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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`Examiner: Gina C. Yu
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`Filed: September 3, 2009
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`Attorney Docket No: 103526-US/NS
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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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`Mail Stop Amendment
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
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`May 8, 2012
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`AMENDMENT B IN RESPONSE TO JANUARY 5, 2012 OFFICE ACTION
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`This amendment is being filed in response to the January 5, 2012 Office action in the
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`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 1038 PAGE 1
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`

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`Amendment Bin Response to January 5, 2012 Office Action
`Appl. No. 12/553,107
`May 8, 2012
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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. (currently amended) A method for delivering a pharmaeeetieal eomposition
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`to a patient in need thereof, eomprising: treating osteoarthritis, rheumatoid arthritis, or
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`ankylosing spondylitis comprising orally administering to said.!! patient a pharmaeeetieal
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`eomposition in need thereof an AM unit dose form eomprising and, 10 hours (±20%)
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`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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`'wherein
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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 [[form]] at a pH of from about 0 or greater, wherein one enit
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`dose ferm is administered as an
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`the AM and PM unit dose forms and a seeond dose administered about 10 hoers
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`later as a Pl.\i dose to target:
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`i) a pharmacokinetic (pk) profile for naproxen where:
`the Aa:l.\i dose has a mean c_ of aboet 81 ttgtmL and a median
`time to maximum eoneentration (T-) of from about 2.S to
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`a)
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`b)
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`about 4 hoers, and
`the Pl.\i dose has a mean c_ of about 7ti.2 ttgtmL and a
`median T- of from about 10 to aboet 14 hoers
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`a)
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`for the AM dose of naproxen, the mean Cmax is 86.2 µg/mL
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`(±20%) and the median Truax is 3.0 hours (±20%); and
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`b)
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`for the PM dose of naproxen, the mean Cruax is 76.8 ug/mL
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`(±20%) and the median Truax is 10 hours (±20%); and
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`ii) a pharmacokinetic (pk) profile for esomeprazole where:
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`Amendment Bin Response to January 5, 2012 Office Action
`Appl. No. 12/553,107
`May 8, 2012
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`a)
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`the Al\1 dese has a meaa 1u·ea eadeF the plasma eeaeeat.-atiea
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`time eeFYe fFem time ~e.-0 whea the A .. 1\1 dese is admiaiste.-ed te
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`abeet 10 heeFs afteF the Al\1 dese is admiaiste.-ed 04.,UC~j
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`ef abeet 8SO hF*J:lg/mL, aad
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`b)
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`the Pl\1 dese has a meaa a.-ea eadeF the plasma eeneentFatien
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`time eeFYe fFem time ~e.-0 whea the Pl\1 dese is administe.-ed te
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`abeet 14 heeFs afteF the Pl\1 dese is administe.-ed (AUC~j
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`ef abeet 0SO hF*J:lg/mL
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`a)
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`for the AM dose of esomeprazole, the mean area under the
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`plasma concentration-time curve from when the AM dose is
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`administered to 10 hours (±20%) after the AM dose is
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`administered (AUCo-10.aml is 1216 hr*ug/mL (±20%),
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`b)
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`for the PM dose of esomeprazole, the mean area under the
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`plasma concentration-time curve from when the PM dose is
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`administered to 14 hours (±20%) after the PM dose is
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`administered (AUCo-14.pml is 919 hr*ug/mL (±20%), and
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`c)
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`the total mean area under the plasma concentration-time curve
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`for esomeprazole from when the AM dose is administered to 24
`hours (±20%) after the AM dose is administered (AUC0 _24) is
`2000 hr*ug/mL (±20%); and.
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`the AM and PM unit dose forms further target a mean % time at which
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`intragastric pH remains at about 4.0 or greater for about a 24 hour period after
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`reaching steady state that is at least about 60%.
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`Claims 20-28 (cancelled).
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`29. (currently amended) The method according to claim [[27]] 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
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`after reaching steady state is at least about 71 %.
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`Claims 30-32 (cancelled).
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`Amendment Bin Response to January 5, 2012 Office Action
`Appl. No. 12/553,107
`May 8, 2012
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`33. (currently amended) The method according to claim 19, wherein said AM and
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`PM unit dose forms are form is administered for a period of at least about 6 days.
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`34. (currently amended) The method according to claim 19, wherein said AM and
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`PM unit dose forms are form is 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 form is a multilayer tablet comprising at least one core and at
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`least a 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 salt thereof is released at a pH of
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`from abaut 0 or greater.
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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 salt thereof is released at a pH of from abaut 0 to 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 Bin Response to January 5, 2012 Office Action
`Appl. No. 12/553,107
`May 8, 2012
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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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`This amendment cancels claims 20-28, 30, 31, 38, and 39. Thus, claims 19, 29, 33,
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`34, 40, 42, and 45 are pending.
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`Claims 19, 29, 33, 34, 40, and 42 have been amended. Applicants submit the
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`amendments do not introduce new matter. Specifically:
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`1.
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`2.
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`Claim 19 has been amended to incorporate the recitations in claims 20, 22, 25,
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`and 28.
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`In several instances in claim 19, the term "about" has been replaced with
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`"(±20%)". This amendment is supported Applicants' specification at, for
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`example, page 6, lines 17-18. Claims 19, 40, and 42 have been amended to
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`remove the "about" characterization of a pH of 0.
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`3.
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`Claim 19 has been amended to recite the dosage amounts of naproxen (or a salt
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`thereof) and esomeprazole (or a salt thereof). This amendment is supported
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`by, for example, originally-filed claim 31; page 25, line 23 to page 26, line 4;
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`and the pk results for PN400/E20 in Example 1, pages 46-53.
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`Claim 29 has been amended to depend from claim 19 rather than cancelled
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`claim 27.
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`Claims 33 and 34 have been amended to more closely track the amended
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`language in claim 19.
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`Claims 40 and 42 have been amended to expressly recite a salt of
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`esomeprazole. This amendment makes the claims more consistent with
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`amended claim 1.
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`4.
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`5.
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`6.
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`7.
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`Other amendments rephrase the claims or correct obvious errors.
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`Applicants reserve their right to pursue any subject matter cancelled or otherwise
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`disclosed in this application in or more later-filed continuations and/or divisionals.
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`II.
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`Response to rejection under 35 U.S.C. § 112 {First Paragraph)
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`Claims 19-31, 33, 34, 38-40, 42, and 45 have been rejected as lacking enablement.
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`Specifically, the Office action asserts that the specification does not enable the delivery of
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`Amendment Bin Response to January 5, 2012 Office Action
`Appl. No. 12/553,107
`May 8, 2012
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`drugs in unspecified routes to unspecified patient populations. Applicants request withdrawal
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`of this rejection.
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`Claims 20-28, 30, 31, 38, and 39 have been canceled. Thus, this rejection has been
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`rendered moot as to those claims.
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`As to the remaining claims, Applicants have amended claim 19 to be focused on
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`treating osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis in a patient in need
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`thereof by a method comprising orally administering the recited unit dose forms. Applicants
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`believe this amendment addresses the concerns raised in the Office action, particularly given
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`the Office action's acknowledgement that the specification does enable oral administration to
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`treat patients suffering from inflammatory diseases.
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`Claims 29, 33, 34, 40, 42, and 45 depend directly or indirectly from claim 19. Thus,
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`the above-discussed amendments to claim 19 should address the concerns raised in the Office
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`action to those claims as well.
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`III.
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`Response to obviousness-type double patenting rejection
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`Claims 19-31, 33, 34, 38-40, 42, and 45 have been rejected on the grounds ofnon(cid:173)
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`statutory obviousness-type double patenting over claims 1-55 of U.S. Patent No. 6,926,907
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`("Plachetka"). Applicants request withdrawal of this rejection.
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`Claims 20-28, 30, 31, 38, and 39 have been canceled. Thus, this rejection has been
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`rendered moot as to those claims. Applicants, therefore, request withdrawal of this rejection
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`as to those claims.
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`As to the remaining claims, Applicants submit this rejection is not yet ripe for
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`response, given that other rejections are pending and the claim scope has not yet been
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`necessarily finalized. Applicants, therefore, respectfully request this rejection be held in
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`abeyance until such time that the claims have been found to be otherwise allowable.
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`Alternatively, Applicants respectfully request this rejection be withdrawn on the
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`merits in view of the claim amendments. In particular, Applicants submit the amended claims
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`are patentably distinct over claims 1-55 of Plachetka for reasons analogous to the reasons
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`discussed below regarding the non-obviousness of claims 19, 29, 33, 34, 40, 42, and 45 over
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`the Plachetka disclosure generally.
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`Amendment Bin Response to January 5, 2012 Office Action
`Appl. No. 12/553,107
`May 8, 2012
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`IV.
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`Response to rejection under 35 U.S.C. §103(a)
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`Claims 19-31, 33, 34, 38-40, and 42 have been rejected as being obvious over
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`Plachetka. Applicants request withdrawal of this rejection.
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`Claims 20-28, 30, 31, 38, and 39 have been canceled. Thus, this rejection has been
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`rendered moot as to those claims.
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`As to the remaining claims, the Office action asserts that it would have been obvious
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`to select a combination of naproxen and esomeprazole as the respective NSAID and acid
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`inhibitor of the drug dosage forms of Plachetka. Although the Office action acknowledges
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`that Plachetka does not disclose the specific pharmacokinetic ("PK") profile recited in
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`Applicants' claims, it suggests that a skilled artisan would have found it obvious to arrive at
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`this profile by merely observing the PK properties of the proposed dosage form containing
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`naproxen and esomeprazole.
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`At the outset, Applicants have amended claim 19 to be focused on the esomeprazole
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`and naproxen PK profiles observed for PN400/EC20 in their Example 1. See Applicants'
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`specification, pages 43-53. Claim 19 also has been amended to recite a pharmacodynamic
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`("PD") endpoint wherein the mean% of time for which the patient's intragastric pH remains
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`at about 4.0 or greater for about 24 hours after reaching steady state is at least about 60%.
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`Such an endpoint was achieved with PN400/EC20. See, e.g., Applicants' specification, Table
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`4, page 41 (mean% time of pH >4.0 = 71.35 (SD= 13.01)). This extended period of having
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`a pH at 4.0 or greater is believed to be advantageous toward protecting patients from
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`adverse effects of naproxen. See, e.g., Applicants' specification, page 1, lines 13-28.
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`Applicants submit that their particular combined PK/PD profile would not have been
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`obvious in view of Plachetka. More specifically, Plachetka discusses dosage forms that
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`release an acid inhibitor that raises the pH of a patient's GI tract, followed by an NSAID.
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`Plachetka gives esomeprazole as an example of such an acid inhibitor, and naproxen as an
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`example of such an NSAID. However, the only specific discussion in Plachetka regarding PK
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`properties is at paragraph [0021]. There, naproxen and naproxen sodium are reported as
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`having half-lives of about 12 to 15 and 12 to 13 hours, respectively. Plachetka does not report
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`any specific PK properties for esomeprazole (or any of the other agents disclosed as able to
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`raise the pH of a patient's GI tract). Moreover, Plachetka does not report any such profile in
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`the context of a combination with naproxen. Thus, Plachetka does not provide or suggest the
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`specific claimed PK profile, much less the claimed specific combined PK/PD profile.
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`Amendment Bin Response to January 5, 2012 Office Action
`Appl. No. 12/553,107
`May 8, 2012
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`Plachetka also does not provide or suggest what parameters must be used to arrive at a
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`dosage form that possesses their particular PK/PD profile. Parameters that may influence PK
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`profile and PD response include, for example, the respective dosages of the NSAID and acid
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`inhibitor, the extent of drug absorption, the extent of drug distribution, and the duration of
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`drug administration. See Applicants' Specification, page 1, lines 20-23. Certain dose ranges
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`and preferred dosages for naproxen and esomeprazole are generally discussed by Plachetka,
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`but the relation of any of these to a specific PK/PD profile --- particularly that recited in claim
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`19 --- is not expressly discussed. See, e.g., Plachetka, at column 3, lines 48-50; column 6,
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`lines 6-11; and column 7, lines 12-13.
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`Simply put, a skilled artisan would have not been able to predict with a reasonable
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`expectation of success whether any particular dosage form of Plachetka containing a
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`naproxen/esomeprazole combination would possess the particular PK profile and/or PD
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`response recited in claim 19. Instead, the skilled artisan would have had no choice but to
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`randomly formulate and test dosage forms in hopes of arriving at such a combined profile.
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`Where an obviousness finding is based on "merely throwing metaphorical darts at a board" in
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`hopes of arriving at a successful result, but "the prior art gave either no indication of which
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`parameters were critical or no direction as to which of many possible choices is likely to be
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`successful," courts should reject such "hindsight claims of obviousness." See Eurand v.
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`Afylan, 2012 U.S. App. LEXIS 7571, *14 (Fed. Cir. April 16, 2012). For at least these
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`reasons, Applicants submit that claim 19 is non-obvious over Plachetka.
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`Claims 29, 33, 34, 40, 42, and 45 depend directly or indirectly from claim 19, and are,
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`therefore, patentable over Plachetka for at least the same reasons as claim 19.
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`*********
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`Applicants request a two-month extension to respond to the January 5, 2012 Office
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`action, and authorize the Commissioner to charge the corresponding fee to Deposit Account
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`No. 260166. If any other fee(s) is due in connection with this filing, Applicants authorize the
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`Commissioner to charge the fee(s) to Deposit Account No. 260166 (referencing Attorney
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`Docket No. 103526-US/NS). 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/NS).
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`Amendment Bin Response to January 5, 2012 Office Action
`Appl. No. 12/553,107
`May 8, 2012
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`Applicants submit the pending claims are in condition for allowance, and requests 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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`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
`FOP2-234
`1800 Concord Pike,
`Wilmington, DE 19850-5437
`Office telephone: (302) 885-6609
`Mobile: (302) 357-4046
`Facsimile: (302) 886-8221
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