IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`Applicants: Brian Ault, et al.
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`Application No: 12/553,107
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`Filed: September 3, 2009
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`Attorney Docket No: 103526-US
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`Examiner: Gina Chieun Yu Justice
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`Confirmation No. 5949
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`Art Unit: 1617
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`Title: Method for Delivering a Pharmaceutical Composition to Patient in Need Thereof
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`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
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`January 30, 2013
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`AMENDMENT C AND RESPONSE TO FINAL OFFICE ACTION
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`This amendment is being filed with an RCE in response to the July 30, 2012 final
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`Office action in the above-referenced patent application.
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`Claim amendments begin on page 2.
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`Remarks begin on page 5.
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`Page 1
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`MYLAN PHARMS. INC. EXHIBIT 1013 PAGE 1
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`

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`Amendment C and Response to Final Office Action
`Appl. No. 12/553,107
`January 30, 2013
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`Claim Amendments
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`Please amend the claims as follows:
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`Claims 1-18 (cancelled).
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`19. (previously presented) A method for treating osteoarthritis, rheumatoid arthritis,
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`or ankylosing spondylitis comprising orally administering to a patient in need thereof an AM
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`unit dose form and, 10 hours (±20%) later, a PM unit dose form, wherein:
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`the AM and PM unit dose forms each comprises:
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`naproxen, or a pharmaceutically acceptable salt thereof, in an
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`amount to provide 500 mg of naproxen, and
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`esomeprazole, or a pharmaceutically acceptable salt thereof, in an
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`amount to provide 20 mg of esomeprazole;
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`said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said
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`AM and PM unit dose forms at a pH of 0 or greater,
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`the AM and PM unit dose forms target:
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`i) a pharmacokinetic (pk) profile for naproxen where:
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`a)
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`for the AM dose ofnaproxen, the mean Cmax is 86.2 µg/mL (±20%)
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`and the median Tmax is 3.0 hours (±20%); and
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`b)
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`for the PM dose ofnaproxen, the mean Cmax is 76.8 µg/mL (±20%)
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`and the median Tmax is 10 hours (±20%); and
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`ii) a pharmacokinetic (pk) profile for esomeprazole where:
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`a)
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`for the AM dose of esomeprazole, the mean area under the plasma
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`concentration-time curve from when the AM dose is administered
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`to 10 hours (±20%) after the AM dose is administered (AUCo-10,am)
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`is 1216 hr*µg/mL (±20%),
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`b)
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`for the PM dose of esomeprazole, the mean area under the plasma
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`concentration-time curve from when the PM dose is administered
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`to 14 hours (±20%) after the PM dose is administered (AUC0_14,pm)
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`is 919 hr* µg/mL ( ±20% ), and
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`c)
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`the total mean area under the plasma concentration-time curve for
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`esomeprazole from when the AM dose is administered to 24 hours
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`Amendment C and Response to Final Office Action
`Appl. No. 12/553,107
`January 30, 2013
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`(±20%) after the AM dose is administered (AUC0 _24) is 2000
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`hr* µg/mL ( ±20% ); and.
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`the AM and PM unit dose forms further target a mean % time at which intragastric
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`pH remains at about 4.0 or greater for about a 24 hour period after reaching steady state
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`that is at least about 60%.
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`Claims 20-28 (cancelled).
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`29. (previously presented) The method according to claim 19, wherein the mean%
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`time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period after
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`reaching steady state is at least about 71 %.
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`Claims 30-32 (cancelled).
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`33. (previously presented) The method according to claim 19, wherein said AM and
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`PM unit dose forms are administered for a period of at least about 6 days.
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`34. (previously presented) The method according to claim 19, wherein said AM and
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`PM unit dose forms are administered for a period of at least about 9 days.
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`Claims 35-39 (cancelled).
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`40. (currently amended) The method according to claim 19, wherein said AM and
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`PM unit dose forms are each a multilayer tablet comprising at least one core and at least a first
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`layer and a second layer, wherein:
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`i)
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`ii)
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`said core comprises naproxen, or pharmaceutically acceptable salt thereof;
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`said first layer is a coating that at least begins to release the naproxen, or
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`pharmaceutically acceptable salt thereof, when the pH of the surrounding
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`medium is about 3.5 or greater; and
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`iii)
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`said second layer comprises esomeprazole or a pharmaceutically acceptable
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`salt thereof, wherein said esomeprazole or pharmaceutically acceptable salt
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`thereof is released at a pH of from 0 or greater.
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`MYLAN PHARMS. INC. EXHIBIT 1013 PAGE 3
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`Amendment C and Response to Final Office Action
`Appl. No. 12/553,107
`January 30, 2013
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`Claim 41 (cancelled).
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`42. (currently amended) The method according to claim 40, wherein said
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`esomeprazole or pharmaceutically acceptable salt thereof is released at a pH of from 0 to
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`about 2.
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`Claims 43 and 44 (cancelled).
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`45. (previously presented) The method according to claim 40, wherein said multi(cid:173)
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`layer tablet is substantially free of sodium bicarbonate.
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`Claims 46 and 47 (cancelled).
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`Amendment C and Response to Final Office Action
`Appl. No. 12/553,107
`January 30, 2013
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`Remarks/ Arguments
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`Applicants request reconsideration of this application on the merits.
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`I.
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`Claim amendments
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`Claims 19, 29, 33, 34, 40, 42, and 45 are pending. Applicants have amended claims
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`40 and 42 to characterize the recited salt as "pharmaceutically acceptable." This makes
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`claims 40 and 42 more consistent with claim 19, i.e., the claim from which claims 40 and 42
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`ultimately depend.
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`Applicants continue to reserve their right to pursue any subject matter cancelled or
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`otherwise disclosed in this application in or more later-filed continuations and/or divisionals.
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`II.
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`Response to obviousness-type double-patenting rejection
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`Claims 19, 29, 33, 34, 40, 42, and 45 have been rejected as obviousness-type double(cid:173)
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`patenting over claims 1-55 of Plachetka (U.S. Patent No. 6,926,907). Applicants request
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`withdrawal of this rejection.
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`Applicants respectfully submit that claims 19, 29, 33, 34, 40, 42, and 45 are patentably
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`distinct over Plachetka's claims 1-55 for reasons analogous to those discussed below
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`regarding the non-obviousness of claims 19, 29, 33, 34, 40, 42, and 45 over Plachetka
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`generally. On this ground alone, Applicants submit this rejection should be withdrawn on the
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`merits.
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`In addition, Applicants respectfully submit that this rejection is not ripe until at least
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`one of the rejected claims has been found to be otherwise patentable. Accordingly, to the
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`extent this rejection is not withdrawn on the merits, Applicants request that it be held in
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`abeyance until there is at least one claim in this application found to be otherwise allowable.
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`III.
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`Response to rejection under 35 U.S.C. §103(a)
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`Claims 19, 29, 33, 34, 30, 42, and 45 have been rejected as being obvious over
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`Plachetka. Applicants request withdrawal of this rejection.
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`A.
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`Claim 19
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`Applicants respectfully submit that claim 19 represents a non-obvious selection over
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`Plachetka. This selection is characterized by unexpected results. Nothing in Plachetka would
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`have suggested such unexpected results at the time of Applicants' filing.
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`Amendment C and Response to Final Office Action
`Appl. No. 12/553,107
`January 30, 2013
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`Claim 19 recites multiple selections over Plachetka, which include:
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`(1)
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`(2)
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`the use of the specific combination of naproxen and esomeprazole;
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`the specific combined doses of naproxen (i.e., 500 mg/unit dose) and
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`esomeprazole (i.e., 20 mg/unit dose); and
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`(3)
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`the administration of the above combination in an AM unit dose form, and, 10
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`hours (±20%) later, a PM unit dose form.
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`Plachetka fails to teach or suggest any one these specific selections or the combination
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`thereof.
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`The Combination o(Naproxen and Esomeprazole
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`Applicants selected one NSAID, naproxen, from the many possible NSAIDs
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`mentioned in Plachetka. See, e.g., Plachetka, col. 5, line 20 to col. 6, line 67 (naproxen is
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`merely one of 26 specific NSAIDs mentioned). Applicants further selected one acid inhibitor,
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`esomeprazole, from the many acid inhibitors mentioned in Plachetka. These include two
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`general categories (H2 blockers and proton pump inhibitors), and esomeprazole is merely one
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`of the eleven example acid inhibitors Plachetka mentions. See e.g., Plachetka, col. 7, lines 1-
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`18.
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`Although Plachetka does mention both naproxen and esomeprazole, Plachetka places
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`no particular emphasis on the specific combination of the two. Nor does Plachetka describe
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`any formulation or in vitro or in vivo experiments using such a combination. Thus, a skilled
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`artisan, when reading Plachetka, would have had no guidance or motivation to specifically
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`select the combination of naproxen and esomeprazole, when confronted with hundreds of
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`possible combinations Plachetka presents. Nor would the skilled artisan have had any
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`expectation that the combination of naproxen and esomeprazole, as currently recited in claim
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`19, would produce Applicants' unexpected pharmacodynamic profile (see below).
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`500 mg o(Naproxen Combined with 20 mg Esomeprazole per Unit Dose
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`Claim 19 recites a selection of a combination of 500 mg of naproxen with 20 mg of
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`esomeprazole for each unit dose form. Plachetka fails to specifically teach or suggest these
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`doses when these ingredients are used in combination with each other. In fact, Plachetka,
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`while mentioning various dosage ranges for naproxen and esomeprazole, provides that 550
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`mg/unit dose is generally preferred for naproxen and 40 mg/unit dose is generally preferred
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`for esomeprazole. See, e.g., Plachetka, col. 6, lines 6-11 and col. 7, lines 12-13.
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`Amendment C and Response to Final Office Action
`Appl. No. 12/553,107
`January 30, 2013
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`Consequently, a skilled artisan reading Plachetka, even if choosing naproxen and/or
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`esomeprazole, would have had no guidance or motivation to specifically select Applicants'
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`recited combined doses for naproxen and esomeprazole, particularly when confronted with
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`the many choices of doses for the various drugs Plachetka mentions.
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`Administering the Above Combination in
`an AA1 Unit Dose Form and. 10 hours (±20%) Later. a P1~f Unit Dose Form
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`Claim 19 recites administering the combination, 500 mg of naproxen and 20 mg of
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`esomeprazole, in an AM unit dose form and, 10 hours (±20%) later, a PM unit dose form.
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`Plachetka fails to specifically teach or suggest such a treatment regime. Plachetka does
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`discuss twice-daily treatment (see, e.g., Plachetka, Example 9). But nowhere does Plachetka
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`specifically discuss when each of the two doses should be administered, or at what time
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`interval. Thus, a skilled artisan reading Plachetka, even if selecting a twice-daily treatment
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`regime, would not have had any specific guidance or motivation to select Applicants' recited
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`treatment regime.
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`Lack of Prima Facie Case I Presence of Unexpected Results
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`To establish a prima facie case of obviousness, some reason must be identified that
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`would have led a skilled artisan to pursue a claimed species. See Yamanouchi Phann. Co.
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`Ltd. V Danbury Pharmacol., Inc., 231F.3d1339, 1344 (Fed. Cir. 2000) (holding that to
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`establish a prima facie case of obviousness post-KSR, there must be a showing that those of
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`skill in the art would have had motivation to pursue the claimed species); see also Takeda
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`Chem. Indus, v. Alphapharm Pty, Ltd., 492 F.3d 1350, 1356 (Fed. Cir. 2007). Plachetka fails
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`to meet this requirement because it fails to specifically teach or suggest any of the above three
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`selections, much less Applicants' recited combination thereof.
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`Against this backdrop, Applicants further point out that they have unexpectedly
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`discovered and demonstrated that, by practicing the recited method, they can achieve a
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`pharmacodynamic profile in which the mean % of time for which a patient's intragastric pH
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`remains at about 4.0 or greater for about 24 hours after reaching steady state is at least about
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`60%. More specifically, in a 9-day clinical study, they achieved a pharmacodynamic profile
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`in which the mean% time of intragastric pH at above 4.0 over 24 hours was about 71.35%.
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`See, e.g., Specification, page 41, Table 4. By contrast, among the tested formulations in
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`Plachetka , the combination of 40 mg of famotidine with 550 mg of naproxen maintained the
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`intragastric pH at greater than 4.0 for only 49% of the time during the 8-10 hours following
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`Amendment C and Response to Final Office Action
`Appl. No. 12/553,107
`January 30, 2013
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`naproxen sodium dosing. See Plachetka, col. 19, Example 9. Applicants submit that a skilled
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`artisan would readily correlate the extended pH> 4.0 period produced by Applicants' method
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`with desired reduced gastrointestinal risk associated with stomach acid secretion.
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`Plachetka fails to specifically teach or suggest that the beneficial pharmacodynamic
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`profile observed with Applicants' method could be obtained when (1) using esomeprazole
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`with naproxen, (2) using the specific dosages of 20 mg/unit esomeprazole with 550 mg/unit
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`dose naproxen, and (3) following a treatment regimen that comprises a PM dose administered
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`10 hours (±20%) after an AM dose. Thus, a skilled artisan reading Plachetka would not have
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`expected the beneficial results of Applicants' method, specifically the post-administration
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`intragastric pH> 4.0 period discussed above.
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`Inherencv
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`The obviousness rejection appears to be based on a conclusion that Applicants'
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`pharmacokinetic and pharmacodynamics profiles are inherent results of administering the
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`formulation according to Plachetka's teachings twice per day, and, as such, are not evidence
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`of inventiveness. See page 8 of the Office action. Applicants respectfully traverse --- this
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`reliance on inherency is improper.
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`At the outset. while inherency may apply to anticipation determinations, it has only
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`verv limited application in the context of obviousness. And the Courts have often balked at
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`basing an obviousness finding on an unknown inherent property present in the prior art. See
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`Trintec Indus., Inc. v. TOP-US.A. Corp., 295 F.3d 1292, 1296 (Fed. Cir. 2002) ("obviousness
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`is not inherent anticipation"); In re Rijckaert, 9 F.3d 1531, 1534 (Fed. Cir. 1993) ("Such a
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`retrospective view of inherency is not a substitute for some teaching or suggestion supporting
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`an obviousness rejection."). See also, In re Spormann, 363 F.2d 444, 448 (C.C.P.A. 1966)
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`("That which may be inherent is not necessarily known."). This makes sense. After all, the
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`suggestion to combine or modify prior art must occur before an Applicant's date of invention.
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`If an inherent property is unknown at the time, it obviously cannot provide such a suggestion.
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`See, In re Rijckaert, 9 F.3d at 1534.
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`Moreover, the use of inherency in the instant rejection is wholly misplaced because
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`the inherency is being used to characterize the unexpected results of the claimed method.
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`More specifically, the Office action concedes that Plachetka fails to specifically disclose the
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`particular combination of operative elements recited in claim 19. The Office action, however,
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`justifies the obviousness rejection by asserting that the unexpected results of the combination
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`Amendment C and Response to Final Office Action
`Appl. No. 12/553,107
`January 30, 2013
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`are inherent from the combination. Applicants are unaware of any law allowing this type of
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`reasoning. Inherency cannot be used, as it has here, to disregard the unexpected results of a
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`novel combination of operative elements.
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`Simply put, Plachetka fails to specifically teach or suggest the novel selections of
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`Applicants' method. And Plachetka fails to predict the unexpected results of Applicants'
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`claimed method, particularly the above-described percentage of time over which the
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`intragastric pH is maintained at 4.0 or above. Accordingly, Applicants respectfully submit
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`that Plachetka fails to render claim 19 obvious.
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`B.
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`Claims 29, 33, 34, 40, 42, and 45
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`Claims 29, 33, 34, 40, 42, and 45 depend directly or indirectly from claim 19. Thus,
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`they too are necessarily patentable over Plachetka for at least the same reasons as claim 19.
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`*********
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`Applicants request a three-month extension to respond to the July 30, 2012 final
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`Office action, and authorize the Commissioner to charge the corresponding fee to Deposit
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`Account No. 260166. If any other fee(s) is due in connection with this filing, Applicants
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`authorize the Commissioner to charge the fee(s) to Deposit Account No. 260166 (referencing
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`Attorney Docket No. 103526-US). In addition, ifthere is ever any other fee deficiency or
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`overpayment under 3 7 C.F .R. § 1.16 or 1.17 in connection with this patent application, the
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`Commissioner is hereby authorized to charge such deficiency or overpayment to Deposit
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`Account No. 260166 (referencing Attorney Docket No. 103526-US).
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`Applicants submit the pending claims are in condition for allowance, and request this
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`application be allowed. The Examiner is requested to call the Undersigned if any issues arise
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`that can be addressed over the phone to expedite examination.
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`Amendment C and Response to Final Office Action
`Appl. No. 12/553,107
`January 30, 2013
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`Respectfully submitted,
`/David M. Gryte, Reg. No. 41809/
`David M. Gryte, PTO Reg. No. 41,809
`Senior Patent Attorney
`Intellectual Property, Patents
`AstraZeneca Pharmaceuticals LP
`PO Box 15437
`FOP3-033
`1800 Concord Pike,
`Wilmington, DE 19850-5437
`Office telephone: (302) 885-6609
`Mobile: (302) 357-4046
`Facsimile: (302) 886-8221
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