03822.000060.
`
`PATENT APPLICATION
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Application of:
`
`JATIN PATEL ET AL.
`
`Application No.: N.Y.A.
`
`Int'l Appln No. PCT/US2011/025994
`
`Filed: February 24, 2011
`
`)
`
`)
`
`)
`
`)
`
`)
`
`Examiner: Not Yet Assigned
`
`Group Art Unit: Not Yet Assigned
`
`Confirmation No.: Not Yet Assigned
`
`For: APIXABAN FORMULATIONS
`
`) August 17, 2012
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-14 5 0
`
`PRELIMINARY AMENDMENT
`
`Sir:
`
`Prior to calculating the filing fee and conducting the examination on the
`
`merits, please amend the above-captioned application as follows.
`
`MYLAN EXHIBIT 1003
`
`

`

`SPECIFICATION
`
`Below the title, and before the FIELD OF THE INVENTION section, please
`
`add the following paragraph:
`
`--This application is the National Stage oflntemational Application No.
`
`PCT/US2011/025994, filed February 24, 2011, which claims the benefit of U.S.
`
`Provisional Application No. 61/308,056, filed February 25, 2010.--
`
`2
`
`

`

`CLAIMS
`
`A complete listing of all the claims appears below; this listing replaces all
`
`earlier amendments and listings of the claims.
`
`1.
`
`(Original) A composition comprising crystalline apixaban particles
`
`having a mean particle size equal to or less than about 89 µm and a pharmaceutically
`
`acceptable diluent or carrier.
`
`2.
`
`(Original) A composition comprising crystalline apixaban particles
`
`having a mean particle size equal to or less than about 85 µm and a pharmaceutically
`
`acceptable diluent or carrier.
`
`3.
`
`(Currently Amended) A composition as defined in claim 1 or claim
`
`2-, wherein said composition comprises Form N-1 of apixaban.
`
`4.
`
`(Original) A composition as defined in claim 1, wherein particles
`
`with a D90 equal to or less than 89 µm.
`
`5.
`
`(Original) A composition as defined in claim 2, wherein particles
`
`with a D90 equal to or less than 85 µm.
`
`6.
`
`(Currently Amended) A composition as defined in any one of claims
`
`-!-§.claim 1, wherein particles with a D 90 equal to or less than 50 µm.
`
`3
`
`

`

`7.
`
`(Currently Amended) A composition as defined in any one of claims
`
`-!-§.claim 1, wherein particles with a D90 equal to or less than 30 µm.
`
`8.
`
`(Currently Amended) A composition as defined in any one of elaims
`
`-!-§.claim 1, wherein particles with a D90 equal to or less than 25 µm.
`
`9.
`
`(Original) A composition as defined in claim 1 which exhibits an
`
`AUC and/or Cmax that is at least 80% of the mean AUC and/or Cmax observed for an
`
`equivalent formulation differing only in that the apixaban mean particle size is 89 µm.
`
`10.
`
`(Original) A composition as defined in claim 1 which exhibits an
`
`AUC and/or Cmax that is at least 80% of the mean AUC and/or Cmax observed for an
`
`equivalent formulation differing only in that the apixaban mean particle size is 85 µm.
`
`11.
`
`( Currently Amended) A composition as defined in any one of claims
`
`-1-1-0claim 1, further comprising:
`
`from 1 % to 2 % by weight of a surfactant.
`
`12.
`
`(Original) A composition as defined in claim 11, wherein the
`
`surfactant is sodium lauryl sulfate.
`
`4
`
`

`

`13.
`
`(Currently Amended) A composition as defined in any one of claims
`
`1 12 for use in treating method for the treatment or prophylaxis of a thromboembolic
`
`disorder, comprising administering to a patient in need of such treatment or prophylaxis a
`
`therapeutically effective amount of a composition as defined in claim 1.
`
`14-15. (Cancelled)
`
`16.
`
`(Currently Amended) A process of manufacturing apixaban tablets
`
`having a composition as defined in any one of claims 1 12claim 1, comprising the steps of:
`
`(1)
`
`blending raw materials prior to granulation;
`
`(2)
`
`granulating the raw materials from the step (1) using a wet or dry
`
`granulation process;
`
`(3)
`
`blending the granules obtained in the step (2) with extragranular raw
`
`materials;
`
`( 4)
`
`compressing the blend from the step (3) into tablets; and
`
`( 5)
`
`film coating the tablets from the step ( 4 ).
`
`17.
`
`(Currently Amended) A process of manufacturing apixaban tablets
`
`having a composition as defined in any one of claims 1 12claim 1, comprising the steps of:
`
`(1)
`
`blending raw materials with apixaban of controlled particle size to
`
`form a mix;
`
`(2)
`
`adding intragranular portions of a binder, a disintegrant and at least
`
`one filler to the mix from the step (1) to form a blend;
`
`5
`
`

`

`(3)
`
`granulating the materials from the step (2) using a dry granulation
`
`process or a wet granulation process,
`
`wherein the dry granulation process comprises:
`
`delumping an intragranular lubricant using a screen or mill;
`
`adding the intragranular lubricant to the blend from the step (2) and
`
`blending to form a lubricated blend;
`
`compacting the lubricated blend to ribbons of density in a range of 1.1 to 1.2
`
`glee and sizing the compacted ribbons using a roller compactor, and
`
`wherein the wet granulation process comprises:
`
`wet granulating the blend from the step (2) using water to a target end point
`
`and, optionally, sizing the wet-granules by passing through a screen or mill;
`
`removing the water from the granulation by drying in a convection oven or a
`
`fluid-bed dryer; and
`
`sizing the dried granules by passing through a screen or mill;
`
`( 4)
`
`blending the granules obtained in the step (3) and an extragranular
`
`disintegrant in a blender;
`
`( 5)
`
`delumping an extragranular lubricant using a screen or mill and
`
`blending with granules from the step ( 4);
`
`( 6)
`
`(7)
`
`compressing the blend from the step ( 5) into tablets; and
`
`film coating the tablets from the step ( 6).
`
`18.
`
`(Original) A process of manufacturing apixaban tablets according to
`
`claim 1 7, wherein the dry granulation process is used.
`
`6
`
`

`

`19.
`
`(New) A composition as defined in claim 2, wherein said
`
`composition comprises Form N-1 of apixaban.
`
`20.
`
`(New) A composition as defined in claim 2, wherein particles with a
`
`D90 equal to or less than 50 µm.
`
`21.
`
`(New) A composition as defined in claim 2, wherein particles with a
`
`D90 equal to or less than 30 µm.
`
`22.
`
`(New) A composition as defined in claim 2, wherein particles with a
`
`D90 equal to or less than 25 µm.
`
`23.
`
`(New) A composition as defined in claim 2, further comprising:
`
`from 1 % to 2 % by weight of a surfactant.
`
`24.
`
`(New) A composition as defined in claim 23, wherein the surfactant
`
`is sodium lauryl sulfate.
`
`25.
`
`(New) A method for the treatment or prophylaxis of a
`
`thromboembolic disorder, comprising administering to a patient in need of such treatment
`
`or prophylaxis a therapeutically effective amount of a composition as defined in claim 2.
`
`7
`
`

`

`REMARKS
`
`The claims are 1-13 and 16-25, with claims 1 and 2 being independent.
`
`Claims 14 and 15 have been cancelled without prejudice or disclaimer. Claims 3, 6-8, 11,
`
`13, 16, and 17 have been amended to remove multiple dependencies without prejudice or
`
`disclaimer as to any excised subject matter. Claim 13 has also been revised to better
`
`comply with formal requirements. Support for the changes in claim 13 may be found, for
`
`example, in the specification at paragraph [0009]. New claims 19-25 have been added
`
`based on original claims 3, 6-8, and 11-13. The specification has been amended to recite
`
`the benefit claims to a prior provisional application.
`
`No new matter has been added. Favorable consideration of the claims is
`
`respectfully requested.
`
`Applicants' undersigned attorney may be reached in our New York office by
`
`telephone at (212) 218-2100. All correspondence should continue to be directed to our
`
`below listed address.
`
`Respectfully submitted,
`
`/Jason M. Okun/
`Jason M. Okun
`Attorney for Applicants
`Registration No. 48,512
`
`FITZPATRICK, CELLA, HARPER & SCINTO
`1290 Avenue of the Americas
`New York, New York 10104-3800
`Facsimile: (212) 218-2200
`
`8
`
`FCHS WS 7891782vl.doc
`
`

`

`Electronic Patent Application Fee Transmittal
`
`Application Number:
`
`Filing Date:
`
`Title of Invention:
`
`APIXABAN FORMULATIONS
`
`First Named Inventor/Applicant Name:
`
`Jatin Patel
`
`Filer:
`
`Attorney Docket Number:
`
`Filed as Large Entity
`
`Jason M. Okun
`
`03822.000060.
`
`U.S. National Stage under 35 USC 371 Filing Fees
`
`Description
`
`Fee Code
`
`Quantity
`
`Amount
`
`Sub-Total in
`USO($)
`
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`
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`
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`
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`
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`Description
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`
`Miscellaneous:
`
`Total in USD ($)
`
`1300
`
`

`

`Electronic Acknowledgement Receipt
`
`EFSID:
`
`Application Number:
`
`13522764
`
`13579796
`
`International Application Number:
`
`PCT/USl 1/25994
`
`Confirmation Number:
`
`2947
`
`Title of Invention:
`
`APIXABAN FORMULATIONS
`
`First Named Inventor/Applicant Name:
`
`Jatin Patel
`
`Customer Number:
`
`5514
`
`Filer:
`
`Jason M. Okun/DAVID NGUY
`
`Filer Authorized By:
`
`Jason M. Okun
`
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`03822.000060.
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`Receipt Date:
`
`17-AUG-2012
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`Application Data Sheet 37 CFR 1.76
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`Attorney Docket Number
`
`03822.000060.
`
`Application Number
`
`Title of Invention
`
`APIXABAN FORMULATIONS
`
`The application data sheet is part of the provisional or nonprovisional application for which it is being submitted. The following form contains the
`bibliographic data arranged in a format specified by the United States Patent and Trademark Office as outlined in 37 CFR 1.76.
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`D Portions or all of the application associated with this Application Data Sheet may fall under a Secrecy Order pursuant to
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`r
`,DD 1can t I f
`n orma 10n:
`f
`A
`Aoolicant 1
`Applicant Authority (!)Inventor I QLegal Representative under 35 U.S.C. 117
`Prefix Given Name
`Middle Name
`
`I Remove I
`I QParty of Interest under 35 U.S.C. 118
`Family Name
`Suffix
`
`Jatin
`Patel
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`I Country of Residence i I US
`City West Windsor
`State/Province I NJ
`us
`
`Citizenship under 37 CFR 1.41(b) i
`Mailing Address of Applicant:
`Address 1
`c/o Bristol-Myers Squibb Company
`
`Address 2
`I Princeton
`Postal Code
`
`City
`
`08543
`
`Route 206 and Province Line Road
`
`I State/Province
`I Countryi I us
`
`I NJ
`
`Annlicant2
`Applicant Authority (!)Inventor I QLegal Representative under 35 U.S.C. 117
`Prefix Given Name
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`Charles
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`I Country of Residence i I us
`City
`State/Province I PA
`Yardley
`us
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`Citizenship under 37 CFR 1.41(b) i
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`
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`I State/Province
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`Jingpin
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`PTO/SB/14 (11-08)
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`Application Data Sheet 37 CFR 1.76
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`APIXABAN FORMULATIONS
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`Citizenship under 37 CFR 1.41(b) i
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`Address 1
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`us
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`c/o Bristol-Myers Squibb Company
`
`Route 206 and Province Line Road
`
`Address 2
`I Princeton
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`08543
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`I NJ
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`Aoolicant4
`Applicant Authority (!)Inventor I QLegal Representative under 35 U.S.C. 117
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`Chandra
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`Hillsborough
`IN
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`Mailing Address of Applicant:
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`c/o Bristol-Myers Squibb Company
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`Route 206 and Province Line Road
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`I Princeton
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`Application Information:
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`Title of the Invention
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`APIXABAN FORMULATIONS
`
`Attorney Docket Number 03822.000060.
`
`Application Type
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`Nonprovisional
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`Utility
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`

`Sheet 1 of 4
`
`Scatter Plot oflndividual Dose-Normalized AUC(INF) Values for
`Figure I:
`Solutions (CV185001, CV185006, and CV185007) and Tablets (CV185001 and
`CV185024)
`
`800
`
`700
`
`600
`
`ai"
`UI
`8
`OI
`E 500
`::i
`E
`i::
`.c 400
`•
`OI
`C
`ii:" 300
`z
`rr
`::,
`<
`
`200
`
`100
`
`0
`
`<>
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`
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`3
`T T
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`9
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`
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`C
`0
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`C
`'.fl.
`
`100
`
`90
`
`80
`
`70
`
`•
`
`$
`
`&
`
`t
`
`0.5 mg 1 mg 2.5 mg 20 mg 2.5 mg 5 mg 5 mg A 5 mg B 5 mg C
`
`Solution
`CV185001
`
`Tablet
`Solution
`CV185006 CV185001
`CV185007
`
`Tablet
`CV185024
`
`Source: CV185001, CV185006, CV185007, and CV185024 Clinical Study Reports
`The solid line represents the geometric mean of AUC(INF) and the solid square represents the
`average %in-vitro dissolved at 30 minutes (using QC method in Table I .2C). The X-axis represents
`the dose administered.
`For CV185024, 5 mg A = Apixaban Phase 2 tablet (86% dissolution) 2x2.5 mg (reference
`formulation), 5 mg B = Apixaban Phase 2 tablet (77% dissolution) 2x2.5 mg, 5 mg C = Apixaban
`Phase 3 tablet (89% dissolution) 2x2.5 mg.
`
`

`

`Sheet 2 of 4
`
`Scatter Plot of Individual Dose Normalized Cmax Values for Solutions
`Figure 2:
`(CVI85001, CVI85006, and CVI85007) and Tablets (CVI85001 and CVI85024)
`
`<>
`
`100
`
`i
`
`90
`
`3
`e
`
`t
`
`<>
`&
`
`80
`
`0 ... at:!
`>
`:§.
`Ill
`C: ·e
`
`0
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`C
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`0
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`t t
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`
`0
`0
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`i
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`<>
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`50
`
`40
`
`QI
`Ill
`0
`C
`~30
`
`i .S 20
`i <.>
`
`10
`
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`
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`8
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`0
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`+ "3""
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`e
`<>
`<>
`0
`
`<>
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`<>
`
`0.5 mg 1 mg 2.5 mg 20 mg 2.5 mg 5 mg 5 mg A 5 mg B 5 mg C
`
`Solution
`CV185001
`
`Solution
`CV185006
`CV185007
`
`Tablet
`CV185001
`
`Tablet
`CV185024
`
`Source: CVI85001, CVI85006, CV185007, and CVI85024 Clinical Study Reports
`The solid line represents the geometric mean of Cmax and the solid square represents the averag~
`%in-vitro dissolved at 30 minutes (using QC method in Table 1.2C). The X-axis represents the dose
`administered.
`For CV185024, 5 mg A "' Apixaban Phase 2 tablet (86% dissolution) 2x2.5 mg (reference
`formulation), 5 mg B "'Apixaban Phase 2 tablet (77% dissolution) 2x2.5 mg, 5 mg C = Apixaban
`Phase 3 tablet (89% dissolution) 2x2.5 mg.
`
`

`

`Sheet 3 of 4
`
`Figure 3:
`
`Dissolution Rates of 2.5-mg Apixaban Tablets Using Drug Substance
`
`of Different Particle Size
`
`................... , ........................................................ .
`
`•
`
`95
`
`45
`
`35+-----,..---...-----.-----.------.---...----1
`80
`40
`60
`120
`140
`100
`0
`20
`Drug Substance Paflicie Size 090 ( Micron)
`
`

`

`Sheet 4 of 4
`
`Figure 4:
`
`Dissolution Rates of 5-mg Apixaban Tablets Using Drug Substance of
`
`Different Particle Size
`
`••
`
`95
`
`C' e 85
`0
`M
`.$ 75
`
`minimum dissolution requirement
`
`i > i 65
`!
`
`~ 0
`
`55
`
`45
`
`35
`
`0
`
`