IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicants: Brian Ault, et al.
`
`Filed: September 3, 2009
`
`Application No: 12/553,107
`
`Attorney Docket No: 103526-US
`
`Examiner: Gina Chieun Yu Justice
`
`Confirmation No. 5949
`
`Art Unit:
`
`1617
`
`Title: Method for Delivering a Pharmaceutical Composition to Patient
`
`in Need Thereof
`
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
`
`January 30, 2013
`
`AMENDMENT C AND RESPONSE TO FINAL OFFICE ACTION
`
`This amendment
`
`is being filed with an RCE in response to the July 30, 2012 final
`
`Office action in the above-referenced patent application.
`
`Claim amendments begin on page 2.
`
`Remarks begin on page 5.
`
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`Amendment C and Response to Final Office Action
`Appl. No. 12/553,107
`January 30, 2013
`
`Claim Amendments
`
`Please amend the claims as follows:
`
`Claims 1-18 (cancelled).
`
`19.
`
`(previously presented) A method for treating osteoarthritis, rheumatoid arthritis,
`in need thereof an AM
`or ankylosing spondylitis comprising orally administering to a patient
`unit dose form and, 10 hours (::E20%) 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
`AM and PM unit dose forms at a pH of 0 or greater,
`the AM and PM unit dose forms target:
`
`salt thereof,
`
`is released from said
`
`a)
`
`b)
`
`i)
`
`ii)
`
`the mean Cmax is 86.2 ~Lg/mL
`
`(::E20%)
`
`(pk) profile for naproxen where:
`a pharmacokinetic
`for the AM dose of naproxen,
`and the median Tmax is 3.0 hours (::E20%); and
`for the PM dose of naproxen,
`the mean Cm,,x is 76.8 [tg/mL (::E20%)
`and the median T. is 10 hours (_L20%); and
`(pk) profile for esomeprazole where:
`a pharmacokinetic
`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 (::E20%) after the AM dose is administered (AUCO-10,11)
`
`a)
`
`b)
`
`C)
`
`(::E20%),
`
`is 1216 hr*~Lg/mL
`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 (:L20%) after the PM dose is administered (AUCo_14,pm)
`
`is 919 hr*[tg/niL (_L20%), and
`
`the total mean area under the plasma concentration-time curve for
`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
`
`(+20%) after the AM dose is administered (AUCO-24)
`
`is 2000
`
`hr*[tg/mL (::E20%)- 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%.
`
`Claims 20-28 (cancelled).
`
`29.
`
`(previously presented) The method according to claim 19, wherein the mean %
`
`time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period after
`
`reaching steady state is at least about 7 1 %.
`
`Claims 30-32 (cancelled).
`
`(previously presented) The method according to claim 19, wherein said AM and
`33.
`PM unit dose forms are administered for a period of at least about 6 days.
`
`(previously presented) The method according to claim 19, wherein said AM and
`34.
`PM unit dose forms are administered for a period of at least about 9 days.
`
`Claims 35-39 (cancelled).
`
`40.
`
`(currently amended) The method according to claim 19, wherein said AM and
`PM unit dose forms are each a multilaycr tablet comprising at least one core and at least a first
`layer and a second layer, wherein:
`
`i )
`
`ii)
`
`said core comprises naproxen, or pharmaceutically acceptable
`
`salt thereof,
`
`said first
`
`layer is a coating that at
`
`least begins to release the naproxen, or
`
`pharmaceutically acceptable salt thereof, when the pH of the surrounding
`medium is about 3.5 or greater; and
`
`iii)
`
`said second layer comprises esomeprazole or a pharmaceutically acceptable
`
`salt thereof, wherein said esomeprazole or pharmaceutically acceptable salt
`
`thereof is released at a pH of from 0 or greater.
`
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`Amendment C and Response to Final Office Action
`Appl. No. 12/553,107
`January 30, 2013
`
`Claim 41 (cancelled).
`
`42.
`
`(currently amended) The method according to claim 40, wherein said
`
`esomeprazole or pharmaceutically
`
`acceptable salt thereof is released at a pH of from 0 to
`
`about 2.
`
`Claims 43 and 44 (cancelled).
`
`45.
`
`(previously presented) The method according to claim 40, wherein said multi-
`
`layer tablet is substantially free of sodium bicarbonate.
`
`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
`
`Remarks/Ar2uments
`
`Applicants request reconsideration of this application on the merits.
`
`1.
`
`Claim amendments
`
`Claims 19, 29, 33, 34, 40, 42, and 45 are pending. Applicants have amended claims
`
`40 and 42 to characterize the recited salt as "pharmaceutically acceptable." This makes
`
`claims 40 and 42 more consistent with claim 19, i.e.,
`
`the claim from which claims 40 and 42
`
`ultimately depend.
`
`Applicants continue to reserve their right to pursue any subject matter cancelled or
`
`otherwise disclosed in this application in or more later-filed continuations and/or divisionals.
`
`11.
`
`'Response to obviousness-type double-patentin2 r6ection
`
`Claims 19, 29, 33, 34, 40, 42, and 45 have been rejected as obviousness-type
`
`double-
`
`patenting over claims 1-55 of Plachetka (U.S. Patent No. 6,926,907). Applicants request
`
`withdrawal of this rejection.
`
`Applicants respectfully submit that claims 19, 29, 33, 34, 40, 42, and 45 are patentably
`
`distinct over PlachetIc-a's claims 1-55 for reasons analogous to those discussed below
`
`regarding the non-obviousness of claims 19, 29, 33, 34, 40, 42, and 45 over Plachetka
`
`generally. On this ground alone, Applicants submit this rejection should be withdrawn on the
`
`merits.
`
`In addition, Applicants respectfully submit that this rejection is not ripe until at least
`
`one of the rejected claims has been found to be otherwise patentable. Accordingly,
`
`to the
`
`extent this rejection is not withdrawn on the merits, Applicants request
`
`that it be held in
`
`abeyance until there is at least one claim in this application found to be otherwise allowable.
`
`111.
`
`'Response to re4ection under 35 U.S.C. ~103(a)
`
`Claims 19, 29, 33, 34, 30, 42, and 45 have been rejected as being obvious over
`
`Plachetka. Applicants request withdrawal of this rejection.
`
`A.
`
`Claim 19
`
`Applicants respectfully submit that claim 19 represents a non-obvious selection over
`
`Plachetka. This selection is characterized by unexpected results. Nothing in Plachetka would
`
`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
`
`Claim 19 recites multiple selections over Plachetka, which include:
`
`(1)
`
`(2)
`
`(3)
`
`the use of the specific combination of naproxen and esomeprazolel
`
`the specific combined doses of naproxen (i.e., 500 mg/unit dose) and
`
`esomeprazole (i.e., 20 mg/unit dose); and
`the administration of the above combination in an AM unit dose form, and, 10
`hours (::E20%) later, a PM unit dose form.
`
`Plachetka falls to teach or suggest any one these specific selections or the combination
`
`thereof.
`
`Applicants selected one NSAID, naproxen,
`
`The Combination ofNar2roxen and Esomet2razole
`from the many possible NSAIDs
`
`mentioned in Plachetka. See, e.g., Plachetka, cot. 5, line 20 to cot. 6,
`merely one of 26 specific NSAIDs mentioned). Applicants further selected one acid inhibitor,
`
`line 67 (naproxen is
`
`esomeprazole,
`
`from the many acid inhibitors mentioned in Plachetka. These include two
`
`general categories (1-12 blockers and proton pump inhibitors), and esomeprazole is merely one
`
`of the eleven example acid inhibitors Plachetka mentions.
`
`See e.g., Plachetka, cot. 7, lines I -
`
`18.
`
`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 pharmacodynamic
`
`profile (see below).
`
`500 mg ofNa[2roxen Combined with 20 mg Esomer2razole per Unit Dose
`
`Claim 19 recites a selection of a combination of 500 mg of naproxen with 20 mg of
`esomeprazole for each unit dose form. Plachetka fails to specifically teach or suggest these
`
`doses when these ingredients are used in combination with each other.
`
`In fact, Plachetka,
`
`while mentioning various dosage ranges for naproxen and esomeprazole, provides that 550
`
`mg/unit dose is generally preferred for naproxen and 40 mg/unit dose is generally preferred
`
`for esomeprazole. See, e.g., Plachetka, cot. 6, lines 6-11 and cot. 7,
`
`lines 12-13.
`
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`Amendment C and Response to Final Office Action
`Appl. No. 12/553,107
`January 30, 2013
`
`Consequently,
`
`a skilled artisan reading Plachetka, even if choosing naproxen and/or
`
`esomeprazole, would have had no guidance or motivation to specifically select Applicants'
`
`recited combined doses for naproxen and esomeprazole, particularly when confronted with
`
`the many choices of doses for the various drugs Plachetka mentions.
`
`Administering the Above Combination in
`an AM Unit Dose Form and, 10 hours 020%) Later, a PM Unit Dose Form
`
`Claim 19 recites administering the combination, 500 mg of naproxen and 20 mg of
`in an AM unit dose form and, 10 hours (::E20%) later, a PM unit dose form.
`
`esomeprazole,
`
`Plachetka fails to specifically teach or suggest such a treatment regime. Plachetka does
`
`discuss twice-daily treatment (see, e.g., Plachetka, Example 9). But nowhere does Plachetka
`
`specifically discuss when each of the two doses should be administered, or at what time
`
`interval. Thus, a skilled artisan reading Plachetka, even if selecting a twice-daily treatment
`
`regime, would not have had any specific guidance or motivation to select Applicants'
`
`recited
`
`treatment
`
`regime.
`
`Lack ofPrima Facie Case 1fresence of UnLMected Results
`
`To establish a prima facie case of obviousness, some reason must be identified that
`
`would have led a skilled artisan to pursue a claimed species. See Yamanouchi Pharm. Co.
`
`Ltd. V. Danbury Pharmacol., Inc., 231 F.3d 1339, 1344 (Fed. Cir. 2000) (holding that to
`
`establish a primajacie case of obviousness post-KSR, there must be a showing that those of
`
`skill
`
`in the art would have had motivation to pursue the claimed species); see also Takeda
`
`Chem. Indus, v. Alphapharin Pty, Ltd., 492 F.3d 1350, 1356 (Fed. Cir. 2007). Plachetka falls
`
`to meet this requirement because it
`
`fails to specifically teach or suggest any of the above three
`
`selections, much less Applicants'
`
`recited combination thereof.
`
`Against this backdrop, Applicants further point out that they have unexpectedly
`
`discovered and demonstrated that, by practicing the recited method,
`they can achieve a
`pharmacodynamic profile in which the mean % of time for which a patient's intragastric pH
`
`remains at about 4.0 or greater for about 24 hours after reaching steady state is at least about
`
`60%. More specifically,
`in a 9-day clinical study, they achieved a pharmacodynamic profile
`in which the mean % time of intragastric pH at above 4.0 over 24 hours was about 71.35%.
`page 41, Table 4. By contrast, among the tested formulations in
`
`See, e.g., Specification,
`
`Plachetka,
`
`the combination of 40 mg of famotidine with 550 mg of naproxen maintained the
`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
`
`artisan would readily correlate the extended pH
`
`4.0 period produced by Applicants' method
`
`with desired reduced gastrointestinal risk associated with stomach acid secretion.
`
`Plachetka fails to specifically teach or suggest that the beneficial pharmacodynamic
`
`profile observed with Applicants' method could be obtained when (1) using esomeprazole
`
`(2) using the specific dosages of 20 mg/unit esomeprazole with 550 mg/unit
`with naproxen,
`dose naproxen, and (3) following a treatment regimen that comprises a PM dose administered
`10 hours (-L20%) after an AM dose. Thus, a skilled artisan reading Plachetka would not have
`
`expected the beneficial results of Applicants' method, specifically the post-administration
`
`intragastric pH
`
`4.0 period discussed above.
`
`Inherenc
`
`The obviousness rejection appears to be based on a conclusion that Applicants'
`
`pharmacokinetic
`
`and pharmacodynamics
`
`profiles are inherent
`
`results of administering the
`
`formulation according to Plachetka's teachings twice per day, and, as such, are not evidence
`
`of inventiveness.
`
`See page 8 of the Office action. Applicants respectfully traverse ---
`
`this
`
`reliance on inherency is improper.
`At the outset, while inherency mU apply to anticipation determinations,
`it has only
`verv limited application in the context of obviousness. And the Courts have often balked at
`
`basing an obviousness finding on an unknown inherent property present
`
`in the prior art. See
`
`Trintec Indus.,
`
`Inc. v. TOP-U.S.A. Corp., 295 F.3d 1292, 1296 (Fed. Cir. 2002) ("obviousness
`
`is not inherent anticipation");
`
`In re Rijckaert, 9 F.3d 1531, 1534 (Fed. Cir. 1993) ("Such a
`
`retrospective view of inherency is not a substitute for some teaching or suggestion supporting
`
`an obviousness rejection."). See also, In re Spormann, 363 F.2d 444, 448 (C.C.P.A. 1966)
`
`("That which may be inherent
`
`is not necessarily known."). This makes sense. After all,
`
`the
`
`suggestion to combine or modify prior art must occur before an Applicant's date of invention.
`If an inherent property is unknown at the time, it obviously cannot provide such a suggestion.
`
`See,
`
`In re Rijckaert, 9 F.3d at 1534.
`
`Moreover,
`
`the use of inherency in the instant rejection is wholly misplaced because
`
`the inherency is being used to characterize the unexpected results of the claimed method.
`
`More specifically,
`
`the Office action concedes
`
`that Plachetka fails to specifically disclose the
`
`particular combination of operative elements recited in claim 19. The Office action, however,
`
`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
`
`are inherent
`
`from the combination. Applicants are unaware of any law allowing this type of
`
`reasoning.
`
`Inherency cannot be used, as it has here, to disreUard the unexl2ected results of a
`
`novel combination of operative elements.
`
`Simply put, Plachetka fails to specifically teach or suggest the novel selections of
`Applicants' method. And Plachetka fails to predict the unexpected results of Applicants'
`
`claimed method, particularly the abovc-dcscribed percentage of time over which the
`
`intragastric pH is maintained at 4.0 or above. Accordingly, Applicants respectfully submit
`
`that Plachetka fails to render claim 19 obvious.
`
`B.
`
`Claims 29, 33, 34, 40, 42, and 45
`
`Claims 29, 33, 34, 40, 42, and 45 depend directly or indirectly from claim 19. Thus,
`
`they too are necessarily patentable over Plachetka for at least the same reasons as claim 19.
`
`Applicants request a three-month extension to respond to the July 30, 2012 final
`
`Office action, and authorize the Commissioner to charge the corresponding fee to Deposit
`
`Account No. 260166.
`
`If any other fee(s) is due in connection with this filing, Applicants
`
`authorize the Commissioner to charge the fee(s) to Deposit Account No. 260166 (referencing
`
`Attorney Docket No. 103526-US).
`
`In addition, if there is ever any other fee deficiency or
`
`overpayment under 37 C.F.R.
`
`§ 1. 16 or 1. 17 in connection with this patent application,
`
`the
`
`Commissioner is hereby authorized to charge such deficiency or overpayment
`
`to Deposit
`
`Account No. 260166 (referencing Attorney Docket No. 103526-US).
`
`Applicants submit the pending claims are in condition for allowance, and request this
`
`application be allowed.
`
`The Examiner is requested to call the Undersigned if any issues arise
`
`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
`
`Respectfully submitted,
`/David M. Gryte, Re2. 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
`(302) 885-6609
`Office telephone:
`(302) 357-4046
`Mobile:
`(302) 886-8221
`Facsimile:
`
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