`

`•
`
`PT0-1390 (Rev. 09-2007)updated 10/04/07 by IPDASIBSKB
`Approved for use through 03/31/2007. OMB 0651-0021
`U. S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`·o
`Under the Pape!WO!k Reduction Act of 1995, no persons are required to respond to a collection of information unless it d1splays a valid MB control number.
`ATTORNEY'S OOCKET NUMBER
`0020-5610PUS1
`
`U.S. APPLICAtrt>· t~·te'Jc{) 118 'INTERNATIONAL APPLICATION NO.
`
`PCT/JP2006/31 0571
`
`iAP17 Rec'd PCT/PTO 31 OCT 2001
`
`2o.G Other items or information:
`
`Return Receipt Postcard;
`PCT/18/308 (2 sheets); PCT/18/304; PCT/ISA/237 (4 sheets); PCT/ISA/210; Drawings
`(3 sheets)
`
`The following fees have been submitted
`
`21.0 Basic national fee (37 CFR 1.492(a)) ................................................. $310
`
`CALCULATIONS
`$
`310.00
`
`PTO USE ONLY
`
`22.0 Examination fee (37 CFR 1.492(c))
`If the written opinion prepared by ISAIUS or the international preliminary examination report
`prepared by I PEA/US indicates all claims satisfy provisions of PCT Article 33(1 )-(4) .................. $0
`All other situations
`....................................................................................................................... $210
`
`$
`
`210.00
`
`23.G Search fee (37 CFR 1.492(b))
`If the written opinion of the ISAIUS or the international preliminary examination report prepared by
`IPEAIUS indicates all claims satisfy provisions of PCT Article 33(1 )-(4) ............................... $0
`Search fee (37 CFR 1.445(a)(2)} has been paid on the international application to the USPTO as an
`International Searching Authority ........................................................................................ $100
`International Search Report prepared by an ISA other lhan the US and provided to the Office or
`previously communicated to the US by the IB. .................................................................... $410
`All other situations ........................................................................................................................... $510
`TOTAL OF 21,22 and 23 =
`~ Additional fee for specification and drawings filed in paper over 100 sheets (excluding
`
`sequence listing in compliance with 37 CFR 1.821 (c) or (e) or in an eleclronic medium or
`computer program listing in an eleclronic medium) (37 CFR 1.492(j)).
`The fee is $260 for each additional 50 sheets of paper or fraction thereof.
`
`Total Sheets
`
`Extra Sheets
`
`Number of each additional 50 or fraction
`thereof (round up to a whole number)
`
`57
`
`-100=
`
`/50=
`
`RATE
`
`X $260.00
`
`Surcharge of $130 for furnishing any of the search fee. examination fee. or the oath or declaration
`after the date of commencement of the national stage (37 CFR 1.492(h)).
`
`CLAIMS
`
`Total claims
`
`NUMBER FILED
`
`NUMBER EXTRA
`
`24-20 =
`
`4
`
`X
`
`RATE
`
`X
`
`$50
`
`$
`
`$
`
`$
`
`$
`
`Independent claims
`
`5-3=
`MULTIPLE DEPENDENT CLAIM(S) (if applicable)
`
`2
`
`X
`
`X $210
`+ $370
`+
`TOTAL OF ABOVE CALCULATIONS= $
`~ Applicant claims small entity status. See 37 CFR 1.27. Fees above are reduced by Y..
`SUBTOTAL= $
`Processing fee of $130.00 for furnishing the English translation later than 30 months from the earliest
`claimed priority date (37 CFR 1.492(i)).
`
`$
`
`410.00
`
`930.00
`
`200.00
`
`420.00
`
`1,550.00
`
`1,550.00
`
`TOTAL NATIONAL FEE= $
`Fee for recording the enclosed assignment (37 CFR 1.21(h)). The assignment must be accompanied
`by an appropriate cover sheet (37 CFR 3.28. 3.31 ). $40.00 per property
`+
`
`$
`
`1,550.00
`
`40.00
`
`I
`
`$
`TOTAL FEES ENCLOSED= $
`Amount to be
`refunded:
`
`Amount to be
`charged
`
`$
`
`$
`
`1,590.00
`
`Birch. Stewart, Kolasch & Birch, LLP
`
`Page 2 of3
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 002
`
`

`

`

`

`

`

`•
`
`PT0-1390 (Rev. 09-2007)updated 10/04/07 by IPDASIBSKB
`Approved for use through 03/31/2007. OMB 0651-0021
`U. S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`·o
`Under the Pape!WO!k Reduction Act of 1995, no persons are required to respond to a collection of information unless it d1splays a valid MB control number.
`ATTORNEY'S OOCKET NUMBER
`0020-5610PUS1
`
`U.S. APPLICAtrt>· t~·te'Jc{) 118 'INTERNATIONAL APPLICATION NO.
`
`PCT/JP2006/31 0571
`
`iAP17 Rec'd PCT/PTO 31 OCT 2001
`
`2o.G Other items or information:
`
`Return Receipt Postcard;
`PCT/18/308 (2 sheets); PCT/18/304; PCT/ISA/237 (4 sheets); PCT/ISA/210; Drawings
`(3 sheets)
`
`The following fees have been submitted
`
`21.0 Basic national fee (37 CFR 1.492(a)) ................................................. $310
`
`CALCULATIONS
`$
`310.00
`
`PTO USE ONLY
`
`22.0 Examination fee (37 CFR 1.492(c))
`If the written opinion prepared by ISAIUS or the international preliminary examination report
`prepared by I PEA/US indicates all claims satisfy provisions of PCT Article 33(1 )-(4) .................. $0
`All other situations
`....................................................................................................................... $210
`
`$
`
`210.00
`
`23.G Search fee (37 CFR 1.492(b))
`If the written opinion of the ISAIUS or the international preliminary examination report prepared by
`IPEAIUS indicates all claims satisfy provisions of PCT Article 33(1 )-(4) ............................... $0
`Search fee (37 CFR 1.445(a)(2)} has been paid on the international application to the USPTO as an
`International Searching Authority ........................................................................................ $100
`International Search Report prepared by an ISA other lhan the US and provided to the Office or
`previously communicated to the US by the IB. .................................................................... $410
`All other situations ........................................................................................................................... $510
`TOTAL OF 21,22 and 23 =
`~ Additional fee for specification and drawings filed in paper over 100 sheets (excluding
`
`sequence listing in compliance with 37 CFR 1.821 (c) or (e) or in an eleclronic medium or
`computer program listing in an eleclronic medium) (37 CFR 1.492(j)).
`The fee is $260 for each additional 50 sheets of paper or fraction thereof.
`
`Total Sheets
`
`Extra Sheets
`
`Number of each additional 50 or fraction
`thereof (round up to a whole number)
`
`57
`
`-100=
`
`/50=
`
`RATE
`
`X $260.00
`
`Surcharge of $130 for furnishing any of the search fee. examination fee. or the oath or declaration
`after the date of commencement of the national stage (37 CFR 1.492(h)).
`
`CLAIMS
`
`Total claims
`
`NUMBER FILED
`
`NUMBER EXTRA
`
`24-20 =
`
`4
`
`X
`
`RATE
`
`X
`
`$50
`
`$
`
`$
`
`$
`
`$
`
`Independent claims
`
`5-3=
`MULTIPLE DEPENDENT CLAIM(S) (if applicable)
`
`2
`
`X
`
`X $210
`+ $370
`+
`TOTAL OF ABOVE CALCULATIONS= $
`~ Applicant claims small entity status. See 37 CFR 1.27. Fees above are reduced by Y..
`SUBTOTAL= $
`Processing fee of $130.00 for furnishing the English translation later than 30 months from the earliest
`claimed priority date (37 CFR 1.492(i)).
`
`$
`
`410.00
`
`930.00
`
`200.00
`
`420.00
`
`1,550.00
`
`1,550.00
`
`TOTAL NATIONAL FEE= $
`Fee for recording the enclosed assignment (37 CFR 1.21(h)). The assignment must be accompanied
`by an appropriate cover sheet (37 CFR 3.28. 3.31 ). $40.00 per property
`+
`
`$
`
`1,550.00
`
`40.00
`
`I
`
`$
`TOTAL FEES ENCLOSED= $
`Amount to be
`refunded:
`
`Amount to be
`charged
`
`$
`
`$
`
`1,590.00
`
`Birch. Stewart, Kolasch & Birch, LLP
`
`Page 2 of3
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 005
`
`

`

`

`

`..
`
`1
`
`tt/9196/8
`IAP05Rec'd P~1 3l OCT··· , .
`
`Docket No.: 0020-5610PUS1
`(PATENT)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Patent Application of:
`Kazuyuki FUJll:IARA
`
`International Application No.: PCT/JP2006/310571
`
`Application No.: NEW
`
`Filed: October 31, 2007
`
`Art Unit: N/ A
`
`Examiner: Not Yet Assigned
`
`For: PHARMACEUTICAL COMPOSITION
`
`PRELIMINARY AMENDMENT
`
`MSPCT
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`INTRODUCTORY COMMENTS
`
`The following preliminary amendments and remarks are respectfully submitted m
`
`connection with the above-identified application.
`
`This amendment includes:
`
`Amendments to the Claims are reflected in the listing of claims which begins on page 2
`
`of this paper.
`
`Remarks/Arguments begin on page 6 of this paper.
`
`Birch, Stewart, Kolasch & Birch, LLP
`
`DRN//scp
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 007
`
`

`

`

`

`Application No.: NEW
`
`Docket No.: 0020-5610PUS1
`
`6.
`
`(Original) A method of granulation of a powder mixture which comprises granulating a
`
`powder mixture comprising a pregelatinized starch and a water-soluble excipient by using a
`
`solution or dispersion of lurasidone and a water-soluble polymer binder.
`
`7.
`
`(Original) The method of granulation of claim 5 wherein the water-soluble excipient is
`
`mannitol or lactose.
`
`8.
`
`(Currently Amended) The oral preparation of any eHe efelaims 1 te 4claim 1 wherein the
`
`pregelatinized starch is incorporated in an amount of 10 to 50% (wt/wt) based on the weight of
`
`the preparation.
`
`9.
`
`(Currently Amended) The oral preparation of any eHe efelaims 1 te 4claim 1 wherein the
`
`pregelatinized starch is incorporated in an amount of 20 to 30% (wt/wt) based on the weight of
`
`the preparation.
`
`10.
`
`(Currently Amended) The oral preparation of any eHe ef elaims 1 te 4claim 1 wherein a
`
`content of lurasidone in the preparation is 20 to 45% (wt/wt).
`
`11.
`
`(Currently Amended) The oral preparation of any eHe ef elaims 1 te 4claim 1 wherein a
`
`content of lurasidone in the preparation is 25 to 40% (wt/wt).
`
`12.
`
`{Currently Amended) The oral preparation ofaHy eHe efelaims 1 te 4claim 1 wherein a
`
`content oflurasidone per tablet is 10 to 160 mg.
`
`13.
`
`(Currently Amended) The oral preparation of aHy eHe ef elaims 1 te 4claim 1 wherein a
`
`content oflurasidone per tablet is 20 to 120 mg.
`
`14.
`
`{Currently Amended) The oral preparation of aHy eHe ef elaims 1 te 4claim 1 wherein a
`
`content oflurasidone per tablet is 40 to 120 mg.
`
`3
`
`DRN//scp
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 009
`
`

`

`Application No.: NEW
`
`Docket No.: 0020-5610PUSI
`
`15.
`
`(Currently Amended) The oral preparation of any ene efelaims 1 te 4claim 1 wherein the
`
`water-soluble excipient is mannitol or lactose and the pregelatinized starch is incorporated in an
`
`amount of 1 0 to 50% ( wt/wt) based on the weight of the preparation.
`
`16.
`
`(Currently Amended) The oral preparation of any ene ef elaims 1 te 4claim 1 wherein the
`
`water-soluble excipient is mannitol or lactose and a content of lurasidone in the preparation is 25
`
`to 40% (wt/wt).
`
`17.
`
`(Currently Amended) The oral preparation of any ene efelaims 1 te 4claim 1 wherein the
`
`pregelatinized starch is incorporated in an amount of 10 to 50% (wt/wt) based on the weight of
`
`the preparation and a content of lurasidone in the preparation is 25 to 40% (wt/wt).
`
`18.
`
`(Currently Amended) The oral preparation of any ene ef elaims 1 te 4claim 1 wherein the
`
`water-soluble excipient is mannitol or lactose, the pregelatinized starch is incorporated in an
`
`amount of 10 to 50% {wt/wt) based on the weight of the preparation and a content of lurasidone
`
`in the preparation is 25 to 40% (wt/wt).
`
`19.
`
`(Currently Amended) The oral preparation ofaay ene efelaims 1 te 4claim 1 wherein the
`
`water-soluble excipient is mannitol or lactose, the pregelatinized starch is incorporated in an
`
`amount of20 to 30% (wt/wt) based on the weight ofthe preparation and a content oflurasidone
`
`in the preparation is 25 to 40% (wt/wt).
`
`20.
`
`(Currently Amended) The oral preparation of aHy ene ef elaims 1 te 4claim 1 wherein the
`
`water-soluble excipient is mannitol or lactose, the pregelatinized starch is incorporated in an
`
`amount of 20 to 30% {wt/wt) based on the weight of the preparation and a content of lurasidone
`
`per tablet is 40 to 120 mg.
`
`4
`
`DRN//scp
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 010
`
`

`

`Application No.: NEW
`
`Docket No.: 0020-56IOPUSI
`
`21.
`
`(Currently Amended) The oral preparation of any ane af elaims 1 ta 4claim 1 wherein a
`
`pregelatinizing ratio of the pregelatinized starch is 50 to 95%.
`
`22.
`
`(Currently Amended) The oral preparation of any ane ef elaims 1 te 4claim 1 wherein an
`
`average particle size of lurasidone is 0.1 to 8 J.lm. 23.
`
`(Currently Amended) The oral
`
`preparation of any ene ef elaims 1 ta 4claim 1 wherein the pregelatinized starch contains water
`
`soluble matter of 30% or less.
`
`24.
`
`(Currently Amended) The oral preparation of any ene efelaims 1 ta 4claim 1 wherein the
`
`water-soluble excipient is mannitol or lactose, the pregelatinized starch is incorporated in an
`
`amount of 20 to 30% (wt/wt) based on the weight of the preparation, a content of lurasidone in
`
`the preparation is 25 to 40% (wtlwt) and a content oflurasidone per tablet is 20 to 120 mg.
`
`5
`
`DRN//scp
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 011
`
`

`

`Application No.: NEW
`
`Docket No.: 0020-5610PUSI
`
`\
`
`REMARKS
`
`The claims have been amended to remove the multiple dependencies listed therein.
`
`Claims 1-24 are pending in this application.
`
`CONCLUSION
`
`Entry of the above amendments is earnestly solicited. An early and favorable first action
`
`on the merits is earnestly solicited.
`
`Should there be any outstanding matters that need to be resolved in the present
`
`application, the Examiner is respectfully requested to contact Mark J. Nuell (Reg. No. 36,623 ) at
`
`the telephone number of the undersigned below, to conduct an interview in an effort to expedite
`
`prosecution in connection with the present application.
`
`If necessary, the Commissioner is hereby authorized in this, concurrent, and future replies
`
`to charge payment or credit any overpayment to Deposit Account No. 02-2448 for any additional
`
`fees required under 37.C.F.R. §§1.16 or 1.14; particularly, extension oftime fees.
`
`Dated: October 31, 2007
`
`By~~~~ ---+---~-~.~-
`-:::f:v'Ma
`Registration No.: 36,623
`BIRCH, STEW ART, KOLASCH & BIRCH, LLP
`12770 High BluffDrive
`Suite 260
`San Diego, California 92130
`(858) 792-8855
`Attorney for Applicant
`
`6
`
`DRN//scp
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 012
`
`

`

`tY/919678 ..
`fAP05Rec'd PGT 31 OCT lOOTl
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Docket No.: 0020-5610PUS1
`(PATENT)
`
`In re Patent Application of:
`Kazuyuki FUJIHARA
`
`Application No.: NEW
`
`Filed: October 31, 2007
`
`Confirmation No.: N/A
`
`Art Unit: N/A
`
`For:
`
`PHARMACEUTICAL COMPOSITION
`
`Examiner: Not Yet Assigned
`
`INFORMATION DISCLOSURE STATEMENT (IDS)
`
`MSPCT
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`Pursuant to 37 CFR 1.56, 1.97 and 1.98, the attention of the Patent and Trademark Office
`
`is hereby directed to the references listed on the attached PTO/SB/08. It is respectfully requested
`
`that the information be expressly considered during the prosecution of this application, and that
`
`the references be made of record therein and appear among the "References Cited" on any patent
`
`to issue therefrom.
`
`This Information Disclosure Statement accompanies the new patent application submitted
`
`herewith.
`
`A summary/abstract translation of the non-English language references BA and BB is
`
`enclosed. Reference AA corresponds to reference BA. The references can be found cited in the
`
`International Search Report.
`
`Birch, Stewart, Kolasch & Birch, LLP
`
`DRN//scp
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 013
`
`

`

`Application No.: NEW
`
`'tf/9196?8
`lAP05Rec'd PGT 31 OCT ?.an~ . ;
`Docket No.: 0020-5610Plml"'~
`
`A concise explanation of relevance of the items listed on form PTO/SB/08 is in the form
`
`of an English language copy of a Search Report from a foreign patent office, issued in a
`
`counterpart application, which refers to the relevant portions of the references.
`
`In accordance with 37 CFR 1.97{g), the filing of this Information Disclosure Statement
`
`shall not be construed to mean that a search has been made or that no other material information
`
`as defined in 37 CFR 1.56(a) exists.
`
`In accordance with 37 CFR 1.97(h), the filing of this
`
`Information Disclosure statement shall not be construed to be an admission that any patent,
`
`publication or other information referred to therein is "prior art" for this invention unless
`
`specifically designated as such.
`
`It is submitted that the Information Disclosure Statement is in compliance with 37 CFR
`
`1.98 and the Examiner is respectfully requested to consider the listed references.
`
`If necessary, the Commissioner is hereby authorized in this, concurrent, and future
`
`replies, to charge payment or credit any overpayment to our Deposit Account No. 02-2448 for
`
`any additional fees required under 37 C.F.R. § 1.16 or under § 1.17; particularly, extension of
`
`time fees.
`
`Dated: October 31, 2007
`
`Attachment( s)
`
`By~~~~+---~~~------------
`~M .Nuel
`Registration No.: 36,623
`BIRCH, STEW ART, KOLASCH & BIRCH, LLP
`12770 High Bluff Drive
`Suite 260
`San Diego, California 92130
`(858) 792-8855
`Attorney for Applicant
`
`2
`
`DRN//scp
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 014
`
`

`

`Jf/919678
`fAP05Rec;d PGT 3 1 OCT 2007l
`
`Used in Lieu of PTO/SB/08A/B
`(Based on PTO 10.()7 version)
`
`Substitute for form 1449/PTO
`
`INFORMATION DISCLOSURE
`STATEMENT BY APPLICANT
`
`(Use as many sheets as necessary)
`
`Sheet I
`
`1
`
`I of I
`
`1
`
`Application Number
`
`Filing Date
`
`Complete if Known
`NEW
`October 31, 2007
`First Named Inventor Kazuyuki FUJIHARA
`N/A
`Not Yet Assigned
`Attorney Docket Number 0020-5610PUS1
`
`Art Unit
`
`Examiner Name
`
`Document Number
`Publication Date
`Examiner Cite
`No.' Number-Kind Code2 (if known) MM-00-yyyy
`Initials•
`AA* US-2004/00287 41-A 1 02-12-2004 Fujihara
`
`Name of Patentee or
`Applicant of Cited Document
`
`Pages, Columns. lines, Where
`Relevant Passages or Relevant
`Fgures Appear
`
`U.S. PATENT DOCUMENTS
`
`FOREIGN PATENT DOCUMENTS
`Publication
`Forei!ln Patent Document
`Examiner Cite
`Date
`No' Coumry Code' -l'l!rnbef' -Kind Code5 (if known) MM-DD-YYYY
`Initials•
`
`Name of Patentee or
`Applicant of Cited Document
`
`Pages. caumns. Unes.
`Where Relevant
`Passages Or Relevant
`Fogures Appear
`
`BA W0-02/24166-A1
`BB W0-2004/078173-A 1
`BC
`JP-8-325146-A
`
`03-28-2002
`09-16-2004
`12-10-1996
`
`1"
`
`ABS
`ABS
`
`•EXAMINER: Initial if reference considered, whether or not citation is in conformance with MPEP 609. Draw fine through citation if not in conformance and not
`considered. Include copy of this form with next communication to appticant. • CITE NO.: Those application(s) which are marl<ed with an single asterisk (•) next
`to !he Cite No. are not supplied (under 37 CFR 1.98(a)(2)(iii)) because !hat application was filed after June 30, 2003 or is available in !he IFW.
`'APPiicanfs
`unique citation designation number (optional). 2 See Kinds Codes of USPTO Patent Documents at www.uspto.gov or MPEP 901.04. 3 Enter Office !hat issued
`!he document, by !he two-letter code (WIPO Standard ST.3). 4 For Japanese patent documents. !he indication of !he year of the reign of !he Emperor must
`precede !he serial number of !he patent document. 5 Kind of document by !he appropriate symbols as indicated on !he document under WIPO Standard ST.16 if
`possible. 6 Applicant is to place a check marl< here if English language Translation is attached.
`
`Exami~er Cite
`No. 1
`Initials
`
`NON PATENT LITERATURE DOCUMENTS
`Include name of the author (in CAPITAL LEITERS). title of the article (when appropriate). title of the item (book,
`magazine. journal, serial, symposium, catalog, etc.). date. page(s), volume-issue number(s), publisher. city
`and/or country where published.
`
`T'
`
`'EXAMINER: Initial if reference considered, whether or not citation is in conformance with MPEP 609. Draw line through citation if not in conformance and not
`considered. Include copy of !his form with next communication to applicant.
`
`'APPiicanrs unique citation designation number (optional). 2Applicant is to place a check marl< here if English language Translation is attached.
`
`Examiner I
`
`Sionatur~
`
`Birch, Stewart, Kolasch & Birch. LLP
`
`'
`
`I Date
`
`Constdered
`
`DRN//scp
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 015
`
`

`

`\
`
`' •'
`
`,-y/9.19678 ;
`.
`fAP05Rec'd PST 81-0CT za~·
`
`1
`
`DESCRIPTION
`
`PHARMACEUTICAL COMPOSITION
`
`5
`
`TECHNICAL FIELD
`
`[0001]
`
`The present invention relates to an oral preparation with a good
`
`disintegration which comprises as an active ingredient N-[4-[4-(1,2-
`
`benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl]-
`
`10
`
`(1 'R,2'S,3'R,4'S)-2,3-bicyclo[2,2, 1]heptanedicarboxyimide hydrochloride
`
`(lurasidone). More particularly, the present invention relates to a
`
`preparation for oral administration, particularly a tablet, comprising
`
`lurasidone as an active ingredient, which has an equivalent dissolution
`
`profile of the active ingredient even though contents of the active
`
`15
`
`ingredient therein are varied.
`
`BACKGROUND ART
`
`[0002]
`
`Patent Document 1 discloses
`
`that a compound such as
`
`20
`
`lurasidone can be orally administered and an oral preparation can be
`
`prepared by blending an active ingredient with a conventional carrier,
`
`excipient, binder, stabilizer and the like, but there is no disclosure of an
`
`oral preparation which shows a rapid dissolution and has an equivalent
`
`dissolution profile of the active ingredient even though contents of the
`
`25
`
`active ingredient therein are varied in the wide range, particularly an
`
`oral preparation with increased contents of the active ingredient which
`
`has a similar dissolution profile to that of multiple tablets with a lower
`
`content of the active ingredient per tablet.
`
`[0003]
`
`30
`
`For the purpose of securing the bioequivalence when
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 016
`
`

`

`.-
`
`2
`
`pharmaceutical preparations with different contents of the active
`
`ingredient were administered so as to be the same dose to each other, a
`
`guideline has been issued, i.e., "Guideline for Bioequivalence Studies of
`
`Oral Solid Dosage Forms with Different Content" (Notification No. 64 of
`
`5
`
`the Evaluation and Licensing Division, Pharmaceutical and Food Safety
`
`Bureau, promulgated on February 14, 2000) by which it has been
`
`required that pharmaceutical preparations with different contents
`
`should have an equivalent dissolution profile in each test solution such
`
`as buffers of pH1.2, 3.0 to 5.0 and 6.8 (which correspond to the pH
`
`10
`
`values of stomach, intestine and oral cavity, respectively), water, and
`
`saline.
`
`[0004]
`
`Patent Document 2 discloses an oral preparation comprising
`
`lurasidone as an active ingredient, which shows a rapid dissolution and
`
`15
`
`has an equivalent dissolution profile even though contents of the active
`
`ingredient therein are varied, particularly an oral preparation with
`
`increased contents of the active ingredient which has an equivalent
`
`dissolution profile to that of multiple tablets with a lower content of the
`
`active ingredient per tablet and can release a slightly water-soluble
`
`20
`
`active ingredient therefrom at a desired concentration.
`
`[0005]
`
`Patent Document 2
`
`further discloses an oral preparation,
`
`.particularly a tablet, which shows a rapid dissolution of the active
`
`ingredient even though contents of the active ingredient therein are
`
`25
`
`varied in the range of several mg to several tens of mg (e.g. in the range
`
`of 5 mg to 20 mg or in the range of 5 mg to 40 mg), and further has an
`
`equivalent dissolution profile in the same componential ratio. An oral
`
`preparation has been frequently required to be a preparation with
`
`higher contents of the active ingredient in order to get higher clinical
`
`30
`
`effects, or a preparation which has an equivalent dissolution profile to
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 017
`
`

`

`3
`
`that of multiple tablets and can release the active ingredient therefrom
`
`at a desired concentration in wider ranges of contents in order to adjust
`
`clinical effects depending on conditions of patients. The art disclosed in
`
`Patent Document 2 may provide an oral preparation which has an
`
`5
`
`equivalent dissolution profile in the range of 5 mg to 40 mg of
`
`lurasidone per tablet, as shown in Figure 1. However, as shown in
`
`Figure 2, when the content of the active ingredient per tablet was
`
`increased to double, i.e., 80 mg tablet, it could not have. an equivalent
`
`dissolution profile. Henee, it.·· remains .in: a· state of administering
`
`10
`
`multiple tablets at one time or using a tablet having a big size which is
`
`difficult to administer.
`
`Therefore~ for such a slightly water-soluble
`
`active ingredient as lurasidone, it has been difficult to provide an oral
`
`preparation having an equivalent dissolution profile even in high
`
`content or in wider ranges of contents of the active ingredient.
`
`15
`
`[0006]
`
`In Patent Document 2, a water-soluble polymer binder includes
`
`starch, but there is no description about a pregelatinized starch therein.
`
`The pregelatinized starch
`
`is known
`
`to
`
`remarkably
`
`improve a
`
`disintegration and a dissolution of a pharmaceutical composition as
`
`20
`
`described, for example, in Patent Document 3, but it is often used,
`
`typically, in 10o/o or less of contents as also described in Non-patent
`
`Document 1.
`
`[0007]
`
`Patent Document 1:
`
`JP2800953
`
`25
`
`Patent Document 2:
`
`W02002/024166
`
`Patent Document 3:
`
`JP2000-26292
`
`Non-patent Document 1:
`
`Handbook of Pharmaceutical Excipients,
`
`2nd edition, 491, 1994, The .Pharmaceutical Press
`
`30
`
`DISCLOSURE OF INVENTION
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 018
`
`

`

`4
`
`PROBLEMS TO BE RESOLVED BY THE INVENTION
`
`. [0008]
`
`The present invention is directed to provide an oral preparation
`
`comprising lurasidone as an active ingredient which shows a rapid
`
`5
`
`dissolution and has an equivalent dissolution profile even though
`
`contents of the active ingredient therein are varied in the wide range,
`
`particularly an oral preparation with increased_ contents of the .active
`
`ingredient which has a similar dissolution profile to that of multiple
`
`tablets with a lower content of the active ingredient per tablet and can
`
`10
`
`release the active ingredient therefrom at a desired concentration.
`
`[0009]
`
`The present invention is directed to provide a preparation for oral
`
`administration which comprises as an active ingredient N -[4-[4-( 1 ,2-
`
`benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R}-2,3-tetramethylene-butyl]-
`
`15
`
`(1 'R,2'S,3'R,4'S)-2,3-bicyclo[2,2,1]heptanedicarboxyimide hydrochloride
`
`(hereinafter referred
`
`to as lurasidone), which has an equivalent
`
`dissolution profile of the active ingredient even though contents of the
`
`active ingredient therein are varied.
`
`MEANS OF SOLVING THE PROBLEMS
`
`20
`
`[0010]
`
`The present inventors have intensively studied in order to solve
`
`the above problems and found to solve said problems by means of the
`
`following methods.
`
`[0011]
`
`25
`
`The present invention includes the following embodiments:
`
`[0012]
`
`(1)
`
`An oral preparation which comprises N-[4-[4-(1,2-benzisothiazol-
`
`3-yl}-1-piperazinyl]-(2R,3R)-2,3-tetramethylene-butyl]-( 1 'R,2 'S,3 'R,4'S}-
`
`2 ,3-bicyclo[2 ,2, 1 ]heptanedicarboxyimide hydrochloride (lurasidone} of
`
`30
`
`the formula (1):
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 019
`
`

`

`5
`
`HCI
`
`(1)
`
`a pregelatinized starch, a water-soluble excipient and a water-soluble
`
`polymer binder.
`
`(2)
`
`An oral preparation which is prepared by granulating a powder
`
`5
`
`mixture comprising lurasidone, a pregelatinized starch and a water(cid:173)
`
`soluble excipient by using a solution of a water-soluble polymer binder.
`
`(3)
`
`An oral preparation which is prepared by granulating a powder
`
`mixture comprising a pregelatinized starch and a water-soluble
`
`excipient by a solution or dispersion of lurasidone and a water-soluble
`
`10
`
`polymer binder.
`
`(4)
`
`The oral preparation of any one of {1) to (3) wherein the water-
`
`soluble excipient is mannitol or lactose.
`
`(5)
`
`A method of granulation of a powder mixture which comprises
`
`granulating a powder mixture comprising lurasidone, a pregelatinized
`
`15
`
`starch and a water-soluble excipient by using a solution of a water(cid:173)
`
`soluble polymer binder.
`
`(6)
`
`A method of granulation of a powder mixture which comprises
`
`granulating a powder mixture comprising a pregelatinized starch and a
`
`water-soluble excipient by using a solution or dispersion of lurasidone
`
`20
`
`and a water-soluble polymer binder.
`
`(7)
`
`The method of granulation of (5) wherein the water-soluble
`
`excipient is mannitol or lactose.
`
`(8)
`
`The oral preparation of any one of {1)
`
`to (4) wherein the
`
`pregelatinized starch is incorporated in an amount of 10 to 50o/o (wt/wt)
`
`25
`
`based on the weight of the preparation.
`
`(9)
`
`The oral preparation of any one of (1)
`
`to (4) wherein the
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 020
`
`

`

`6
`
`pregelatinized starch is incorporated in an amount of 20 to 30o/o (wt/wt)
`
`based on the weight of the preparation.
`
`(10) The oral preparation of any one of (1) to (4) wherein a content of
`
`lurasidone in the preparation is 20 to 45°/o (wt/wt).
`
`5
`
`(11) The oral preparation of any one of (1) to (4) wherein a content of
`
`lurasidone in the preparation is 25 to 40% (wt/wt).
`
`(12) ·The oral preparation of any one of(1) to (4) wherein a content of
`
`·.•
`
`... · _: lurasidqne per tablet is 10 to 160 mg.
`
`(13) · The oral preparation of any one of (1) to (4) wherein a content of
`
`10
`
`lurasidone per tablet is 20 to 120 mg.
`
`(14) The oral preparation of any one of (1) to (4) wherein a content of
`
`lurasidone per tablet is 40 to 120 mg.
`
`(15) The oral preparation of any one of (1) to (4) wherein the water(cid:173)
`
`soluble excipient is mannitol or lactose and the pregelatinized starch is
`
`15
`
`incorporated in an amount of 10 to 50%> (wt/wt) based on the weight of
`
`the preparation.
`
`(16) The oral preparation of any one of (1) to (4) wherein the water(cid:173)
`
`soluble excipient is mannitol or lactose and a content of lurasidone in
`
`the preparation is 25 to 40°/o (wt/wt).
`
`20
`
`(17) The oral preparation of any one of (1)
`
`to (4) wherein the
`
`pregelatinized starch is incorporated in an amount of 10 to 50o/o (wt/wt)
`
`based on the weight of the preparation and a content of lurasidone in
`
`the preparation is 25 to 40o/o (wt/wt).
`
`(18) The oral preparation of any one of (1) to (4) wherein the water-
`
`25
`
`soluble excipient is mannitol or lactose, the pregelatinized starch is
`
`incorporated in an amount of 10 to 50°/o (wt/wt) based on the weight of
`
`the preparation and a content of lurasidone in the preparation is 25 to
`
`40°/o (wt/wt).
`
`(19) The oral preparation of any one of (1) to (4) wherein the water-
`
`30
`
`soluble excipient is mannitol or lactose, the pregelatinized starch is
`
`Par Pharm., Inc.
`Exhibit 1015
`Page 021
`
`

`

`7
`
`incorporated in an amount of 20 to 30o/o (wt/wt) based on the weight of
`
`the preparation and a content of lurasidone in the preparation is 25 to
`
`40°/o (wt/wt).
`
`(20) The oral preparation of any one of (1) to (4) wherein the water-
`
`S
`
`soluble excipient is mannitol or lactose, the pregelatinized starch is
`
`incorporated in an amount of 20 to 30o/o (wt/wt) based on the weight of
`
`the preparation and a content of lurasidone per tablet is 40 to 120 mg.
`
`(21) The oral preparation of any one of (1)
`
`to
`
`(4) wherein a
`
`pregelatinizing ratio of the pregelatinized starch is 50 to 95o/o.
`
`10
`
`(22) The oral preparation of any one of (1) to (4) wherein an average
`
`particle size of lurasidone is 0.1 to 8 pm.
`
`(23) The oral preparation of any one of (1)
`
`to (4) wherein the
`
`pregelatinized starch contains water soluble matter of 30o/o or less.
`
`(24) The oral preparation of any one of (1) to (4) wherein the water-
`
`IS
`
`soluble excipient is mannitol or lactose, the pregelatinized starch is
`
`incorporated in an amount of 20 to 30o/o (wt/wt) based on the weight of
`
`the preparation, a content of lurasidone in the preparation is 25 to 40o/o
`
`(wt/wt) and a content of lurasidone per tablet is 20 to 120 mg.
`
`EFFECTS OF INVENTION
`
`20
`
`[0013]
`
`It has been confirmed in the art disclosed in Patent Document 2
`
`that a pharmaceutical preparation with low contents of lurasidone up to
`
`40 mg per tablet could provide an oral preparation having an equivalent
`
`dissolution profile. However, a pharmaceutical preparation with higher
`
`25
`
`contents of lurasidone could not have an equivalent dis·solution profile.
`
`Therefore, double amounts or more of the preparation with low contents
`
`·should have been administered to a patient in need of high doses of
`
`lurasidone, which imposed increased burdens on the patient, and hence
`
`an improvement thereon has been required. The preparation of the
`
`30
`
`present invention which