IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`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
`
`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:
`
`September 25. 2015
`Date
`
`/Steven L. Highlander/
`Steven L. Highlander
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`RESPONSE TO FINAL OFFICE ACTION MAILED MARCH 26, 2015
`
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
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`Commissioner:
`
`This is in response to the Office Action ("Action") mailed on March 26, 2015, to
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`which a response is due on September 26, 2015, by virtue of the accompanying Petition for
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`Extension of Time (3 months) and payment of fees. No other fees are believed due in
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`connection with this response; however, should applicants payment be missing, or any other
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`fees due, the Commissioner is authorized to debit Parker Highlander PLLC Deposit Acct. No.
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`50-5902/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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`[00274186}
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`DRL EXHIBIT 1040 PAGE 1
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`

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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:
`
`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)
`
`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 (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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`(±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)
`
`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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`[00274186}
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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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`[00274186}
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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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`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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`To establish prima facie obviousness of a claimed invention, all the claim features
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`must be taught or suggested by the prior art. In re Royka, 490 F.2d 981, 180 USPQ 580
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`(CCPA 1974). Indeed, all words in a claim must be considered in judging the patentability of
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`that claim against the prior art. In re Wilson, 424 F.2d 1382, 1385, 165 USPQ 494, 496
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`(CCPA 1970). Once again, the examiner has not addressed at least the following highlighted
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`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
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`[00274186}
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`b)
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`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:
`for the AM dose of naproxen, the mean Cmax is 86.2
`a)
`µglmL (±20%) and the median Tmax is 3.0 hours (±20%);
`and
`for the PM dose ofnaproxen, 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:
`for the AM dose of esomeprazole, the mean area under the
`a)
`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)
`
`c)
`
`There simply is no question, on the record, that the cited art lacks any teaching or suggestion
`
`of these features.
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`Applicants begin by directing the examiner to the decision in In re Cyclobenzaprine
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`Hydrochloride Extended-Release Capsule Patent Litigation (Fed. Cir. 2012), the facts and
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`holding of which are relevant to the instant application. There, the Federal Circuit concluded
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`that the district court's determination of obviousness was in error because the district court
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`failed to consider the lack of a known pharmacokinetic (pK)lpharmacodynamics (pD)
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`[00274186}
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`relationship for the claimed drug formulation. 1 The same arguments apply to the instant
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`application.
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`In In re Cyclobenzaprine, the Federal Circuit criticized the district court in its
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`improper assumption of bioequivalence between immediate release and extended release drug
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`forms. Here, the examiner similarly argues expected equivalence between immediate release
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`esomeprazole (present claims) and extended release esomeprazole (Hassan-Alin), which as
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`shown in the present specification, is not supported by the data. 2 Key in this aspect of the
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`Federal Circuit's holding was that cyclobenzaprine "lacked a known pK/pD relationship at
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`the time of invention," which the Federal Circuit believed was critically important because
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`"[w]ithout such a known relationship [], skilled artisans could not predict whether any
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`particular pK profile, including a bioequivalent one, would produce a therapeutically effective
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`formulation" (emphasis added).
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`Likewise, in the instant application, claim 19 focuses on esomeprazole and naproxen
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`pharmacokinetic ("pK") profiles (see Applicants' specification, pp. 43-53), and
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`the
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`pharmacodynamic ("pD") endpoint wherein the mean % of time for which the patient's
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`intragastric pH remains at about 4.0 or greater for about 24 hours after reaching steady state is
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`at least about 60% (see Applicant's specification, Table 4, p. 41 (mean % time of pH >4.0 =
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`71.35 (SD = 13.01))), for PN400/E20 (having immediate release esomeprazole) in
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`Example 1. These profiles and endpoint were not a "known pK/pD relationship at the time of
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`invention," and in fact were unexpected and surprising in light of the data also found in
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`Applicants' specification showing significantly different results for EC E20+naproxen
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`(having extended release esomeprazole), as shown at least by the following results:
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`1 In particular, the court focused on the pharmacokinetic values in claim 3.
`2 See discussion of Hassan-Alin et al., 2005 in Section II(A), below, regarding this point.
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`•
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`"On Day 9,
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`... PN400/E20 treatments resulted in a greater percent time with
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`intragastric pH>4.0
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`than
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`treatment with EC E20 + naproxen"
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`(Applicants'
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`specification, p. 41 and see Table 4);
`
`•
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`"By Day 9, however, the esomeprazole AUC0_10 for the PN400/E20 treatment group
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`was greater than the EC E20 + naproxen treatment group (1216 vs 1046 hr·ng/mL,
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`respectively) and Cmax,am from the PN400/E20 treatment group was almost double that
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`of the EC E20+naproxen treatment group (715 vs 435 ng/mL, respectively)."
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`(Applicants specification, p. 47);
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`•
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`"Repeat doses of PN 400/E30 and PN 400/E20 resulted in faster onset of increased
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`intragastric pH (at about 1 hour post dose) than EC E20 + naproxen, which was at
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`about 1.5 hours post-dose (Figure 1). As shown in the Figure 8A, the release of
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`naproxen from PN 400 occurred 1. 5 to 2 hours post AM dose. Before naproxen was
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`absorbed to peak concentrations following PN 400 treatment, intragastric pH had
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`already achieved high levels, well above pH 4.0 (Figure 8A). In fact, with the BID
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`regimen of PN 400/E20, given 1 hour before a meal, the intragastric pH was
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`maintained at above 4.0 for greater than 70% of time over a 24-hour period, which
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`would encompass any rise in plasma naproxen concentrations throughout the day. In
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`contrast, EC E20 + naproxen produced peak naproxen concentrations that preceded
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`the increase in intragastric pH (Figure 8B ). In fact, peak naproxen concentrations
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`occurred 1 to 2 hours post dose, which coincided with the time period when
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`intragastric pH was lowest." (Applicants' specification, p. 54).
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`This extended period of pH at 4.0 or greater provided by PN400/E20 (having immediate
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`release esomeprazole) over EC E20+naproxen (having extended release esomeprazole) is
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`believed to be advantageous toward protecting patients from adverse effects of naproxen, and
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`is a surprising and unexpected result given that this difference is maintained over an extended
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`[00274186}
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`period of time even though both formulations include esomeprazole, which as the examiner
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`asserts, was known to provide "more time with intragastric pH>4 than other proton pump
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`inhibitors." See Action at page 3. Therefore, as shown above, it is improper for the examiner
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`to assume bioequivalence between immediate release and extended release esomeprazole drug
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`forms (just as the district court did in In re Cyclobenzaprine, before being reversed by the
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`Federal Circuit).
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`In In re Cyclobenzaprine,, the Federal Circuit also distinguished its findings over KSR
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`Int'l Co. v. Teleflex Inc., quoting that opinion for the proposition that an invention is obvious
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`when the skilled worker pursues "known options" from "a finite number of identified,
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`predictable solutions" (emphasis added) The Federal Circuit went on to analogize the district
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`court's opinion with the Federal Circuit's language in In re Kubin, 561 F.3d 1351, 1359 (Fed.
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`Cir. 2009) as an improper obviousness analysis that is really hindsight reconstruction: when a
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`defendant is "'merely throw[ing] metaphorical darts at a board' in hopes of arriving at a
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`successful result," and "the prior art gave either no indication of which parameters were
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`critical or no direction as to which of many possible choices is likely to be successful," this is
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`not obviousness but hindsight reconstruction.
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`In summary, on facts very similar to those presented here, the USPTO's reviewing
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`court struck down a comparable finding of unpatentability on the grounds that the prior art's
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`general guidance was insufficient to render a claim obvious where that claim recited specific
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`pK/pD parameters that were nowhere present in the art, nor could they be selected from a
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`"finite" number of options readily apparent to those of skill in the art. As such, there is no
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`justification for holding that the presently claimed subject matter was reasonable suggested by
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`Hassan-Alin, even when taken in view of Plachetka.
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`[00274186}
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`A.
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`Enteric Coating
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`Applicants previously asserted that it was almost certain that the esomeprazole used
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`by Hassan-Alin was enterically-coated. Thus, any attempted extrapolation from this material
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`to the pharmacokinetic profile of esomeprazole of the present claims is completely
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`inappropriate due to the fact that the esomeprazole used to generate the data that is embodied
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`in the present claims was not enterically-coated. This provides yet another reason that the
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`skilled artisan could not have envisioned, nor expected to succeed with, the presently claimed
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`subject matter.
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`The examiner argues that Applicants have presented no evidence that the form of
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`esomeprazole in Hassan-Alin is enterically-coated. As a preliminary matter, it should be noted
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`that it is the examiner's burden, not Applicants', to establish that the cited art is in fact
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`relevant to the claimed subject matter, as well as how. Here all Applicants need to do is point
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`out there is no evidence of record that Hassan-Alin's esomeprazole was not enteric coated
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`(which was the state of the art at the time of publication), and the rejection is rebutted.
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`Simply put, Applicants need not disprove that which has not been proven.
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`Nevertheless, in the interest of advancing prosecution, Applicants provide the
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`following additional information. In 2005, in what was undoubtedly the follow up publication
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`to the presently cited reference, Hassan-Alin et al. stated in "Lack of Pharmacokinetic
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`Interaction between Esomeprazole and the Nonsteroidal Anti-Inflammatory Drugs Naproxen
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`and Rofecoxib in Healthy Subjects," Clin. Drug. Invest. 25(11):731-740, that their patients
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`took Nexium®, AstraZeneca Tablet Production, Sweden, which is well known to be
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`enterically-coated. Notably, that paper further provides a very different pK/pD profile than the
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`pending claims, thereby completely undercutting the examiner's argument that one could
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`necessarily achieve the same result if following Hassin-Alin' s 2003 teachings.
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`[00274186}
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`B.
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`Inherency
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`Without explicitly invoking the doctrine, the examiner attempts to sweep away the fact
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`that the cited references provide none of the preceding claim recitations by resorting to an
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`inherency theory, noting that "the resulting pharmacokinetics necessarily flow from such [an]
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`obvious administration method." As will be explained below, the examiner is applying
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`inherency in a way that cannot be supported by the relevant legal precedent.
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`Even assuming the examiner's characterization of the art to be correct - something
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`that is conceded only for the purpose of the following argument - the claims are nonetheless
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`patentable. The critical mistake arises in the examiner's implicit assertion that inherency can
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`address the limitations of applicants' claims that are missing from the art. The topic of
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`inherency, in the context of obviousness, is discussed in MPEP § 2141, the relevant portion of
`
`which is reproduced below:
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`In determining whether the invention as a whole would have been obvious under 35
`U.S.C. 103, we must first delineate the invention as a whole. In delineating the
`invention as a whole, we look not only to the subject matter which is literally recited
`in the claim in question ... but also to those properties of the subject matter which are
`inherent in the subject matter and are disclosed in the specification ... Just as we look
`to a chemical and its properties when we examine the obviousness of a composition of
`matter claim, it is this invention as a whole, and not some part of it, which must be
`obvious under 35 U.S.C. 103." In re Antonie, 559 F.2d 618, 620, 195 USPQ 6,8
`(CCPA 1977) (emphasis in original) (citations omitted) (The claimed wastewater
`treatment device had a tank volume to contractor area of 0.12 gal./sq. ft. The court
`found the invention as a whole was the ratio of 0.12 and its inherent property that the
`claimed devices maximized treatment capacity regardless of other variables in the
`devices. The prior art did not recognize that treatment capacity was a function of the
`tank volume to contractor ratio, and therefore the parameter optimized was not
`recognized in the art to be a result-effective variable.). See also In re Papesch, 315
`F.2d 381, 391, 137 USPQ 43, 51(CCPA1963) ("From the standpoint of patent law, a
`compound and all its properties are inseparable.").
`
`Obviousness cannot be predicated on what is not known at the time an invention is
`made, even if the inherency of a certain feature is later established. In re Rijckaert, 9
`F.2d 1531, 28 USPQ2d 1955 (Fed. Cir. 1993). See MPEP § 2112 for the requirements
`of rejections based on inherency.
`
`Emphasis added. Thus, it is quite clear that, in the context of obviousness, inherency is a
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`very, very limited doctrine. The examiner also makes reference to MPEP § 2112 (mentioned
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`in the passage above), which must be examined to better understand the limited use of
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`inherency in obviousness:
`
`There is no requirement that a person of ordinary skill in the art would have
`recognized the inherent disclosure at the time of invention, but only that the subject
`matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm.
`Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the
`contention that inherent anticipation requires recognition by a person of ordinary skill
`in the art before the critical date and allowing expert testimony with respect to post(cid:173)
`critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355
`F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004)("[T]he fact that a
`characteristic is a necessary feature or result of a prior-art embodiment (that is itself
`sufficiently described and enabled) is enough for inherent anticipation, even if that fact
`was unknown at the time of the prior invention."); Abbott Labs v. Geneva Pharms.,
`Inc., 182 F.3d 1315, 1319, 51USPQ2d1307, 1310 (Fed.Cir.1999) ("If a product that
`is offered for sale inherently possesses each of the limitations of the claims, then the
`invention is on sale, whether or not the parties to the transaction recognize that the
`product possesses the claimed characteristics."); Atlas Powder Co. v. Ireco, Inc., 190
`F.3d 1342, 1348-49 (Fed. Cir. 1999) ("Because 'sufficient aeration' was inherent in
`the prior art, it is irrelevant that the prior art did not recognize the key aspect of [the]
`invention.... An inherent structure, composition, or function is not necessarily
`known."); SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1343-44, 74
`USPQ2d 1398, 1406-07 (Fed. Cir. 2005) (holding that a prior art patent to an
`anhydrous form of a compound "inherently" anticipated the claimed hemihydrate form
`of the compound because practicing the process in the prior art to manufacture the
`anhydrous compound "inherently results in at least trace amounts of' the claimed
`hemihydrate even if the prior art did not discuss or recognize the hemihydrate) ....
`
`Where applicant claims a composition in terms of a function, property or characteristic
`and the composition of the prior art is the same as that of the claim but the function is
`not explicitly disclosed by the reference, the examiner may make a rejection under
`both 35 U.S.C. 102 and 103, expressed as a 102/103 rejection. "There is nothing
`inconsistent in concurrent rejections for obviousness under 35 U.S.C. 103 and for
`anticipation under 35 U.S.C. 102." In re Best, 562 F.2d 1252, 1255 n.4, 195 USPQ
`430, 433 n.4 (CCPA 1977). This same rationale should also apply to product,
`apparatus, and process claims claimed in terms of function, property or characteristic.
`Therefore, a 35 U.S.C. 102/103 rejection is appropriate for these types of claims as
`well as for composition claims ....
`
`Products of identical chemical compos1t10n can not have mutually exclusive
`properties." A chemical composition and its properties are inseparable. Therefore, if
`the prior art teaches the identical chemical structure, the properties applicant discloses
`and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d
`1655, 1658 (Fed. Cir. 1990) (Applicant argued that the claimed composition was a
`pressure sensitive adhesive containing a tacky polymer while the product of the
`reference was hard and abrasion resistant. "The Board correctly found that the virtual
`identity of monomers and procedures sufficed to support a prima facie case of
`unpatentability of Spada's polymer latexes for lack of novelty.") ....
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`[00274186}
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`From all of the foregoing, it is evident that inherency is a doctrine that primarily focuses on
`
`anticipation, usually where a composition in the prior art appears to be the same as that being
`
`claimed, and must therefore exhibit the same properties or activities as the prior art, even
`
`though that property or activity was unrecognized. However, as stated in In re Rijckaert, it is
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`quite illogical to rely on inherency in the context of obviousness, which requires an analysis
`
`of what those of ordinary skill in the art would have known at the time the invention was
`
`made. Where the reference is silent on a feature, how could the skilled artisan be presumed to
`
`be imbued with such knowledge?
`
`In stark contrast to the focus on anticipation and compositions of matter, there is only
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`a passing mention of obviousness and methods in these sections of the MPEP. Yet the issue
`
`presented here is precisely that - the obviousness of a method. If this rejection is to be
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`sustained, applicants submit that some case law citation is required supporting a rejection that
`
`on inherent obviousness of a method, based on the combination of two references, when it is
`
`admitted by all parties that no one has ever practiced that method in the past. Without such a
`
`citation, there simply can be no reason to sustain this rejection.
`
`Significantly, the Federal Circuit has just issued further guidance on the notion of
`
`applying inherency in the context of obviousness in Par Pharm. Inc. v. Alkermes Pharma
`
`Ireland Ltd., Case No. 2014-1391 (Fed. Cir. 2014). Not surprisingly, the court cited In re
`
`Rijckaert, discussed above, in arriving at the conclusion that an "inherent obviousness"
`
`rejection, while possibly proper, is highly constrained and "must be carefully circumscribed in
`
`the context of obviousness." Indeed, this is not the sort of case where the "[m]ere recitation of
`
`a newly discovered function or property, inherently possessed by things in the prior art, does
`
`not distinguish a claim drawn to those things from the prior art," citing In re Oelrich, 666.
`
`F.2d 578, 581 (CCPA 1981) (emphasis added). Clearly the claimed methods do not constitute
`
`part of the prior art, or the rejection would be under § 102 and not § 103. As such, the
`
`[00274186}
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`Page 13
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`DRL EXHIBIT 1040 PAGE 13
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`

`

`fundamental principle that "obviousness cannot be predicated on what is unknown" controls
`
`here.
`
`C.
`
`Conclusion
`
`To conclude, the examiner has failed to establish that the general teachings of the cited
`
`art would lead the skilled artisan to the pending claims, and do so with a reasonable
`
`expectation of success. Applicants
`
`therefore respectfully request reconsideration and
`
`withdrawal of this rejection.
`
`III. Rejections for Obviousness-Type Double-Patenting
`
`A.
`
`Plachetka and Hassan-Alin
`
`Claims 19, 29, 33, 34, 30, 42, and 45 have been rejected as being obvious over claims
`
`1-55 of Plachetka in view of Hassan-Alin, both cited above. Applicants traverse.
`
`In essence, this rejection is the same as the one immediately above, except that
`
`Platchetka is used here as the primary reference, and only the claims of Plachetka are
`
`available for citation against the present claims. Therefore, the arguments advanced above
`
`apply to Platchetka in view of Hassan-Alin with equal, and perhaps greater force, given the
`
`limited scope of citable disclosure from Plachetka. Applicants therefore respectfully request
`
`reconsideration and withdrawal of this rejection.
`
`B.
`
`U.S. Serial No. 14/045,156
`
`Claims 19, 29, 33, 34, 30, 42, and 45 have been provisionally rejected as being
`
`obvious over claims 57-75 of U.S. Serial no. 14/045, 156. Applicants traverse.
`
`Once again, this rejection is effectively based on the same logic as above, except that
`
`here, there is no secondary reference to rely upon, and only the claims of the '156 application
`
`are available for citation against the present claims. Therefore, the arguments advanced above
`
`apply here with equal, and perhaps greater force, given the limited scope of citable material
`Page 14
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`100274186}
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`DRL EXHIBIT 1040 PAGE 14
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`

`

`from the '156 application. Applicants therefore respectfully request reconsideration and
`
`withdrawal of this rejection as well. Applicants therefore respectfully request reconsideration
`
`and withdrawal of this rejection.
`
`C.
`
`U.S. Serial No. 12/822,612
`
`Claims 19, 29, 33, 34, 30, 42, and 45 have been provisionally rejected as being
`
`obvious over claims 1-4, 18-20, 25, 26, 31, 38, 46-48, 64 and 65 of U.S. Serial no.
`
`12/822,612.
`
`Applicants traverse, but given that the rejection is provisional in nature, request that
`
`the rejection be held in abeyance until one of the applications at issue has matured into an
`
`issued patent.
`
`IV.
`
`Conclusion
`
`In light of the foregoing, applicants respectfully submit that all claims are in condition
`
`for allowance, and an early notification to that effect is earnestly solicited. The examiner is
`
`invited to contact the undersigned with any questions or comments regarding this response.
`
`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: September 25, 2015
`
`[00274186}
`
`Page 15
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`DRL EXHIBIT 1040 PAGE 15
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`

`

`APPENDIX
`APPENDIX
`
`DRL EXHIBIT 1040 PAGE 16
`
`DRL EXHIBIT 1040 PAGE 16
`
`

`

`C!•~ D1~g l11V'3st 2Q1t>: LS ( ~ l)· rs :.;~CJ
`ORIGINAL RESEARCH ARTICLE
`~ ~ ?}·.?~i':.35.:C'O f; ·ffi-31 /SJ•~:i~/D
`.............................................................................................................................................................................. "'''"""''''"'"'''''''''"''''''''''''''''''''''"''"'''''-''"'''"''"''"'-"'''''-'''''''"'-'""-'''''"'''''''''''''''''''''''''''''''''''''''-''''''''''''''''''''''''''''''''''''''''''''''''''"
`:;_- 201.S A.:t~~ Da~0 tri:-C•i:"':o:fc·-· ~\:. 1~.•! ~:9:-.~~ r;:.:i!:-1'.·en
`
`Lael< of Pharmacokinetic Interaction
`between Esomeprazole and the
`Nonsteroidal Anti-Inflammatory
`Drugs Naproxen and Rofecoxib in
`Healthy Subjects
`l\!I. Hassan-Alin,1 J, Naesda/,t C. Nilsson-Pieschl, 1 G. Ldngstn'iml and T. Andersson2
`
`l AstraZeneca R&D Mcilndal, ivfolndal, Sv~'eden
`2 AstraZt'neca LP .. Wilmington, Delaware, USA
`
`Abstract
`
`Background: 'We investigated the po1c.ntial i.nieractions between csomcprnzole
`and a non-selective non~teroidal anti-inflammatory drug (NSAID; naproxt~n) nr a
`cyclo-oxygcnase (COX)-2-sdectivc NSAID {rofecoxih) in ht~althy subjects.
`
`Methods! Two studies of identical randomised, open, three-way crossover design
`were conducted. Subjecr.s (n = 32 for both studies) were to receive l week's
`treatment with csomcprazolc 40mg once daily (~tudies A and B), napro:<cn 250mg
`t<.vice daily (study A), rofecoxib 1.2.Smg once daily (study B), and esomeprazole
`in combination with naproxcn (study A) or rofecoxih (study B). Study periods
`were separated by a 2-week washout period.
`Results: On day 7 of dosing, the ratios (and 95%· Cb) for the area under the
`plasma concentration-time curve during the dosing interval (AUC,) and ohserved
`maximum plasma concentration (Crnax) of esorneprazole and NSAID comhinu(cid:173)
`tion/NSAID alone were 0.98 (0.94, I ,OJ) and 1.00 (0.97, J .04}, respectively, for
`study A, and l.l 5 ( l.06, 1.24) and 1.14 (!.02, l.28), rc~pectivdy, for study B. The
`ratios (and 95ck· Cls) for AUCt and Cmax of esnmeprnz.ole and NSAlD comhina(cid:173)
`tion/esomeprazn!e alone were 0.% {0.89, I .ffi) and 0.92 (0.85, l .00), respective(cid:173)
`ly, for study A, and 1.05 (0.96, l.15} and l.05 (0.94, 1.18), respectively, for study
`B. All treatments were well tolerated during the study period.
`Conclusion: Naproxen and rofecoxib do not interact with esomeprazole, and
`esorneprazok does no! al'foct the phannacokinelics of naproxen or rnfocoxib.
`These findings indicate thal esomcprnzole. can be used in combina1ion wi1h
`NS/UDs without the risk of a pharmacokinetic interaction.
`
`DRL EXHIBIT 1040 PAGE 17
`
`

`

`732
`
`J-la.~sr.ur-Al in t:f al.
`
`Nonsteroidal anti-inllammalory drugs (NSAIDs)
`are widely used for lht' lreatment of rheumatoid
`arthritis (RA). oskoanhritis (OA) and a wide variety
`or other acute ~md chronic painful musculoskdetal
`disorders, and can, in mnst countries, be us