#P(D
`3laf2 400,1005
`UNITED STATES PATENT & TRADEMARK OFTICE
`x = aw
`fa & m
`Applicationof:
`Xiu Xin Cheng,et al.
`7
`o
`ga
`Serial No.:
`09/705,630
`ma
`Sf
`fe
`3 oh ,
`Filed:
`November3, 2000
`For:
`Controljed Release Metformin Compostistns
`
`a=
`
`Examiner: T, Ware
`
`Art Unit: 1615
`
`
`
`Assistant Commissioner for Patents
`Washington, D.C. 20231
`
`February 24, 2003
`
`AMENDMENT UNDER37 CPR, § 1.111
`
`a
`
`sir
`
`{n response to the Office Action mailed on October 22, 2002, Applicants respectfully
`
`reconsicleration ofthe application in view ofthe following amendments and remarks.
`
`IN THE CLAIMS
`
`Please cancel claims 2-3, 6, 28, and 31-42 without prejudice.
`
`Please amend the claims as follows:
` aee
`
`1.
`
`(Amended) A controlled release oral dosage form for the reduction of serum glucose
`
`levels in jwmanpatients with NIDDM, comprising an effective dose of metformin or a
`
`pharmaceutically acceptable salt (aereof and a controlled-release carrier to control the release of
`
`said metformin or pharmaceutically acceptable sult thereof from said dosage form, said dosage
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`form being suilable for providing once-a-day oral administration of the metformin or
`pharmaceutically acceptable salt thereof,wherein following oral administration of a single dose,
`
`the cosape form prevides a mean time to maximum plasma concentration (Tmax) of the
`
`metformin from 5.5 to 7.hours after administration following dinner.
`
`St _ensere
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`_
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`AUROBINDO EX1010, 1
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`AUROBINDO EX1010, 1
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`

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`300.1005
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`= i, /Amiended) The controlled release oral dosage form of claim 1, which provides a mean time ta
`‘maxiniem plasmaconcentration (Tynax) of metformin at from 6.0 to 7.0 hours afterthe
`administration ofthe dose.
`
`L-Ot
`
`A(Amended) The controlled release oral dosage form ofclaim i, which provides a mean time to
`maximum plasma concentration (T-na,) of metforminat from 5.5 to 7.0 hoursafter the
`administration of the dose.
`
` if 7¢(Amended) The controlled release oral dosage form of claim 1, which exhibits the following
`.
`Ydiesolulton profiles when tested in a USP type 2 apparatus at 75 rpm in 900 miofsimulated
`intestinal fluid (pH 7 3 phosphate buffer) and at 37 C:
`-30%of the metfonnin or salt thereofis released after 2 hours;
`{0-45% ofthe metformin or salt thereofis released after 4 hours;
`30-90%of metformin or salt thereofis released after 8 hours;
`nol less than 50%of the metforminor salt thereof is released after 12 hours;
`
`VC}
`() ?
`.
`
`not less than 60%of the metforminorsalt thereof is released after 16 hours; and
`nol less than 70% of the metformin or salt (hereof is released after 20 hours.
`
`A>Amended) The controlled release oral dosage form ofclaim 1, which exhibits the
`following dissolution profiles when tested in a USP type 2 apparatus al 75 rpm in 900 ml
`of simulated intestinal fluid (pH! 7.5 phosphate buffer) and at 37 C:
`0-25% of the metformin orsalt thereof is released afler 2 hours;
`
`20-40% of the metformin or salt thereof is released after 4 hours;
`
`45-90% of the metforminor salt thereof is released after 8 hours;
`
`not less than 60% of the metformin orsalt thereof is released after 12 hours;
`
`not less than 70% of the metformin or salt thereofis released after 16 hours; and
`notless than 80% ofthe metformin orsalt thereof is released after 20 hours.
`
`b/s (Anended) The controlled release oral dosage form ofclaim 1, which provides a width at SO%
`"oF the height of a mean plasma concentration/ime curveof the metformin from about 4.5 to
`about 13 hours.
`
`
`AUROBINDO EX1010, 2
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`AUROBINDO EX1010, 2
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`

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`300.1005
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`(Amended) The controlledrelease oral dosage form of claim 1, which provides a widthat
`a AS
`f
`“somofthe height of a mean plasmaconcentration/time curve of the metformin from about 5.5 lo
`about 10 hours.
`
`(1)ve
`cons a,
`
`=
`
`(Amended)Thecontrolled releaseoral dosage form ofclaim |, whichprovides a
`
`.
`1
`.
`1
`“
`ean Niaximum plasma coricentration (Cmax) of metformin which is more than about 7 times the
`
`_ meanplasma level of said metformn at about 24 hours afler the administration.
`
`Tie (Amended) The controlled release oral dosage form of claim |, which provides a
`o
`‘
`.
`mean maximumplasina concentration (Ciux) of metformin which is from about 7 times to about
`14 limes the plasma level of said metfonnin at about 24 hours after administration.
`
`SOX (Amended) The controlledrelease oral dosage form of claim 1 which provides a mean
`“maximumplasma concentration (Cm) of metformin whichis from about 8 times to about 12
`
`limes the plasma level of said metformin at about 24 hours after administration.
`
`A }a (Amended) The controlled release oral dosage form ofclaim 1 which provides a mean
`‘maxinum plasma concentration (Cmax) of metformin from about 1500 ng/ml to about 3000
`ng/ml, based on administrasion of a 2000 mg once-a-day dose of metformin.
`
`(Amended) The controlled release oral dosage form ofclaim 1, which provides a
`LS s/
`frean maximumplasma concentration (Ciax) ofmetformin from about 1700 ng/mlto about 2000
`ng/ml, based on administration of a. 2000 mg once-a-day dose of metfonnin.
`
`/ch\gr (Amenced) The controlled release oral dosage form ofclaim 1 which provides a mean
`
`‘Avcans ofat least 80%ofthe mean AUCp.24 provided by administration ofan immediate
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`release relerence standard twice a day, wherein the daily dose of the reference standardis
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`‘hstantially equal to the once-a-dey dose of metformin administered in the controiled release
`
`sage form.
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`AUROBINDO EX1010, 3
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`AUROBINDO EX1010, 3
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`

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`300.1005
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`'t
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`(Amended) The con:rolled release oral dosage form ofclaim 1 whichprovides a meaa
`hy *
`“s UCp.2an of at least 90% of the mean AUCy.2g provided by administration of an immediate
`release reference standard twice a day, wherein the daily dose of the reference standardis
`substantially equal to the once-a-day dose of metformin administered in the controlled release
`
`te
`
`‘),H, _ oral dosage form.
`[ry .
`Us
`: \Sur
`(Amended) The controlled release oral dosage form ofclaim 1 which provitles a mean
`* AUCo-rqy from about 17200 ng. hr/ml to about 33900 ng.hr/ml, based on administration-of a 2000
`mg onee-a-day dose of metformin,
`
`low (Amended) The controlled release ora! dosage form ofclaim | which provides a mean
`“AUCo20nr trom about 17200 ng.hr/ml (a about 26500 ng.hr/ml, based on administration of a 2000
`
`mg once-a-day dose of metformin.
`
`lip (Amended) The controlled release oral dosage form ofclaim 1 which provides a mean
`“Al JCo.2nw from about] 9800 ng. hr/ni] 10 about 33900 ng.hr/ml, based on administration of a 2000
`mg once-a-day dose of metformin. |
`
`12x (Amended) The controlledrelease oral dosage form of claim | which provides a mean
`“ AUC... of 18277 4 2961 ngvhr/ml and a mean Ca, of 1929 + 333 ng/ml, for administration of a
`1700 mg once-a-day dose of metformin after an evening meal.
`
`fAmended) The controlled release oral dosage form of claim 1 which provides a mean
`KP o
`“AUCo.. Of 20335 + 4360 nghréAnit ind a mean Cy, of from 2053 + 447 ng/ml, for
`
`administration of a 2000 mg once-a-duy dose of metformin after an evening meal.
`
`[Amended) The controlled release oral dosage form ofclaim 1 which provides a mean
`BO2.
`“"AUCy.24 of 26818 + 7052 ngvhr/ml and a mean Cray of 2849 + 797 ng/ml, for
`administration of a 2000 mg once-a-day dose of metformin after an evening meal.
`
`AUROBINDO EX1010, 4
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`AUROBINDO EX1010, 4
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`

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`300.1605
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`Nae (Amended) The con-rolled release oral dosage form ofclaim 1 whichprovides a mean
`AUCo..4 Of 22590 + 3626 ngrhr/ml and a mean Crux of 2435 + 630 ng/mlon the first day of
`a
`administration and amean AUCo.24 of24136 + 7996 ng‘hr/ml and a mean Cyox of2288 4 736
`()
`conhe ny/ml on the 14™ dayofadministration, for[basedon] administration ofa2000 mgonce-a-day
`dose of metformin after an evening meal,
`a
`Ay?
`JA.
`(Amended) The controlled release oral dosage form of clainy2T whichprovides a mean
`
`# tq from2.8 to 4.4,
`ee
`
`
`
`aee
`‘AS Bx(Amended)Thecontrolled releaseoral dosage form ofclaim %whichprovidesa mean
`f
`\
`# iene to maximum plasma concentration (Tmax) of metformin from 5,5 to 7.0 hours alter
`
`|
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`administration.
`
`———————ee)
`————
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`‘pharmaceutically acceptable salt thereof is provided by at least one controlled-release tablet, said
`
`28pry tAmended) Thecontrolled release dosage form ofclaim 1, wherein the metformin or
`Q0
`tablet comprising:
`
`(a)
`
`acore comprising:
`
`(i)
`
`(ii)
`
`(ii)
`
`the metformin or a pharrnaceutically acceptable salt;
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`optionally a binding agent; and
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`optionally aa absomtion enhancer,
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`(b)
`
`(c}
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`a membrane coating surrounding the core; and
`
`at least one passagewayin the membrane.
`
`REMARKS
`Reconsideration ofthe present application is respectfully sequcated. An early and
`favorutle action on the merits is earnestly solicited,
`
`1.
`
`Status of theClairns
`
`Claims t, 4-, 7-30 are pending; claims 2-3, 6, and 31-42 have been cancelled without
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`prejudice; and claims 1 and 4-5, 7-25, 27 and 29 have been amended without prejudice.
`
`It is
`
`respectfully submitted that no new multer has been added by virtue of this amendment.
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`AUROBINDO EX1010, 5
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`AUROBINDO EX1010, 5
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`

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`
`
`300, 1005
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`I,
`
`
`Rejections Under 35 U.S.C, § 112, First Paragraph
`In the Office Action, claims 1-30 were rejected under 35 U.S.C. § 112, first paragraph as
`conaining subject matter which was not described in the specification in such a way as to enable
`one skilled in the art to whichit pertains, or with whichit is most nearly connected, to make
`and/oruse the invention. The Examinerstates that “{t]he instant specification fails to provide
`
`informationthat wouldallow the skilled artisan to practice the instant invention without undue
`
`experimentation.” The Examinerdirects the Applicants attention to In re Wands, 8 USPQ2d
`
`1400, 1404 (Fed. Cir. 1988)andthe eight factors discussed therein when assessing if’ a disclosure
`
`would have required undue experimentation.
`
`The Examinernotes that “these examples are neither exhaustive, nor define the class of
`
`compoundrequired,”and that “(t]he pharmaceuticalart is unpredictable, requiring each
`embodiment to be individually assessed for physiological activily.” The Examiner further states
`thal “the instant claims read on all antihyperglycemic drug compositions where the maximum
`
`plasmaconcentration accurs from 5,5-7.5 hours after administration, necessitating an exhaustive
`
`search for the embodiments suilable to practice the claimed invention.”
`
`In response andin order to advance the prosecution of the present application, claim 1
`
`has been urnended without prejudice to recite “metformin” in place of “antihyperglycemic drug.”
`
`As mentioned above, the claims of the present application are clearly enabled for metformin or a
`
`pharmaceutically acceptab‘e sali thereof, and as amended, the present claims do not “read onall
`
`antihyperglyceniic carapositions”.
`
`{n any event, Applicants are nol. required to exemplify every formulation which would be
`encompassed by the claim and it would be tremendously costly, inefficient and perhaps unethical
`to require manufacturing and testing of alternative formulations as apparently deemed necessary
`
`by the Examiner in the last Office Action. At the time the present application wasfiled, there
`
`were numerous controlled release zechnologies in the art, and testing for drug-plasma levels is
`routine in clinical studies.
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`AUROBINDO EX1010,6
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`AUROBINDO EX1010, 6
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`

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`300.1005
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`Therefore,it is respectfully submitted that once the Twax range which provides for a
`useful dosage form has been established, other controlled release technologies knownin the art
`can he manipulated and testedto achicve this Tix range without undue experimentation as
`discussed below.
`
`
`A, The Test for Enablement
`
`L: is well recognized that “[the test of enablementis whether one reasonablyskilled in
`the art could make or use the invention {rom the disclosures in the patent coupled with
`
`information known in the art withort undue experimentation.” United States v, Telectranics,
`Ine, 8 USPQ2d 1217, 1223 (Fed. Cir. 1988), cert. denied, 490 U.S. 8 USPQ2d at 1046 (1989).
`“The determination of what constitutes undue experimentation in a given case requires the
`application of a standard of reasonableness, having due regard for the nature ofthe invention and
`the state of the art.” Jn re Wands, 8 USPQ2d at 1404 (citations omitted). Thetest is notmerely
`
`since a considerableamount of experimentation is permissible, ifit is merely
`quinutative
`
`mt of guidance withrespect
`a reasonable
`routine, or if the specificationin questionprovides
`othedirectioninwhichtheexperimentation should proceed.” Jd. (Emphasis added), The very
`nature of pharmaceuticals requires oth formulation work and clinical (in-vivo) evaluation, and
`
`therefore giving due regard for the aature of the invention, the amountof experimentation
`needed to prepare a suitable contro‘led release formulation using a technology otherthan that
`
`exempl|:fied in the specification docs not amount to undue experimentation.
`
`B. Dosage Forms and Plasma Profile of the Present Invention
`
`In the Office Action the Examinerstates that “Applicant fails to set forth the criteria that
`defines the dosage formorsteps in the production of the composition that results in the dosage
`
`fonn having the instant claimed plasma profile,” and that “Applicantfails to provide information
`allowing the skilled artisan to ascertain the plasma profile without undue experimentation.”
`
`Theinventionas claimed is directed to a controlled release oral dosage form for the
`
`reduction of serum glucoselevels in human patients with NIDDM wherein a maximum plasma
`
`7
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`<j
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`AUROBINDO EX1010, 7
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`AUROBINDO EX1010, 7
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`

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`300.1005
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`concentration is obtainei at 5.5 lo 7.5 hours after administration, irrespective of the particular
`technulogy employed in the controllec release dosage form. Certain representative examples of
`these formulations are provided in the present application, and it is explained in the specification
`thal a nutnber ofcontrolled release technologies are useful in orderto obtain the claimed
`~yharmacokinetic parameters of the present invention.
`
`Examples 1-3 of the present application whichare <lirected to a tablet formulation
`containing metformin HCl, a seal coating, and a sustained release coating. Example 3 of the
`present application described clinical studies which were conducted to evaluate formulations
`prepared in accordance with Examples 1-3, which together with the specification enable the
`claimed the controlled releas2 oral dosage forms of metformin or a pharmaceutically salt thereof
`which provide the Tma. values ofthe present invention.
`‘The Examiner’s attention is respectfully
`directed to page 19, line 21 to page 20, line 14 which slates the following:
`
`Other controlled release technologies known to those skilled in the
`art can be used in order to achieve the controlled release formulations of the present
`inverttion, ie,, formulations which provide a mean Tyyax of the drug and/or other
`pharmacokinetic: parameters described herein when orally administered to human
`patients, Such formulations can be manufactured as a controlled ora! formulation ina
`suitable tablet or multiparticulate formulation knownto those skilled in the art... .
`
`\/
`
`ln addition, at Ihe tirne the application was filed, numerous controlled release
`technologies were well within the knowledge of pharmaceutical formulators having ordinary
`
`skill in the art. Such pharmaceutical [ormulators know that controlled release technologies can
`be manipulated, e.g., by varying the amount of controlled release carrier (among other things), to
`provide a formulation which upon in-vivo testing will provide the T,uz range of the present
`invention. This fact is supported, e.g., by a simple review of patents discussed in the
`
`specification concerning formulation technologies, whichpatents provide ranges of ingredients.
`Viiese: ranges represent the acknowledgement ofthose skilled in the art that a certain amount of
`experimentation is considered to be necessary to manipulate a controlled release technologyto
`obtain a desired release patlem of the drug. Such release patterns are demonstrated by the (well-
`
`known)use of in-vitro dissolution testing, which is considered by pharmaceutical formulators of
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`2
`
`a
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`AUROBINDO E1010, 8
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`AUROBINDO EX1010, 8
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`300.1005
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`ordinaryskill in the art to provide guidance as to which particular formulations might provide the
`
`desired in-vivo performance.
`
`‘Next, it is well knownto those of ordinary skill in the art that upon formulating
`prospective products which might be useful in humans, in-vivo clinical studies must he
`conducled to determine whether Lhe prospective product actually provides the desired in-vivo
`performance. Plasmaprofiles are routinely obtained during clinical trials and in particular during
`
`phase J-Ill studies as indicated in J.T. Cartensen, Pharmaceutical Principles of SolidDosage
`
`Forms, 1993 (attached herewith).
`
`It is respectfully submitted that none of the above steps, either separately or collectively,
`
`rise to the level of undue experimeatation. Once the goal has been identified and has been
`atlained(as in the present exemplitied formulationsset forth in the specification),it is
`respectfully submitted that a pharmaceutical formulatorof ordinary skill in the art can
`manufacture prospective dosage forms for evaluation (to determine if they meet the required in-
`vivo parameters), a clinician of ordinary skill in the art can administer the dosage forms and
`
`draw blood at appropriate time intervals, and a pharmacokineticist of ordinary skifl in the art can
`
`evaluate the in-vivo blood plasma results.
`
`‘These steps represent a clear pattern followed by every pharmaceutical company in the
`
`world, There is no altemative short-cut known which is considered to be acceptable by
`
`government regulatory agencies (such as FDA). Since humanexperiments with pharmaceuticals
`
`are generally considered unethical if being done solely for patent purposes, the Examiner appears
`
`to be requiring this Applicant to canduct studies that are unethical, unnecessary and not Jegally
`
`required to support the rightful sccpe af Applicant’s claims. Accordingly, it is earnestly
`
`requested thai the Examiner removethis basis for rejection,
`
`The Examineris reminded that Applicants are not required to exemplify every
`formulation which would be encompassed by the claim. See, e.g., In re Fisher, 427 F.2d 833,
`839, 166 USPQ 18, 34 (CCPA 1970); MPEP 2164.01(b) (8™ Bdition) (“As longas the
`specification discloses at least one method for making and using the claimed invention that bears
`9
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`AUROBINDO EX1010, 9
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`AUROBINDO EX1010, 9
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`

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`300.1005
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`a reasonable correlation to the entire scope of the claim, then the enablement requirement of 35
`
`U.S.C, 112 is satisfied.”),
`
`In Telectronics, for example, the court found that “[s]ince one embodimentis admittedly
`
`disclosed in the specification, along: with the general manner in whichits current range was
`
`ascertuined, we are convinced that other permutations of the invention could be practiced by
`
`those skilled in the art without undue experimentation.” Telectronics, 8 USPQ2d at 1223 (citing
`
`SRI Int'l vy. Matsushita Elec. Corp. ofAmerica, 775 F.2d 1107, 1121, 227 USPQ 577, 586 (FecL
`
`Cir, 1985) (the law does not requirean applicant to describe in his specification every
`
`conceivable embodiment of the invention)).
`
`Therefore, it is respectfully subinitted that by virtue of the present application Applicants
`
`have disclosed a Tax range which srovides for a useful dosage form of metformin or
`
`pharmaceutically acceptable salt thercof, and other conlrofled release technologies known in the
`
`arl can be manipulated by one of ordinary skill in the art to achieve this Tmax range without
`
`undue experimentation,
`
`C. U.S. Patent No. 6,099,459
`
`In the rejection, the Examiner states that “[iJn the instant case, the provided examplesset
`forth dosaye forms made according to a process where the dosage forms have the same
`
`composition as those of U.S. 6,099,859 (‘859),” However, the Examiner notes that “ ‘859
`
`discloses that the pesk plasmaprofile is approximately 8-12 hours after administration, whereas
`the instant specificalion/claimsstate (hat the dosage forms, which appear to have the same
`composition and process of making as ‘859, have a peak plasmaprofile of $.5-7,5 hours.”
`
`(1) The specification of ‘859 states in a preferred embodiment, that peak plasma levels
`
`are obtained between 8-12 hours after administration (See column 2, lines 50-55),
`
`(2) In actuality however, the exemplified formulations did not provide a Tyuax between 8-
`
`)2 hours except when the formulation prepared in accordance with Example 3 was administered
`
`at dinner. As set forth in an Information Disclosure Statement which will subsequently be hand
`10
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`0
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`AUROBINDO EX1010, 10
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`AUROBINDO EX1010, 10
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`

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`300.1005
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`delivered to the Examiner, the mean T may Values for the Examples of the ‘859 were as follows:
`
`Exaniple 1 (fasting) 4.67 hours; Example 2 (fasting) 4.33 hours; Example 2 (fed a.m.) 6.80
`
`hours; Example 3 (fed a.m.) 6.67 hours; Example 3 (Fed p.m.) 9.67 hours. Therefore, the only
`
`instance was Example 3 fed in the P.M. (at dinner).
`
`The claims have now been amended to state the “Ty, of metformin at from 5.5 to 7.5
`
`hours after single dose administration following dinner.” The claims as now written are directed
`
`to methods and treatments which were never accomplished in the Examples of the ‘859 patent.
`
`Withrespect to the Examiner's position that the provided examples ofthe present
`
`application set forth dosage forms made according to a process where the dosage forms have the
`
`same caimposition as those of U.S. 6,099,359 (‘859), the Examiner's attention is respectfully
`
`directed to the fact that the formulations exemplified and tested in the present application are
`
`indeed «different as the formulations of the Examplesof the present application differ from those
`of the* 859 by havingtwo las.er¢drilled holes,and the methodachieved adifferent resultthanthat-.
`reportediin the ‘859 or achievedby clinicaltesting ofExamples 13, However, it is respectfully
`subinitted that one skilled in the art would be able to manipulate the processes and formulations
`
`of (he ‘859 by other methodsto obtain the claimed pharmacokinetic parameters of the present
`
`invention byroutine experimentation.
`
`Therefore, in view of the aforementioned, it is respectfully submitted that the
`formulations of the present invention are different than (hose of the ‘859 patent.
`
`D. Conclusion
`
`Ia the specification, Applicants have provided formulations, methods of making the
`
`formulations, and clinical studies of these formulations, that support the limitations (¢.g., Tax
`
`values} reciled in the present claims. Furthér, the prior art is replete with controlled release
`
`lechnology and, as stated in the present application, a number of controlled release technologies
`
`cur be used to manufacture formulations which providethe results recited in the present claims
`
`without undue experimentation, Therefore, the Examiner is respectfully requested to remove ihe
`
`35 U.S.C. 8112 rejection of the pending claims.
`
`1]
`
`Oh
`|
`%
`a AUROBINDO Extoro, 11
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`AUROBINDO EX1010, 11
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`

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`300.1005
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`Il,
`
`
`Rejections Under 35 U.S.C. § 112, Second Paragraph
`
`Claims 21-30 were rejected under 35 U.S.C. §112, second paragraph, on the grounds of
`indefiniteness,
`
`Specifically, the Examinerstates (hat “[c]laims 26-30 recite the limitation where the drug
`is metformin,”and “{t|here is insufficient antecedent basis for this limitation in the claim (the
`claims from which these depend do not have metformin in the compositions).”
`
`‘n response, claim | has been amended without prejudice to recite metforminora
`pharmaceutically acceptable salt thereo!. Therefore, there is now antecedentbasis for this (erm
`in clajirg 26-30,
`
`The Examinerfurther states thal “{rJecitation of ‘based on’ in claims 21-25 is indefinite
`
`sinceit is unclear whether Applicantis claiming that the dose of administration for metformin is
`
`*X’ mg after an evening meal or whether another dose of metformin provides these limitations.
`In the event the AUCo.infinity for a particular dose of metformin is claimed, amendment with‘for
`administration’ is suggested to overcome the instantrejection.”
`
`In response, claims 21-24 have been amended without prejudice to recite the term ‘‘for”
`
`administration rather than “based on” administration, as suggested by the Examiner.
`
`In view of the actions taker, the Examineris respectfully requested to removethe
`rejection of claims 21-30 under 33 U.S.C, §112, second paragraph.
`
`IV,
`
`Rejections Under 35 U.S.C. § 102
`
`Claims 31-42 were rejected under 35 U.S.C, 102(b) “as being anticipated hy Cheng et al
`
`(WO 99/47125; hereafter ‘125)”, The Examinerstates that ‘“125 discloses controlled release
`
`artihyperglycemic dosage form that has the same composition taught by the specification as
`
`providing the instant mean fluctuation indexes.”
`
`12
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`AUROBINDO EX1010, 12
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`AUROBINDO EX1010, 12
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`

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`400.1005
`
`{t. view of the present amendment, claims 31-42 of the present application have been
`canceled without prejudice rendering the Examiner’srejection moot. Therefore,the Examineris
`respectlully requested to withdraw the rejection of claims 31-42 under 35 U.S.C. §102(b) for the
`ahove-reterenced application.
`
`Vv.
`
`Conclusion
`
`Attached hereio is a marked-up version of the changes madeto the claims by the current
`amendment, The attached pages are captioned “Version With Markings To Show Changes
`
`Made.”
`
`it js now believed that the above-referenced rejections and objections have beenobviated
`andit is respectfully requested-that the rejections and objections be withdrawn.
`It is believed
`that all claims are nowin condition for allowance.
`
`According to currently recommended Patent Office policy the Examineris requested to
`contact the undersigned in the event that a telephonic interview will advancethe prosecution of
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`this application.
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`Anearly and favorable ac:ionis earnestly solicited,
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`Respectfully submitted,
`DAVIDSON, DAVIDSON & KAPPEL, LLC
`
`
`
`eg. No. 32,728
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`Davidson, Davidson & Kappel, LLC
`485 Seventh Avenue, 14th Floor
`NewYork, New York 10018
`(212) 736-1940
`
`ae
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`AUROBINDO EX1010, 13
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`AUROBINDO EX1010, 13
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`300.1005
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`Version With Markings To Show Changes Made
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`Claims ?-3,6, 28, and 31-42 have been cancelled without prejudice.
`The claims have been amended as follows:
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`(Amended) A controlled release oral dosage form for the reduction of serum glucose
`“2.
`levels in human patients with NIDOIM, comprising an effective dose of [at least one suitable
`
`antihyperglycemic drug] metformin or a pharmaceutically acceptable salt thereof anda
`controlled-release carrier to control the rclease of said metformin or pharmaceutically
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`acveptuble salt thereof from suid dosage form, said dosage form being suitable for providing
`once-a-clay oral administration ofthe [ageut] metformin or pharmaceutically acceptable salt
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`thereol, wherein following oral administration of a single dose, the dosage form provides a
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`mean lime 1o maximum plasma concentration (Tyux) of the [agent] metformin from 5.5 to 7.5
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`hours after [the] administration following dinner.
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`4. (Amended) The controlled release oral dosage form of claim 1, which provides a meantime to
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`maximumplasma concentration (Twas) of [the drug] metformin at from 6.0 to 7.0 hoursafter
`the administration ofthe dose.
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`5, (Amended) The controlled release oral dosage form ofclaim 1, which provides a mean time to
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`Inaxinuim plasma concentration (Tmax) of [the drug) metformin at from 5.5 to 7.0 hours after
`the administration ofthe dose{, when the dose is administered at dinner time].
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`ti. (Amended) The controlled release oral dosage form of claim 1, which provides a mean time to
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`inaximum plasma concentration (Tmax) of [the drug] metformin at from about 6.0 to 7.5 hours
`after the administration of the dose, when the dose is administered at breakfast.
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`;wi
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`AUROBINDO EX1010, 14
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`AUROBINDO EX1010, 14
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`300.1005
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`7, (Amended) The controlledrelease: oral dosage form of claim 1, which exhibits the following
`dissolution profiles when tested in a USP type 2 apparatus at 75 rpm in 900 mlof simulated
`intestinal fluid (pHT 7.4 phosphate buffer) and at 37 C:
`0-30% ofthe [drug] metforminor salt thereofis released after 2 hours,
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`10-45%of the [drug] metformin or salt thereofis released after 4 hours;
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`30-90% of [drug] metformin orsalt thereof is released after 8 hours;
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`not less than 50% ofthe {drug} metforminor salt thereof is released after 12
`hours;
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`not less than 60% ofthe (drug| metformin or salt thereofis released after 16
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`hours; and
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`not less than 70%ofthe [drug] metformin or salt thereofis released after 20
`hours,
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`8. (Amended) The controlled release oral dosage form of claim 1, which exhibits the
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`following dissolution profiles whentested in a USP type 2 apparatus at 75 rpmin 900 ml
`of simulated intestinal uid (pH 7.£ phosphate buffer) and at 37 C:
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`(}-28%of the [drug] metformin orsalt thereof is released after 2 hours;
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`20-40% of the [drug] metformin or salt thereof is released afler 4 hours;
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`45-90% of the [druz] metformin or salt thereof is released after 8 hours;
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`not Jess than 60% of the [drug| metformin or salt thereof is released after 12
`‘ours;
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`nol less than 70% of the [drug] metformin or salt thereof is released after 16
`hours; and
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`not less than 80%of the [drug] metformin or salt thereof is released after 20
`hours.
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`9, (Arnended) The controlled release oral dosage form of claim 1, which provides a width at 50%
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`of the height of a mean plasma concentration/time curve ofthe [drug] metformin from about
`4.5 to about 13 hours.
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`10, (Arnended) The controjled release oral dosage formof claim 1, which provides a width at
`1$
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`
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`__AUROBINDO EX1010, 15
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`AUROBINDO EX1010, 15
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`300.1005
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`$0%ofthe height of a mean plasma concentratiorvtime curve of the [drag] metformin from
`about 5,4 to about 10 hours.
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`{1. (Amended) The controlled retease oral dosage form of claim [3] 1, which provides a mean
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`maximunplasma concentration (Cyax) of metformin which is more than about 7 times the mean
`plasmalevel of said metformin at about 24 hours after the administration.
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`12, (Amended) The controlled release oral dosage form of claim [3] 1, which provides a mean
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`maximumplasma concentration (C,,,) of metformin which is from about 7 times to about 14
`
`times the plasma level of said metformin at about 24 hours after administration.
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`13. (Amended) The controlled release oral dosage form of claim [3] 1 which provides 4 niean
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`maximum plasma concentration (Cyux) of metformin which is from about 8 times to about 12
`
`limes the plasma level of said metforminat about 24 hours afler administration.
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`14. (Amended) The controlled relezse oral dosage form of claim [3] 1 which provides a mean
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`maximum plasma concentration (Cyax) of metformin from about 1500 ng/ml to about 3000
`
`ng/ml, based on administration of a 2000 mg once-a-day dose of metformin.
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`15. (Amended) The controlled release oral dosage form of claim [3] 1, which provides a mean
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`maximum plasma concentration (Caax) of metformin from about 1700 ng/ml to about 2000
`ng/ml, based on administration of a 2000 mg once-a-day dose of metformin.
`
`16. (Amended) The controlled release oral dosage form of claim [3] 1 which provides a mean
`AUCo-2anr Of at least 80% of the mean AUCo.24 provided by administration of an immediate
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`release reference standard twice a day, wherein the daily doseof the reference standard is
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`substantially equal to the once-a-dey dose of metformin administered in the controlled release
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`oral dosage form,
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`17. (Amended) The controlled release oral dosage fonnof claim [3] 1 which provides a mean
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`16
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`_
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`AUROBINDO EX1010, 16
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`AUROBINDO EX1010, 16
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`300.1005
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`AUCo.24ir of at least 90% of the mean AUCp.24 provided by administration of an immediate
`release reference standard twice a day, wherein the daily dose of the reference standard is
`substantially equal to the once-a-day dose of metformin administered in the controlled release
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`oral dosage form.
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`18. (Amended) The controlled release oral dosage form of claim [3] ] which provides a mean
`AUCo-24n- from about 17200ng.hr/ral to about 33900 ng.hr/ml, based on administration of a 2006
`
`ing once-a-day dose of metformin.
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`(9, (Amended) The controlled releese oral dosage form of claim [3] 1 which provides a mean
`AUCo.2xn from about 17200 ng.hr/ml to about 26500 ng.hr/ml, based on administration of a 2000
`
`mg, once-a-day dose cf mettormin.
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`20. (Amended) The controlled release oral dosage form of claim [3] 1 which provides a mean
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`AUCo-.nr from about]9800 ng. hr/mi lo about 33900 ng.hr/ml, based on administration of a 2000
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`mgonce-a-day dose of metformin.
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`21, (Amended) The controlled release oral dosage form of claim {3} 1 which provides a mean
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`AUCo.« of 18277 4: 296] ng