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`IN THE UNITED STA'I_'ES PATENT AND TRADEMARK OFFICE
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`In re Application of:
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`Beth A. BURNSIDE at al. _
`Serial No; 093801462
`Filed: July‘ 19, 2001
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`Examiner: Russell Travers, Esq.
`Group An Unit; 1617
`BOX: AF
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`793.”,
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`For: ORAL PULSED DOSE DRUG DELIVERY SYSTEM
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`ANIENDINIENT AFTER FINAL REJECTION
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`E
`1
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`1J
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`.
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`Assistant Commissioner for Patents
`Washington, DC. 20231
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`Sir:
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`The following is responsive to the Office Action of March 4, 2003.
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`Amendments to me claims are reflected in the listing of claims which begins on page 2 of
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`this paper.
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`Remarksfikrgxunents begin on page S of this paper.
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`1
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`PHARNIA-142 P1
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`Amerigen Ex. 1067, p. 1
`Amerigen Ex. 1067, p. 1
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`This listing of claims will replace all prior versions, and listings. of claims in the application:
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`[ASE0 of Claims:
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`Claims 1-102 are canceled -
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`103.
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`(New) A p s . aceutical formulation for delivery of a mixture of amphetamine
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`base salts eifective to treat AD. II in a human patient comprising:
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`an immediate rele e dosage form that provides immediate release upon oral
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`administration to said patient;
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`a delayed enteric rel e dosage form that provides delayed release upon oral
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`adnlinistration to said patient; and
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`a pharmaceutically acc table carrier;
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`wherein said arnphe =
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`a ' e base salts comprise dextroamphetarnjne sulfate,
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`dexiroamphetamine saccharate, amphe .- ' - - aspartate rnonohydrate and amphetamine sulfate;
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`wherein said pliannaceutic: composition is sufiicient to maintain an effective
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`level of amphetamine base salts in the pati - t over the course of at least 8 hours without further
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`administration of amphetamine base salt, an the peak plasma concentration of amphetamine
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`base salts reached after release of said delaye enteric release dosage form exceeds the peak
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`plasma concentration previously reached after
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`- lease of said immediate release dosage form;
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`and
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`wherein said pharmaceutical compotion produces in a human individual a
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`plasma concentration versus time curve (ng/ml vers - hours) having an area under the curve
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`(AUC) of about 467 to about 714 ng hr/ml, for about -. 20 mg total dose, or an AUC
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`proportional thereto for a total dose other than about 2 mg.
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`/
`(New) A formulation of claim 103 wherein aid plasma concentration curve has a
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`104.
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`maximum concentration (Cam) of about 22.5 to about 40 11 ml for about a 10 mg dose in each
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`2
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`Pl-IARMA-142 P I
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`Amerigen Ex. 1067, p. 2
`Ame igen Ex. 1067, p. 2
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`than about 10 mg.
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`of said dosage forms, or a Cm”. pro ortional thereto for a dose in each of said dosage forms other
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`(New) A formulation of claim 101 wherein the time after said oral administration
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`105,
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`to reach said Cum value is about 7 to about 10 hours.
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`(New) A formulation o claim 193 wherein the time after said oral administration
`106.
`to reach maximum concentration of
`id plasma concentration curve is about 7 to about 10
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`hours.
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`hrfml.
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`107.
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`(New) A formulation of laim l0{10:'> or 106 wherein said ADC is about 714 ng
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`Q \
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`(New) A formulation of cl ‘m 10{wherein said AUC is about 714 ng hrfml, the _
`103.
`time after said oral administration to reach aid Cm,“ value is about '7 hours and Cm,‘ is about 40
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`(New) A formulation of clai
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`I04 yvherein Cm.
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`is about 40 ng/ml-
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`109.
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`1 10.
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`(New) A formulation of claim 1 5/or 106 wherein said time is about 7 hours.
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`( New) A formulation of one oft: a1'Jnsll03-106, 108 or 109 wherein said salts are
`11 1.
`contained in about equal amounts within each o said dosage forms and the total amphetamine
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`salt amount in each of said dosage forms 13 abou the same.
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`S’
`\@enteric release do sage form comprises at coa ing of
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`(New) A formulation of on of cl
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`'
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`112.
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`s 1133-106, 108 or 109 wherein said delayed
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`thickness of at least 20 pm which
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`C011-1pI'iSCS dried 30% (dry substance) aqueo
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`methacrylic acid and acrylic acid ethyl ester, s
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`U)
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`ion of an anionic copolymcr based on
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`‘ g being soluble at a pH of 5.5 upwards
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`PH.AR.lV1A- 1 42 Pl
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`Amerigen Ex. 1067, p. 3
`Amerigen Ex. 1067, p. 3
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`113.
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`(New) A formulation of claim léwherein said thickness is at least 25 run.
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`l 14.
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`(New) A pharmaceutica1\’or1nularion for delivery ofa mixture ofamphetamine
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`39/
`’ base salts effective to treat ADHD in a hymen patient comprising:
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`an immediate release dosage form that provides immediate release upon oral administration to
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`said patient;
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`a delayed enteric release dosage to
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`33
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`that provides delayed release upon oral
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`adrniriisrration to said patient, wherein said nteric release dosage form comprises a coating of a
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`thickness of at least 20 pm which comprises
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`‘ed 30% (dry substance) aqueous dispersion of an
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`amonic copolyrner based on methacrylic acid and acrylic acid ethyl ester, said coating being
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`soluble at a pH of5.5 upwards; and
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`a pharmaceutically acceptable carrier;
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`wherein said amphetamine base salts corn rise dcxtroamphetamine sulfate,
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`dextroamphetamine saccharate, amphetamine aspartate rnonohydrate and arnphetai-nine sulfate;
`wherein said pharmaceutical composition is sufficient to maintain an effective level of /
`amphetamine base salts in the patient over the couzse of at least 8 hours without further
`administration of amphetarnine base salt, and the
`plasma concentration of amphetarnine
`base salts reached after release of said delayed enterx‘
`release dosage form exceeds the peak
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`plasma concentration of said salts previously reached
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`er release of said immediate release
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`‘-
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`dosage form.
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`115.
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`(New) A formulation of claim 11{wherein said thickness is at least 25 ;.u:o._
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`i.
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`11
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`4
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`PI-IARNIA-1 42 P 1
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`Amerigen Ex. 1067, p. 4
`Amerigen Ex. 1067, p. 4
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`issues raised by the examiner are rendered moot by the foregoing. This is not to imply any
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`agreement with any aspect of the office action. The previous claims met all requirements of 35
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`U.S.C.
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`Language in claims -1 09 and 11 1 regarding the enteric coating composition is based on
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`conventional knowledge of the chemical composition of the enteric material utilized in Example
`2, i.e., EUDRAGIT ‘B L 30 13-55. Tlttis can be seen from the attached data sheets describing this
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`well known enteric material, e.g., “EUDRAGIT L, Aqueous Dispersion, Data Sheet (lnfo LD-
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`2ie). EUDRAGIT L 30 D” (two pages}, at page 1, top and column 1; and “EUDRAC‘rIT L,
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`Aqueous Dispersion, Standards Sheet (info LD-7/e), EUDRAGIT I.__30 D” (two pages), at page
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`1, top and columns 1 and 2. (The notation “S5” in the nomenclature used in the specification is
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`an equivalent of the older nomenclature L 30 D, ‘'5?’ simply refemng to the pH (5.5) at which
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`the enteric rnateiial becomes soluble.) Conventional values of area under the curve (AUC),
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`maximum plasma concentration (Cmu) and the time to achieve Cmu, i.e., Tum, are taken directly
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`from Figs. 7 and 8 of the application. Approximate AUC values were obtained by conventional
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`weighing techniques and Cm,‘ and Tm,‘ by visual curve reading. The term "about” has its usual
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`meaning in the field, e.g_, roughly 1 20%, for example as used by FDA in its deterrninatiorm of
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`bioequivalency. The values from Figs. 7 and 8 are d-amphetamine levels to one of ordinary skill
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`in the art. the mixture of ainphetatnine salts (“MAS" (page 1.6, lines 1546)) used in the examples
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`being the "rnizmire of four atnphetarnine salts” in ADDERALIJE (page 4, lines 15-17) whose
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`relative salt content is known. (See the PDR excerpts of record and the d—amphetarni_ne plasma
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`curves in the prior art, e.g., in Sue et al_ also ofrecord.)
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`Applicants maintain their position as set forth in the response submitted on October 24,
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`2002. The cited prior art does not render obvious any of the previously pending claims or the
`claims being added at this time, for the reasons set forth in the mentioned amendment. Thus,
`there is nothing in the prior art which would motivate a skilled worker to formulate the claimed
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`active ingredients in the manner recited in the claims. See the case law described in the last
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`response. Moreover, the previous claims and the current claims meet all requirements of 35
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`5
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`PHARMA-142 P1
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`Amerigen Ex. 1067, p. 5
`Amerigen Ex. 1067, p. 5
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`U.S.C. 1 12. The patent specification provides plentiful mformaxion whereby a skilled worker
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`could, without undue experimentation, produce formulations which meet the requirements of the
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`claims. e_g_, the plasma levels as defined previously or in the current claims.
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`As for the comments of the E){¢'1l'I1L'1€1' on pages 4-6, the law has long been that
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`functionality at the point of novelty is acceptable. In re Swtneharz, 439 F.2d 2} 0_ J 69 US P Q
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`2.?6 (CCPA 197.’). Even if this doctrine were relevant and even if there were limits to it, these
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`would not apply here, either for the previous claims or the current claims. The public is clearly
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`informed of the limits oflhe claimed subject matter In both cases and of how to carry out the
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`invention as claimed. Moreover, it is not clear to what multiple medication levels the Examiner
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`refers. As is true for any open formulation claims, rnedicamcnts other than those specifically
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`recued are included_ However, the statute merely requires that the in vcntion as recited in the
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`claims be disclosed, not every possible variation which might be included. The Examiner also
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`raises the issue of unexpected results. Apglicants have not previously or now chosen to rely on
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`any unexpected results.
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`The Commissioner is hereby authorized to charge any fees associated with this response
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`or credit any overpayment to Deposit Account No. 13-3402.
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`Respectfully submitted,
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`eaney, Reg. No. 32,542
`Anthony J. Zelano, Reg. No. 27,969
`Attorncyffirgent for AppIicant(s)
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`MILLEN, WPIITE, ZELANO
`«'1: BRANIGAN, PL‘.
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`Arlington Courthouse Plaza 1, Suite 1400
`2200 Clarendon Boulevard
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`Arlington, Virginia 22201
`Telephone: (703) 243-6333
`Facsimile: (703) 243-6410
`Attorney Docket No.; Pl-iAR.M.A-142 PI
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`Date: April 21, 2003
`K'\Pnan1-n\l42\pl map;
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`6
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`PHARMA4 42 P 1
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`Amerigen Ex. 1067, p. 6
`Amerigen Ex. 1067, p. 6