time in scores of Brief
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`Psychiatric Rating Scale: BPRS, which are indexes for the effects on
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`schizophrenia, of the active compound of the present invention,
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`( 1 R,2S,3R,4S)-N-[{ 1 R,2R}-2-[4-( 1 ,2-benzoisothiazol-3-yl}-1-piperazinyl(cid:173)
`
`methyl]-1-cyclohexylmethyl]-2 ,3-bicyclo[2 .2, l]heptanedica.rboximide
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`20
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`hydrochloride and placebo in the double blind clinical trial.
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`DETAILED DESCRIPTION OF INVENTION
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`As shown in Examples as described hereinafter, when orally
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`administering a prescribed dose of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-{1,2-
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`25
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`benzoisothiazol-3-y1)-1-piperazinylmethy1J-l-cyclohexylmethyl]-2,3-
`bicydo[2,2o lJheptanedica.rboximide hydrochloride once a. day for 6
`weeks to the patients with schizophrenia in the acute exacerbation, the
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`present inventors have found that the excellent effects on the wide(cid:173)
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`ranging symptoms were obtained, and surprisingly, any extrapyramidal
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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,
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`Namely, the present invention provides a novel method for
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`5
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`treatment of schizophrenia improving a wide-ranging schizophrenia
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`including positive symptoms, negative symptoms, and cognitive
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`dysfunction, especially positive symptoms and negative symptoms,
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`without being accompanied by extrapyramidal symptoms which
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`comprises orally administering a prescribed dose of ( 1R~2S~3R,4SJ-N-
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`10
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`[{ 1R~2R)-2-[4-( 1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclo(cid:173)
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`hexy1methyl]-2,3-bicyclo[2.2.1]heptanedicarbmdmide of the above
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`formula ( 1) or a pharmaceutically acceptable salt thereof, especially a
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`hydrochloride thereof, to a patient with schizophrenia once a day,
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`The present invention also provides a novel agent for treatment
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`15
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`of such schizophrenia.
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`According to the present invention, excellent improving effects
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`on the wide-ranging symptoms of schizophrenia may be obtained by
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`orally administering (lR,2S,3R,4S)-N-[(lR,2R)-2-[4-(1,2-benzoisothiazol-
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`3-yl)-1-piperazinylmethy1]-l-cydohexy1methylJ-2,3-bicyclo[2.2.1]-
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`20
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`heptanedicarboximide or a pharmaceutically acceptable salt thereof, for
`
`example, a hydrochloride, at a daily dose of 5 mg to 120 mg, preferably
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`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
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`present invention, side effects such as extrapyramidal symptoms such
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`25
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`as parkinsonism, dyskinesia, akathisia, etc., abnormal electro(cid:173)
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`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
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`medication,
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`Besides, when the present method is applied to a patient with
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`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
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`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
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`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
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`schizophrenia of the present invention is in the fom1 of an oral
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`preparation, which contains the cmnpound of the above formula {1} or a
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`pharmaceutically acceptable salt thereof, especially {1R,2S,3R,4S)-N-
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`10
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`[( l R,2R)-2-[4-( 1 ,2-benzoisothiazol-3-yl)-1-piperazinylmethy1]-1-cydo(cid:173)
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`hexylmethylj-2,3-bicydo[2.2.1]heptanedicarboximide hydrochloride in
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`an amount of 5 mg to 120 mg, preferably in an amount of 10 mg to 100
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`mg, more preferably in an amount of 20 mg to 80 mg per a ~ingle
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`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
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`preparations should be in the form of a preparation for administration
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`once a day.
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`The above preparations may be prepared by a conventional
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`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
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`pharmaceutical formulation, for example, excipients such as lactose,
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`white sugar, glucose, starch, calcium carbonate, kaolin, talc, crystalline
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`cellulose, silicic acid, etc,, binders such as water, ethanol, gelatin,
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`carboxymethylcellulose$ shellac, methylcellulose, gum arabic~
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`25
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`tragacanth powder, polyvinylpyrrolidone, etc,, disintegrating agents
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`such as sodium arginate, agar powder, laminaran powder, sodium
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`hydrogen carbonate, polyoxyethylenesorbitan fatty acid esters~ sodium
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`laurylsulfate, stearic add monoglyceride, etc., lubricants such as
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`purified talc, stearate, boric acid 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
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`effects thereof are illustrated in more detail by Experiments as
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`described hereinafter,
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`5
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`The active compound SM-13496 used in Experiments means
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`( 1R,2S,3R,4S)-N-[( 1R,2R}-2-[4-( 1 ,2-benzoisothiazol-3-yl)-l-piperazinyl(cid:173)
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`methyl]-1-cycloheA'}'lmethylj-2,3-bicydo[2.2, 1jheptanedicarboximide
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`hydrochloride, and the meanings of the abbreviations used in
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`Experiments are as follows.
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`10
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`DSM-IV:
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`Diagnostic and Statistical Manual of Mental Disorders$ 4th
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`CGI-S:
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`CGI-I:
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`AIMS:
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`EPS:
`LOCF:
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`BAS:
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`SAS:
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`PANSS:
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`15
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`20
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`ed.
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`Clinical Global Impressions scale-Severity of Illness
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`Clinical Global Impressions scale-Improvement
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`Abnormal Involuntary Movement Scale
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`Extrap:yramidal symptoms
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`Last Observation Carried FonN"ard
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`(LOCF Analysis: a method of using last not-missing data in
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`cases of dropouts)
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`Barnes Akathisia Scale
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`Simpson-Angust Rating Scale
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`(Rating Scale For Extrapyramidal Reactions)
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`Positive and Negative Syndrome Scale
`(Rating Scale For Positive · Negative symptoms}
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`25
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`Experiment 1
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`First Stage Phase H Clinical Trial
`
`( 1)
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`Test method
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`According to the procedures as shown in Table 1 as described
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`below, the placebo-controlled double blind experiment was done on 149
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`30
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`patients \ovith schizophrenia in the acute exacerbation phase at 15
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`facilities in USA. The efficacy and safeness were studied when SM-
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`13496 at a dose of 40 mg or 120 mg, or a placebo was orally
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`administered once a day for 6 weeks after placebo washout.
`
`Table 1
`Name of -------A doubi';:'f_;lfu:d.':--r;;do~'iZ~d. fmed do~H~, 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
`······--·-----"""'--··----~-- .E~perieneing ~""~E:~.~~--~~~!'E~E~.~--?.f.~yrnptom~~---··-------@·····
`Purpose
`'l'ht~ efficacy and safety on patients with schizophrenia
`in the acute exacerbation phase {DSM-IV criterii't) were
`studied in the placebo-controlled, parallel-group,
`double-blind test.
`------l
`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 ofExtra.cted-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
`
`-----................. ____ _
`
`Sub}ects
`
`Factors for patient exclusion:
`1) Patients with treatment-resistant schizophrenia
`2) Patients being taking depot injections before flnishing
`the therapy cycle
`3) Pa.tknts having a strong m.dddal ideation
`4) .Path~n.ts \<'.tith l?m·klnso.n'a disease, Ah(be.imer dise~:l.s(~,
`drug addi(:tlm>., <XYrl.vul$iVe disorders. epilepsy
`5) Pregn<:mt "\l¥'onwn "1nd any .w<::~men 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
`s~.~bj(.x;ts __ !:W .. J:!_!'i:ndpal k~}~~:~!~&~:~tor
`················--~··--···-···.....
`~ .................. ,--.. -~...-~
`Placebo-contn-'Ued, randomized, comparison \Vith
`Design of
`-.£~.~!2_i'?.~ .. :£rial
`........................
`.. ............ "" ......... ..
`P~E§~g~!::~n)\lp, dg}-!:!?..~.~-~-~.!ind
`Dosage and
`Oral administration of thr.: test compound at a. dose of
`Administration 40mgfday, 120mgjday or a placebo once a day for 6
`route
`weeks
`Washout vv'ith placebo for one week {at least for 3 day)
`Hospitalization during the washout period and two
`weeks after medication
`
`.~-~ ....... , .......... ~-~ ...... ,, ...................... ~----------·---········-··-···-~~ ............ , ........ _____ ............... .
`
`Page 11 of 26
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`9
`
`··Num.'b·;;·~··c;r··----~·
`subjects
`
`···c:-c;!n:'bllie·2c-
`D:rug and
`Combination
`Therapy
`
`~Anoili'e'i"anfipsychotic is no'fadmln.istered~------·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 extrapyramidal symptoms, then
`the administration of an antipa:rkinson agent is
`allowed.
`3) In case of onset of insomnia, lorazepa.m is used.
`In the plannini.stages: 132 sub]eets"(e·aa1"44"suh~j~e;.;..c_ts~4
`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
`~---................... ~--- mg-tre~~!?.!!.~ou~)
`' " ' " " " " ' " " ' " 'm "m • : -= - - - - - - - f
`Evaluation
`Efficacy: PANSS, Extracted-BPRS, CGI-S/I
`Safety: EPS Rating scale (Simpson-Angus, Barnes,
`Items
`AlMS), vital signs (body temperature, blood pressure,
`pulse}, 12-lead electn:.H.:;:.vdiog:rr;un., laJ:mratm:y test
`[hematologic test. biochemical test: of bh:H)d. prolactin,
`urine test], psy(-;.hQSOtnat.k conditions, e:_yegnnlnd·sht--
`t----~------~~~lar.n __ ~P~n:.!cros~?PY,adverse_e~e_n __ t ____________________ ~
`· (2)
`Test results:
`
`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. ·
`
`Page 12 of 26
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`

`

`10
`
`Placebo
`
`(45}
`
`----;~~-~;~~~--~~--:·~ ·
`(47)
`
`(44}
`
`,
`
`SM-13~;~ ~20 ~~ .. l
`!
`,,,, ...... J»««<«<««=--=---" =.-..-,.-,=·=~"'S
`
`Table 2
`! D~~e
`~
`(N'?. of
`Subjects)
`~o"------- .
`
`------- "'<oo<»>«""'""""-.. .
`_10,0
`BPRS
`t 12"79
`Total
`\
`Score
`----------------····--~ r-----~--- ---------------·--········--·~----------------------·····---·-~---·
`PANSS
`-14.1
`-5.8
`-17.4
`, Total
`(14.06)
`(15"70)
`(23. 10)
`j Score
`
`· --
`
`-4J) (8.45)
`
`'"""
`
`,
`1
`
`0.014
`
`0.063
`
`.
`-11.3 (8.89) . 0.003
`
`#: 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
`
`#;Two-sided Dunnett's t-test (comparison between the groups treated by each
`dose and the placebo-treated group)
`Covariance analysis using faculty ru1.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. 1, 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<O.OS}.
`
`(iii)
`
`The ratio of the patients of which the BPRS reduction at the end
`
`of the experiment is 20 °/o or more, or the patients who showed 1 or 2 of
`
`10
`
`CGI-1, those patients are considered as responder, is shown in Table 4.
`
`As is apparent from Table 4, there was a statistically significant
`
`Page 13 of 26
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`

`11
`
`difference between the SM-13496 40 mg- or 120 mg-treated group and
`
`the placebo-treated group.
`
`Table 4
`
`(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
`
`---------------------------- --
`
`------
`
`. ---
`
`! Pl;;;;t;~------- ------40 mg
`
`-1 120-mg
`
`~~;b~:~~~~~~s;;-,: .... 4o51:~
`
`!
`
`·---------.
`
`'
`
`"""'"'"""""""'.----·••
`
`~~;;~===~~:,-=i~-~~
`
`~=~==~Vfi '" '' ~·:-:-:•••••ny~~n;~ ~-
`: .. "ff(j'";"'[<""""""""""""•:::~;;;;,_, ""HHH ~H~._,
`Subject having multiple adverse events \lllas accounted as L
`As is shown in Table 5, 114 subjects among 149 subjects (77 ~Ia)
`
`.,..,..._.lo
`
`.,.
`
`------o---·-·-----·--~--~+-~~~~·ll
`1
`3 {6)
`3 (6)
`
`3 (6 }
`
`[1--------------------w·------
`Number of subjects sho\>Ving serious
`I
`adverse events (%)
`~---·-~-----------·-·-------
`·--~---- """'"""''-'•'·""'>'-' -~-·---......-.f----.-~
`! Number of subjects who drop out from
`6 (12)
`2 (4)
`6 (12)
`the trial due to adverse events (%)
`1
`----- -----------------·------·-- -----------~---- ~---------------
`:-----------------------·············-----··-------
`1--ni~~-;~j~~~~~~~~~~~~~~~~:::::::::::::==-------- --------6---(i2)··--·-r----- 4 (8} 1 2 ~4) ______
`!Occurrence of Adverse events (~lu)
`~ -------- ________ 2 ___ {4) ________ T __________ 5 (10) l 11 (22) I
`1
`I
`--------- -----------------------.!
`---------------------------------~-----·
`8 (16) ... L.~J~L ___ _
`l------H~~~-~:~~---·····--·------~---------
`------------- ---------~---~-:_0}
`!
`4 (8) I 7 (14)
`! Akathlsia
`0 {0)
`f
`1--'-"""'""""W----.-.--------············••••·----·
`'"'""""""'"""'' -. .. ••••••••·-----
`1 Free-floating vertigo (excluding
`
`Page 14 of 26
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`

`12
`
`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
`·······a.d.~erse.e\;ents.was.higher.i.ri.bo1:h. ot.t:he.groiifis .. treateaoy two·ctoses·ar
`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 °/o, 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 "vas less
`
`observed in the SM-13496 40 mg- and 120 mg-treated groups (4% and
`
`2 ~/o, 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.
`
`(H)
`
`The serious adverse events observed in the above phase II
`
`clinical trial are shown in Table 6 as described below.
`
`Page 15 of 26
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`

`13
`
`Table 6
`
`....... ...!
`As is shown in Table 6~ the serious adverse events were observed
`
`1 (2)
`
`in 4 cases of the placebo-treated group, 3 cases of the SM-13496 40
`
`mg-t:reated 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
`
`Page 16 of 26
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`

`14
`
`1 (2}
`
`0 (0)
`
`-~-"""""~··""---------""""--~
`f ~:~;:~~di~tur~arlc~~. r~· Il~~72~rl~ .. distur~~~e(2)···················
`.. d''\t))'''
`..... .
`-------------------.. -r-~--~------.... JT ______________ ...................... _
`---~----------------........ ..
`r·····--·--·
`!
`! Decrease in appetite
`1 (2)
`1 (2)
`1 (2)
`"'::: . "":: :]
`Disturbance in Skin and Hypodermis ~--------·: =::::~:= =~:::::::
`I
`Pruritus
`Infection and parasitosis
`·'
`~"'1"""""~-----,,.-,---~~-""'·~r---"""""" ........ ~,......,1
`0 (0)
`0 (0)
`Tinea pedis
`1 (2)
`----------···----····· .. ----
`--------------------·• ....................................... ~
`---~ ..................... _.._.,_.._ ... _~-~-~-·-~~~······
`,................
`...... ____ .. , ............ ~J~.L .... ---+--·--.......... ~J~L ........... ~.
`~ ..... ~xtemal o~~-~-----------------......
`0 (0)
`..................... ....... ~-~_2EL ______ .................. ~J~L..
`----~J~l.. ............... ,
`L---~~~~ditis
` Urinary tract
`0 (O)
`1 (2 )
`o tO)
`.
`infection
`\
`
`0 (0)
`
`-----~-
`
`1
`
`1
`
`~
`
`11
`
`0 (0)
`1 (2)
`0 (0)
`Tongue disturbance
`r---............... , ..................... ~----------~-----------"""""'""~-------- ........................... _____________________ ~~-~--------------
`1
`Dyspepsia
`2 (4)
`3 {6)
`2 (4)
`l
`lr-____;;._. _____________ .................... ~~------+----------············--------~----- -~~----------------------............ ------------~:.......:.....--
`l
`~ 0 (0)
`Flatulence
`1 {2)
`0 (0)
`--------------------.-.-.-.·---------------....... -
`.
`----------~---------·-----r··--................. ..
`1
`~------------------------
`!
`Dry mouth
`1 {2)
`0 {0)
`0 (0)
`
`~~~::i~~L_--~--~~~-~r_: ::: =~~=-~~:-~-:·i--: ---~--------_----_----
`
`Page 17 of 26
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`

`15
`
`Total disability and local condition
`
`---····---~~-?~~--·
`
`3 J?L ___ ---~t_. ______________ ~--!~L~-~------- ----··············!:J:L ............... ..
`-----~~?-~.:--~~~::.~~~~--------·t------~J!l ______ ~ 1 (2l ~---
`. ~l~L _____________ __
`,_ __ !2::~--~:.::~~~~~----------··-···········-L------------ 1 (2)
`I
`o {Ol
`o (O)
`I
`------3~(4""') __
`i Sleepiness
`1 {2)
`1 (2)
`~,,,,,~....._ ..... ,. ..... ~ .......................... "".--.......... r"""""'--~--~------"""""'-»»i"""------~~~
`Nervous system disorder
`I
`Suppression
`9 {18)
`3 {6)
`~~thi-;i;··------------------------------·---r-------------- o (0)
`4 (8)
`------
`Free~fl~-;fu;g--~~;tig~---------~-----.-················--------------------·--1-~~~,_._.;___~~-+--
`
`7 (14)
`7 (14)
`
`1
`
`I
`(exduding rotatory
`vertigo)
`1
`-----.-----------------········-------------------·---+-----~---~~r-.~--~--------------~---------------------------------------.------.----------------
`
`5 (10)
`
`5 (10)
`
`0 (0)
`
`1 Musculoskeletal system and connective tissue disorder
`I
`-
`.
`'·
`---~---------<-"·-----~-------
`!
`1 Muscle stiffness
`l (2)
`2 (4)
`1 {2)
`r---------
`-----------------------------.---------.-------------·--·'·'·'·"""""'"''"'"""·~--~---+-------~-----------------------
`1 Myalgic pain
`0 (0)
`0 (0)
`1 (2)
`F'
`"""""'"'"'"'"'"""""" ·····"""'''"'"'"'"'"""""'""""""'"' ~--
`-~~-.""""'"'"""""'"'"'"'•·•
`-------~.J?.L ______________ _
`Cervical rigi~-~-~-------------------- -------------------~.J?.L................ ......
`1 (2)
`---------------~J~L ............... .
`r---~culS:: .. ~!!~~-iE! ..........