IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`Applicant: 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: POZN.P0026US
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`Examiner: Gina C. Yu Justice
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`Confirmation No. 5949
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`Title: Method for Delivering a Pharmaceutical Composition to Patient in Need Thereof
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`CERTIFICATE OF ELECTRONIC TRANSMISSION
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`I hereby certify that this correspondence is being electronically filed with the
`United States Patent and Trademark Office via EFS-Web on the date below:
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`December 16. 2014
`Date
`
`/Steven L. Highlander/
`Steven L. Highlander
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`RESPONSE TO NON-FINAL OFFICE ACTION MAILED .TUNE 16, 2014
`
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
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`Commissioner:
`
`This is in response to the Office Action mailed on June 16, 2014, to which a response
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`is due on December 16, 2014, by virtue of the accompanying Petition for Extension of Time
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`(3 months) and payment of fees. No other fees are believed due in connection with this
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`response; however, should applicants payment be missing, or any other fees due, the
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`Commissioner is authorized to debit Parker Highlander PLLC Deposit Acct. No. 50-
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`5902/POZN.P0026US/SLH.
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`A Listing of Claims begins on page 2 of this response; Remarks begin on page 5.
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`MYLAN PHARMS. INC. EXHIBIT 1039 PAGE 1
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`LISTING OF CLAIMS
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`The following listing of claims replaces all previous listings or versions thereof:
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`1-18.
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`(Canceled)
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`19.
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`(Previously presented) A method for treating osteoarthritis, rheumatoid
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`arthritis, or ankylosing spondylitis comprising orally administering to a patient in need thereof
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`an AM 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 of naproxen, the mean Cmax is 86.2 µg/mL (±20%)
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`and the median T max is 3.0 hours (±20% ); and
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`b)
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`for the PM dose of naproxen, the mean Cmax is 7 6. 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 (AUC0_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 (AUC 0_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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`(±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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`20-28. (Canceled)
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`29.
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`(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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`30-32. (Canceled).
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`33.
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`(Previously presented) The method according to claim 19, wherein said AM
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`and PM unit dose forms are administered for a period of at least about 6 days.
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`34.
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`(Previously presented) The method according to claim 19, wherein said AM
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`and PM unit dose forms are administered for a period of at least about 9 days.
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`35-39. (Canceled)
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`40.
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`(Previously presented) The method according to claim 19, wherein said AM
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`and PM unit dose forms are each a multilayer tablet comprising at least one core and at least a
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`first 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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`41.
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`(Canceled)
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`42.
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`(Previously presented) 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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`43-44. (Canceled)
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`45.
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`(Previously presented) The method according to claim 40, wherein said multi-
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`layer tablet is substantially free of sodium bicarbonate.
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`46-47. (Canceled)
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`I.
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`Status of the claims
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`REMARKS
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`Claims 19, 29, 33, 34, 40, 42 and 45 are pending in the application and stand rejected
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`under 35 U.S.C. § 103 and for obviousness-type double-patenting. The specific grounds for
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`rejection, and applicants' response thereto, are set out in detail below.
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`II.
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`Previous Arguments Regarding the Combination of Naproxen and Esomeprazole
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`In the Response to Final Office Action dated January 30, 2013 for the captioned
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`application, Applicants' representative stated:
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`Although Plachetka does mention both naproxen and esomeprazole, Plachetka
`places no particular emphasis on the specific combination of the two. Nor does
`Plachetka describe any formulation or in vitro or in vivo experiments using
`such a combination. Thus, a skilled artisan, when reading Plachetka, would
`have had no guidance or motivation to specifically select the combination of
`naproxen and esomeprazole, when confronted with hundreds of possible
`combinations Plachetka presents. Nor would the skilled artisan have had any
`expectation that the combination of naproxen and esomeprazole, as currently
`recited in claim 19, would produce Applicants' unexpected pharmacodynamics
`profile (see below).
`
`The above statement that "a skilled artisan, when reading Plachetka, would have had no
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`guidance or motivation to specifically select the combination of naproxen and esomeprazole,"
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`is incorrect. Applicants agree generally with the position in the July 30, 2012 Action that
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`Plachetka discloses to a person of ordinary skill in the art the coordinated delivery of
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`esomeprazole and naproxen. But Plachetka, while examining the performance of naproxen
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`and gastric inhibitors, does not disclose any in vitro or in vivo experiments using a
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`combination of naproxen and esomeprazole. Thus, it is important to consider that, in the
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`context of obviousness, Plachetka does not provide any direct information to one of skill in
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`the art regarding the pharmacodynamics profile of the combination of naproxen and
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`esomeprazole.
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`III. Rejection under 35 U.S.C. §103
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`Claims 19, 29, 33, 34, 40, 42, and 45 are rejected over Hassan-Alin et al. in view of
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`Plachetka (U.S. Patent 6,926,907). Applicants traverse.
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`Hassan-Alin is cited as teaching that there are no drug-drug interactions between
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`esomeprazole and naproxen, as demonstrated by a study in human subjects. In addition, the
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`reference indicates that esomeprazole is expected to be more effective than other PPI's against
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`NSAID-associated ulcers and to provide GI protection. Plachetka is cited as teaching a
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`coordinated delivery of NSAIDS, including naproxen, with an acid inhibitor. From this, the
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`examiner argues that use of esomeprazole in combination with naproxen, using an AM-PM
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`dosing regimen, would be obvious.
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`The problem with this line of reasoning is that, even if accepted, it fails to establish a
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`prima facie case of obviousness. To establish prima facie obviousness of a claimed
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`invention, all the claim features must be taught or suggested by the prior art. In re Royka, 490
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`F.2d 981, 180 USPQ 580 (CCPA 1974). Indeed, all words in a claim must be considered in
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`judging the patentability of that claim against the prior art. In re Wilson, 424 F.2d 1382, 1385,
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`165 USPQ 494, 496 (CCPA 1970). Here, the examiner has completely failed to address at
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`least the following highlighted claim features:
`
`A method for treating osteoarthritis, rheumatoid arthritis, or ankylosing
`spondylitis comprising orally administering to a patient in need thereof an AM unit
`dose form and, 10 hours (±20%) later, a PM unit dose form, wherein:
`the AM and PM unit dose forms each comprises:
`naproxen, or a pharmaceutically acceptable salt thereof, in
`an amount to provide 500 mg of naproxen, and
`esomeprazole, or a pharmaceutically acceptable salt thereof,
`in an amount to provide 20 mg of esomeprazole;
`said esomeprazole, or pharmaceutically acceptable salt thereof, is released
`from said AM and PM unit dose forms at a pH of 0 or greater,
`the AM and PM unit dose forms target:
`i) a pharmacokinetic (pk) profile for naproxen where:
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`a)
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`b)
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`for the AM dose of naproxen, the mean Cmax is 86.2
`µglmL (±20%) and the median Tmax is 3.0 hours (±20%);
`and
`for the PM dose of naproxen, the mean Cmax is 76.8 µglmL
`( ±20%) and the median T max is 10 hours ( ±20% ); and
`ii) a pharmacokinetic (pk) profile for esomeprazole where:
`a)
`for the AM dose of esomeprazole, the mean area under the
`plasma concentration-time curve from when the AM dose
`is administered to 10 hours (±20%) after the AM dose is
`administered (AUCo.10,am) is 1216 hr*µglmL (±20%),
`for the PM dose of esomeprazole, the mean area under the
`plasma concentration-time curve from when the PM dose
`is administered to 14 hours (±20%) after the PM dose is
`administered (AUC0.14,pm) is 919 hr*µglmL (±20%), and
`the total mean area under the plasma concentration-time
`curve for esomeprazole from when the AM dose is
`administered to 24 hours ( ±20%) after the AM dose is
`administered (AUC0.24) is 2000 hr*µglmL (±20%); and
`the AM and PM unit dose forms further target a mean % time at which
`intragastric pH remains at about 4.0 or greater for about a 24 hour period after
`reaching steady state that is at least about 60%.
`
`b)
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`c)
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`The examiner attempts to shore up this defect by arguing that "the fact that applicant
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`has recognized another advantage which would flow naturally from the following suggestion
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`of the prior art cannot be the basis for patentability when the differences would otherwise be
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`obvious," citing Ex parte Obiaya (emphasis added). However, the point here is that the
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`above-highlighted differences are not obvious for the simple reasons that there is no teaching
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`or suggestion for the skilled artisan to seek out each and every one of the above claim
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`features. Moreover, even if the skilled artisan could somehow have come up with these claim
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`features, there is no likelihood of success that these parameters would indeed produce the
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`desired therapeutic effect (something only demonstrated by the experiments described in
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`applicants' specification).
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`Finally, though not stated, it is almost certain that the esomeprazole used by Hassan-
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`Alin was enterically-coated. Any attempted extrapolation from
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`this material to
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`the
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`pharmacokinetic profile of esomeprazole of the present claims is completely inappropriate
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`due to the fact that the esomeprazole used to generate the data that is embodied in the present
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`claims was not enterically-coated. This provides yet another reason that the skilled artisan
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`could not have envisioned, nor expected to succeed with, the presently claimed subject matter.
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`To conclude, the examiner has failed to establish that the general teachings of the cited
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`art would lead the skilled artisan to what is now claimed, and do so with a reasonable
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`expectation of success. Applicants
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`therefore respectfully request reconsideration and
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`withdrawal of this rejection.
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`IV.
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`Rejections for Obviousness-Type Double-Patenting
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`A.
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`Plachetka and Hassan-Alin
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`Claims 19, 29, 33, 34, 30, 42, and 45 have been rejected as being obvious over claims
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`1-55 of Plachetka in view of Hassan-Alin, both cited above. Applicants traverse.
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`In essence, this rejection is the same as the one immediately above, except that
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`Platchetka is used here as the primary reference, and only the claims of Plachetka are
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`available for citation against the present claims. It goes to say, therefore, that the arguments
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`advanced above apply here with equal, and perhaps greater force, given the limited scope of
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`citable material from Plachetka. Applicants therefore respectfully request reconsideration and
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`withdrawal of this rejection as well.
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`B.
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`U.S. Serial No. 14/045,156
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`Claims 19, 29, 33, 34, 30, 42, and 45 have been provisionally rejected as being
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`obvious over claims 57-75 of U.S. Serial no. 14/045, 156. Applicants traverse.
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`Once again, this rejection is effectively based on the same logic as above, except that
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`here, there is no secondary reference to rely upon, and only the claims of the '156 application
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`are available for citation against the present claims.
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`It goes to say, therefore, that the
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`arguments advanced above apply here with equal, and perhaps greater force, given the limited
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`scope of citable material from the '156 application. Applicants therefore respectfully request
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`reconsideration and withdrawal of this rejection as well. Applicants therefore respectfully
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`request reconsideration and withdrawal of this rejection.
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`C.
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`U.S. Serial No. 12/822,612
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`Claims 19, 29, 33, 34, 30, 42, and 45 have been provisionally rejected as being
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`obvious over claims 1-4, 18-20, 25, 26, 31, 38, 46-48, 64 and 65 of U.S. Serial no.
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`12/822,612.
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`Applicants traverse, but given that the rejection is provisional in nature, request that
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`the rejection be held in abeyance until one of the applications at issue has matured into an
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`issued patent.
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`V.
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`Conclusion
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`In light of the foregoing, applicants respectfully submit that all claims are in condition
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`for allowance, and an early notification to that effect is earnestly solicited. The examiner is
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`invited to contact the undersigned with any questions or comments regarding this response.
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`Respectfully submitted,
`
`/Steven L. Highlander/
`
`Steven L. Highlander
`Reg. No. 37,642
`Attorney for Applicants
`
`Parker Highlander PLLC
`1120 S. Capital of Texas Highway
`Building One, Suite 200
`Austin, Texas 78746
`512-334-2900 (Telephone)
`512-334-2999 (Fax)
`
`Date: December 16, 2014
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