Declaration Under 37 C.F.R. 1.132
`
`Sir:
`
`I, Masaaki Ogasa, citizen of Japan and residing at One Bridge Plaza, Suite 510, Fort Lee,
`New Jersey, 07024 USA, declare and say as follows.
`1.
`I am a graduate ofFaculty ofPharmacy, Kyoto Pharmaceutical University, Japan in 1991
`and of Master Course, same university in 1993.
`2.
`Since 1993 up till the present, I have been an employee ofDainippon Sumitomo Pharma
`Company, Limited. (Former Sumitomo Pharmaceuticals, Company, Limited), the assignee ofU.S.
`Patent Application No. 10/525,021 and I have been engaged in research and development of
`lurasidone for the treatment of psychiatric disease at the Research Center and Clinical
`Development Department of said company.
`3.
`Under my direction, the following comparative clinical studies have been done.
`
`A STUDY OF THE MAXIMUM TOLERATED DOSE OF SM-13496 (LURASIDONE) IN
`PATIENTS WITH SCHIZOPHRENIA (Study D 1 050217)
`
`Study Design and Methodology
`This was a single-center, randomized, in-patient, double-blind study to determine the safety and
`tolerability of lurasidone administered as repeated oral doses to stable schizophrenic patients. In
`order to determine the maximum tolerated dose (MTD) of lurasidone, study drug was
`administered to 7 fixed dose, sequential, escalating dose cohorts (cohorts 1-7) that were planned
`to consist of a minimum of 6 and maximum of 10 patients each (2 placebo and up to 8 lurasidone
`patients). The minimum intolerable dose (MID) was defined as the dose at which a minimum of 4
`evaluable lurasidone-treated patients in a cohort experienced more than 1 occurrence of moderate
`or severe adverse events related to the lurasidonc, or the dose at which at least 1 lurasidone-treated
`patient experienced a serious adverse event at least possibly related to lurasidone. The next dose
`level below the MID was designated the MTD.
`Following a screening period of up to 30 days, eligible patients entered a 4 day in patient
`single-blind placebo washout period during which they discontinued any previous antipsychotic
`and any other prohibited psychotropic medications. At the end of the washout period, patients
`were randomized to receive lurasidone or placebo once daily. Patients were enrolled into the first
`7 cohorts and received study drug on Days 1-6, and the lurasidone doses per cohort were: 160 mg
`(cohort 1), 200 mg (cohort 2), 240 mg (cohort 3), 280 mg (cohort 4), 320 mg (cohort 5), 400 mg
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`(cohort 6) and 520 mg (cohort 7). The MID was reached in cohort 7. All study drug doses were
`administered to patients in a postprandial state at approximately 8:00AM.
`
`Results: Determination of the Minimum Intolerable Dose (MID)
`The MID was defined as the dose at which a minimum of 4 evaluable lurasidone treated patients
`in a cohort each experienced more than 1 occurrence of moderate or severe adverse experiences
`related [relationship of possibly, probably, or definitely] to the lurasidone, or the dose at which at
`least 1 lurasidone treated patient experienced a serious adverse experience at least possibly related
`to lurasidone ).
`The number of patients experiencing more than 1 moderate or severe
`lurasidone-related adverse experience by
`lurasidone dose was 0 (160 mg), 1 (200 mg),
`1 (240 mg), 1 (280 mg), 0 (320 mg), 2 (400 mg), and 5 (520 mg) (Table 1). There were no
`serious adverse experiences at least possibly related to lurasidone. Therefore, the MID was
`lurasidone 520 mg. Among patients who received the MID in the fixed-dose cohorts (lurasidone
`520 mg), the moderate and severe adverse experiences were akathisia (5 patients); sedation
`(3 patients); restlessness (2 patients); anxiety (1 patient, event was severe); and extrapyramidal
`disorder, muscle spasm, depressed level of consciousness, claustrophobia, bruxism, and dystonia
`(1 patient each).
`
`Table 1 Patients Reaching MID Criteria by Lurasidone Dose
`
`Lurasidone Dose
`160 mg
`(N=6)
`200 mg
`(N=5)
`240 mg
`(N=7)
`(N=6)
`(N=7)
`(N=6)
`
`280 mg
`320 mg
`400 mg
`
`520 mg
`
`(N=7)
`
`Patients with More than 1 Moderate or Severe Treatment-Related Adverse Events
`Adverse Eventa
`--
`none
`01-203
`nausea, vomiting NOS
`01-303
`dystonia, vomiting NOS
`01-406
`bruxism, trismus
`--
`none
`01-601
`sedation, restlessness
`01-605
`akathisia, vomiting NOS, nausea
`akathisia, extrapyramidal disorder, muscle spasm
`akathisia, sedation, depressed level of consciousness
`akathisia, restlessness
`akathisia, anxiety (severe), restlessness, claustrophobia
`akathisia, bruxism, dystonia
`
`01-702
`01-703
`01-704
`01-705
`01-708
`
`NOS = not otherwise specified
`a Adverse experiences were moderate in severity unless otherwise indicated
`
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`Dopamine D2 Receptor Occupancy in Healthy Male Subjects Treated with
`SM-13496 Using Positron Emission Tomography (PET) (Study D1050180)
`
`Study Design and Methodology
`The primary objective of this study was to determine dopamine type-2 (D2) receptor occupancy
`of SM -13496 at 5 single oral doses ranging from 10 mg to 80 mg in healthy male subjects.
`Informed consent and confirmation of eligibility were obtained for each study subject at
`Screening Visit 1; an MRI for brain mapping was performed at Screening Visit 2. Four subjects
`each were sequentially assigned to receive SM-13496 10 mg, 20 mg, 40 mg, 60 mg, or 80 mg;
`progression to each escalating dose cohort was based on the review of safety data. Subjects were
`admitted to the clinical unit on Day -1 and underwent a full physical examination, vital signs
`assessment, electrocardiograms, and laboratory assessments. On the following day, Day 1,
`baseline fasting safety labs and baseline pharmacokinetic sampling were performed, and then a
`baseline PET scan was performed and a standard breakfast was provided to the study subjects 30
`minutes before dosing with SM-13496. A PET scan was performed at 1.5 hours after dosing.
`
`Results:
`Receptor occupancy-CPET relationships were determined in the putamen, caudate nucleus, and
`ventral striatum regions of the brain after oral administration of 10 mg, 20 mg, 40 mg, 60 mg, and
`80 mg of SM-13496 in healthy male volunteers. An increase in percent D2 receptor occupancy
`was observed with each increase in SM-13496 dose up to 60 mg. Further increases in occupancy
`were not observed for the 80 mg group in which receptor occupancy was similar to the 60 mg
`group. The results for each dose group were similar among all three striatal regions. Mean D2
`receptor occupancies for the 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg groups for the three regions
`ranged from 41.3%-43.3%, 51.0%-54.8%, 63.1%-67.5%, 77.4%-84.3%, and 72.9%-78.9%,
`respectively.
`
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`Cl) 100
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`
`60
`
`40
`
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`
`N=4/Dose
`
`•
`I
`
`--.---------------
`
`-
`
`•
`
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`
`--~-------~ --·-· --------
`
`0
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`
`Lurasidone Oral Single Dose (mg)
`
`Figure 1 0 2 Occupancy by C11 -Raclopride in Caudate
`
`The undersigned declares further that all statements made herein of his own knowledge
`are true and that all statements made on information and belief are believed to be true; and further
`that these statements were made with the knowledge that willful false statements and the like so
`made are punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of the
`United States Code and that such willful false statements may jeopardize the validity ofthe
`above-identified application or any patent issuing thereon.
`
`This
`
`day of June, 2008
`
`Masaaki Ogasa
`
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