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`Exhibit 1021
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`‘688 Patent File History (“FH688”),
`Amendment 4/24/2013
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`

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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`Docket No.: 122184—02804
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`(PATENT)
`
`In re Patent Application of:
`William Forbes
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`Application No.: 12/573,081
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`Confirmation No.: 5308
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`Filed: October 2, 2009
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`Art Unit: 1611
`
`For: COMPOSITIONS AND METHODS FOR
`TREATMENT OF BOWEL DISEASES WITH
`GRANULATED MESALAMINE
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`Examiner: FRAZIER, BARBARA S.
`
`MS Amendment
`Commissioner for Patents
`P.O. Box 1450
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`Alexandria, VA 22313-1450
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`RESPONSE UNDER 37 C.F.R.
`
`1.111
`
`Dear Madam:
`
`In reply to the non—final Office Action mailed February 26, 2013, Applicants respectfully
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`request reconsideration of this application in View of the following amendments and remarks.
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`Amendments to the Claims begin on page 2 of this paper.
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`Remarks follow the Amendments to the Claims and begin on page 6.
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`Ex 1021 ME1 15162951V.1
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`MycoNovo, Inc.
`Foxhill Opportunity Fund, L.P.
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`

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`Docket No.: 122184—02804
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`Application No.: 12/573,081
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`AMENDMENTS TO THE CLAIMS
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`This listing of claims will replace all prior versions, and listing of claims, in this
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`application.
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`Listing of Claims:
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`1- 13. (Cancelled)
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`14.
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`(Previously Presented) A method of maintaining the remission of ulcerative colitis in a
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`subject comprising administering to the subject a single 1.5 gram dose of a granulated
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`mesalamine formulation once per day, wherein:
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`said method maintains remission of ulcerative colitis in the subject for a period of at least
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`6 months of treatment;
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`remission is defined as a DAI score of 0 or 1; and
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`the granulated mesalamine formulation is not administered with antacids.
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`15.
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`(Cancelled)
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`16.
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`(Cancelled)
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`17.
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`(Previously Presented) The method of claim 14, wherein the granulated mesalamine
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`formulation is a delayed and extended release formulation.
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`18.
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`(Previously Presented) The method of claim 17, wherein delayed and extended comprises
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`first releasing mesalamine in ileum and continuing to release mesalamine throughout terminal
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`ileum and colon.
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`19.
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`(Original) The method of claim 14, wherein the granulated mesalamine formulation is
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`administered for the maintenance of remission of ulcerative colitis in subjects 18 years of age
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`and older.
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`Docket No.: 122184—02804
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`Application No.: 12/573,081
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`20.
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`(Previously Presented) The method of claim 14, wherein the granulated mesalamine
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`formulation comprises four capsules administered once per day in the morning, afternoon or
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`evening with or without food or without regard to meals.
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`21.
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`(Previously Presented) The method of claim 14, the granulated mesalamine formulation
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`comprises four capsules administered per day in the morning, with or without food.
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`22.
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`(Cancelled)
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`23.
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`(Previously Presented) The method of claim 14, further comprising advising the subject
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`that subjects having hypersensitivity to salicylates, aminosalicylates, or any component of the
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`granulated mesalamine formulation should not be administered the granulated mesalamine
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`formulation.
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`24.
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`(Original) The method of claim 14, further comprising advising the subject that when
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`being administered granulated mesalamine formulation renal impairment may occur.
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`25.
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`(Original) The method of claim 24, further comprising assessing the subject’s renal
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`function one or more of at the beginning of treatment, before initiating therapy, or periodically
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`during therapy.
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`26.
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`(Original) The method of claim 14, further comprising advising the subject that acute
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`exacerbation of colitis symptoms can occur.
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`27.
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`(Original) The method of claim 14, further comprising advising the subject that the
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`granulated mesalamine formulation should be used with caution in subjects with renal disease.
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`28.
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`(Original) The method of claim 14, further comprising monitoring the blood cell counts
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`in geriatric subjects being administered the granulated mesalamine formulation.
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`Docket No.: 122184—02804
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`Application No.: 12/573,081
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`29.
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`(Original) The method of claim 14, further comprising advising the subject that there are
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`adverse reactions associated with administration of the granulated mesalamine formulation.
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`30.
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`(Original) The method of claim 29, wherein the adverse reactions comprise one or more
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`of headache, diarrhea, upper abdominal pain, nausea, nasopharyngitis, flu or flu—like illness,
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`sinusitis.
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`31.
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`(Original) The method of claim 14, further comprising advising the subject that the
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`granulated mesalamine formulation is not expected to inhibit the metabolism of drugs that are
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`substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.
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`32-69. (Cancelled)
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`70.
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`(Previously Presented) The method of claim 14, further comprising selecting a subject
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`with a DAI score of 0 or 1 for maintaining remission of ulcerative colitis with granulated
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`mesalamine.
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`71.
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`(Cancelled)
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`72.
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`(Previously Presented) The method of claim 21, wherein the four capsules each comprise
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`0.375 g granulated mesalamine.
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`73.
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`(New) The method of claim 14, wherein the mesalamine comprised in the formulation is
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`released over approximately 7 hours.
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`74.
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`(New) A method of maintaining the remission of ulcerative colitis in a subject
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`comprising advising the subject that granulated mesalamine should not be taken with antacids
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`and administering to the subject a single 1.5 gram dose of a granulated mesalamine formulation
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`once per day, wherein:
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`said method maintains remission of ulcerative colitis in the subject for a period of at least
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`6 months of treatment;
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`Docket No.: 122184—02804
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`remission is defined as a DAI score of 0 or 1; and
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`the granulated mesalamine formulation is not administered with antacids.
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`Docket No.: 122184-02804
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`Application No.: 12/573,081
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`1.
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`Status of the Claims
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`REMARKS
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`As presented above, new Claims 73 and 74 are added. Support for these new claims can
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`be found in the specification as filed, e.g., on pages 3-4, lines 34-5; page 7, lines 1-3; page 8,
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`lines 28-31; page 12, lines 5-6; and in Example 5 entitled “Studies on Remission from
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`Ulcerative Colitis”.
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`Applicants submit that above amendments raise no issue of new matter. With entry of
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`this response, Claims 14, 17-21, 23-31, 70, 72, 73, and 74 are pending.
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`II.
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`Rejection under 35 U.S.C. § 102
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`Claims 14, 17-19, and 70 have been rejected under 35 U.S.C. § 102(b) as allegedly being
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`anticipated by Salix, Drugs.com, published September 5, 2007 (hereinafter “Salix article”) as
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`evidenced by U.S. 2010/0035850 (hereinafter “Meyer0fi”). Office Action at 3-4. Specifically,
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`the position has been maintained that while the Salix article does not disclose the claimed DAI
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`score, one skilled in the art would recognize that the remission of ulcerative colitis would be
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`defined by a DAI score of 0 or 1 as evidenced by Meyerofl. E. at 3. In addition, it has been
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`alleged that although the prior art does not disclose the absence of antacids during the
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`administration of granulated mesalamine, the skilled artisan would clearly envisage not
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`administering granulated mesalamine with antacids. E. at 2-3. Applicants respectfully disagree
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`and traverse these rejections.
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`Previously, and as admitted by the Examiner, Applicants pointed out that the Salix article
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`does not disclose the co-administration, or lack thereof, of mesalamine with antacids. Therefore,
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`Applicants found it clear that the Salix article does not teach each and every element as set forth
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`in the pending claims and, consequently, does not anticipate the claimed invention. In response
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`to Applicants’ previous submission, it has now been asserted that this argument is not persuasive
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`because it is “burdensome and unrealistic” to require the Salix article to teach everything that is
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`not administered with the active ingredient. Office Action at 5.
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`While Applicants can appreciate that analyzing a prior art reference may sometimes be
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`burdensome, Applicants respectfully submit that endeavors taken during the process of
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`analyzing a prior art reference do not factor into the standard for determining novelty. In
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`addition, Applicants assert that if a prior art reference does not teach an element of a claim, that
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`reference fails to satisfy the requirements under § 102. See e.g., Verdegaal Bros. V. Union Oil
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`Co. of California, 814 F.2d 628, 631, 2 USPQ2d 1051, 1053 (Fed. Cir. 1987). Applicants
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`respectfully submit that the fact of the matter is that the Salix article does not disclose all of the
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`elements of Applicants’ claims. In alternative language:
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`"The prior art reference must clearly and unequivocally disclose the
`claimed invention or direct those skilled in the art to the invention
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`and combining various
`without any need for picking, choosing,
`disclosures not directly related to each other by the teachings of the cited
`reference." In re Arkley, 455 F.2d 586 (CCPA 1972).
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`Here, the Salix article does not “clearly and unequivocally” disclose the claimed DAI
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`score or the administration, or lack thereof, of mesalamine with antacids. Moreover, with respect
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`to new Claim 74, the Salix article does not disclose the step of advising the subject that
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`granulated mesalamine should not be taken with antacids. For at least these reasons, the Salix
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`article and Meyerofl do not anticipate the claimed subject matter. Withdrawal of this rejection is
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`respectfully requested.
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`III.
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`Rejections under 35 U.S.C. § 103
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`The following claims have been rejected under 35 U.S.C. § 103(a): Claims 14, 17-20,
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`23-30, and 70 as allegedly being unpatentable over the Salix article as evidenced by Meyerofl
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`and optionally in view of NetD0ct0r; Claims 21 and 72 as allegedly being unpatentable over the
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`Salix article, as evidenced by Meyerofl optionally in view of NetD0ct0r, and further in view of
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`End0Nurse; and Claim 31 as allegedly being unpatentable over the Salix article as evidenced by
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`Meyerofl optionally in view of NetD0ct0r, and Fischkofl. Office Action at 5-13. Applicants
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`respectfully disagree and traverse these rejections.
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`The Salix Article
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`First, Applicants agree with the statement on page 6 of the Office Action that the Salix
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`Article does not teach that the granulated mesalamine formulation is not administered with
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`antacids. Applicants also submit that the Salix article fails to teach or suggest the claimed
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`remission DAI score of 0 or 1. In addition, and as now recited by new Claim 74, the Salix article
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`further fails to teach or suggest advising subjects not to take antacids.
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`To establish a prima facie case of obviousness there must be "a searching comparison of
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`the claimed invention - including all its limitations - with the teachings of the prior art." In re
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`Ochiai, 71 F.3d 1565, 1572 (Fed. Cir. 1995, emphasis added). As discussed above, and with
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`respect to independent Claim 14, the Salix article fails to teach both the claimed DAI score and
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`not administering granulated mesalamine with antacids. Moreover, with respect to new Claim
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`74, the Salix article fails to teach the additional element of advising the subject that granulated
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`mesalamine should not be taken with antacids. Consequently, the Salix article cannot be used to
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`establish a prima facie case of obviousness.
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`Applicants also take the opportunity to re—address certain statements presented under the
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`§ 102 section on page 5 of the Office Action, which appear to be relied upon in the present § 103
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`rejection. On page 5 of the Office Action, it has been stated that “[i]f a reference teaches the
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`administration of one active ingredient, then the skilled artisan may reasonably assume that no
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`other active ingredients are administered.” In the next line of the Office Action, it has been
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`stated that “assuming arguendo that [the] Salix [article] does not disclose that the granulated
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`mesalamine is not co—administered with antacids, the claims are still rendered obvious in view of
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`the teachings of [the] Salix [article] .
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`.
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`. .” Applicants respectfully traverse these statements and
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`respectfully submit that they are inconsistent with the legal standard for determining
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`obviousness.
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`The fact that a certain characteristic may occur or be present in the prior art is not
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`sufficient to establish the inherency of that characteristic. See M.P.E.P. § 2112(IV), citing In re
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`Rijckaert, 9 F.3d 1531, 1534, 28 USPQ2d 1955, 1957 (Fed. Cir. 1993) (reversed rejection
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`because inherency was based on what would result due to optimization of conditions, not what
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`was necessarily present in the prior art); In re Oelrich, 666 F.2d 578, 581-82, 212 USPQ 323,
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`326 (CCPA 1981). Again, and respectfully submitted, a complaint that it is burdensome to
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`require that the Salix article teach that granulated mesalamine is not (or at best that is should not
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`be) administered with antacids, is not a basis to conclude that the Salix article does, necessarily,
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`teach one of Applicants’ claimed elements. This line of reasoning in the present Office Action
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`was recently struck down in Ex parte Smith (Appeal No. 2010—008057), where the Court re-
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`emphasized the analysis in In Re Olrich stating that "an inherent characteristic must be
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`inevitable, and not merely a possibility or probability. See In re Oelrich, 666 F.2d 578, 581
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`(CCPA 1981)." That is, simply because the Salix article teaches granulated mesalamine, there is
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`no evidence on record, or authority cited or present, that justifies the “assumption” that the
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`granulated mesalamine in the Salix article is not co—administered with antacids. The mere fact
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`that a certain thing may result from a given set of circumstances is not sufficient. See e.g., Ii
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`Robertson, 169 F.3d 743, 745, 49 USPQ2d 1949, 1950-51 (Fed. Cir. 1999).
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`Here the Salix article is deficient in teaching at least the following three of elements of
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`Applicants’ pending claims: 1) advising the subject not to take antacids (e.g., in Claim 74); 2) a
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`DAI score of 0 or 1 (e.g., in Claims 1 and 74); and 3) wherein the granulated mesalamine
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`formulation is not administered with antacids (e.g., in Claims 1 and 74). Consequently, the Salix
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`article does not, and cannot be used, to establish a prima facie case of obviousness.
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`NetD0ct0r
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`In an attempt to cure the deficiencies of the Salix article, the present Office Action has
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`cited NetD0ct0r for its alleged teachings of not taking indigestion remedies at the same time of
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`day as Asacol MR. Office Action at 6-7. Specifically, it has been alleged that “it would have
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`been obvious to a person having ordinary skill in the art at the time of the invention was made
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`not to administer the granulated mesalamine of [the] Salix [article] with antacids, since doing so
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`would allow the granulated mesalamine to dissolve in the stomach instead of the intestine, as
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`taught by [NetD0ct0r], and it is desired that the mesalamine formulation first be distributed in
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`the intestine, as taught by [the] Salix [article]. I_d at 7. Applicants respectfully disagree and
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`traverse these allegations.
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`Applicants point out that the claimed formulation is unique and superior to the
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`formulation taught by NetD0ct0r. In fact, Applicants’ specification directly compares the
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`claimed formulation to Asacol MR (the formulation described in NetD0ct0r). See e.g.,
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`Applicants specification at page 12, lines 1-5; Example 6; and Tables 3-4. While both
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`Applicants’ formulation and the formulation discussed in NetD0ct0r may comprise a form of
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`mesalamine, the chemical makeup of both formulations and, consequently, as is evidenced in
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`Applicants’ specification, the pharmacokinetics and clinical properties are distinct from each
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`other.
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`For example, as described in Applicants specification:
`
`for example in one
`[t]he granulated mesalamine formulation,
`embodiment, comprises a hard gelatin capsule shell containing a
`granulated mesalamine formulation which comprises, for example,
`an inner polymer matrix mesalamine core that is surrounded by an
`outer flavor coating, a middle coating, and an inner enteric pH
`dependent (delayed) release coating. The inner coating dissolves,
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`for example, at pH ~6, but resists dissolution in the stomach,
`where gastric fluid is pH 1 during fasting and approximately pH 4
`during a meal. Applicants’ Specification at 12,
`lines 7-12,
`emphasis added.
`
`In one embodiment, following dissolution of the inner coating, the
`polymer matrix core of the granulated mesalamine provides a
`mechanism by which mesalamine,
`the
`active
`therapeutic
`ingredient, is uniformly and slowly released and distributed in the
`lumen of
`the
`colon. The
`release profile
`and
`additional
`phannacokinetic data show that
`the pellets of the granulated
`mesalamine formulation have a relatively low rate and extent of
`systemic absorption, and that 85% to 90% of drug reaches the
`diseased area. E. at 12, lines 13-18, emphasis added.
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`In contrast, NetDoctor solely indicates that Asacol MR consists of a special coating that
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`allows the medicine to pass through the stomach and be released in the intestine. NetDoctor
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`offers no evidence or data with respect to the chemical makeup, composition, kinetics, or even
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`the release profile of Asacol MR. Absent further evidence, the skilled artisan reading NetDoctor
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`is left with nothing more than a general recommendation that tablet mesalamine should not be
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`taken with indigestion remedies. What is certainly not present in this reference, is any teaching
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`or suggestion that indigestion remedies should not be taken with granulated mesalamine, much
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`less, the claimed formulation comprising granulated mesalamine.
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`Applicants respectfully submit that it is not proper to rely on the teachings of NetDoctor,
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`which is directed to a different formulation with a different mechanism of action, and apply
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`those teachings to the pending claims. Similar to the decision set forth in Ex Parte Issac
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`Ostrovsky (Appeal No. 2011—009091), the formulation described in NetDoctor does not
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`correspond or relate to the instant formulation and any teaching regarding the properties of
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`Asacol MR is irrelevant to the pending claims.
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`As discussed above, and reiterated here, the claimed formulation has a specific pH
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`dependent release profile whereby the inner coating of the claimed formulation resists
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`dissolution at lower pH ranges (e.g., 1 to 4), thus allowing for dissolution and delivery of the
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`granulated mesalamine in the lumen of colon. Disrupting or altering the environmental pH at
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`which the claimed formulation is present, such as, e.g., ingesting antacids which neutralize the
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`pH acid in the stomach, reduces the efficacy of the claimed formulation and renders it less
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`attractive for use in maintaining the remission of ulcerative colitis. NetDoctor is directed to a
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`different chemical formulation and makeup, and does not teach or suggest Applicants’ distinct
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`pH dependent properties. For at least these reasons NetD0ct0r fails to cure any of the
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`deficiencies in the Salix article.
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`Meyeroff
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`Meyerofl is cited in the present Office Action for allegedly teaching that a patient is
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`considered to be in remission for ulcerative colitis if they have a DAI score of less than or equal
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`to 1. Office Action at 3-4. However, Applicants respectfully submit that Meyerofl still does not
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`cure the deficiencies of the Salix article and NetD0ct0r referenced above. As to the individual
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`rejections of dependent Claims 21, 31, and 72 (Office Action at 10-12), Applicants submit that
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`these rejections are moot on the basis that independent Claim 14, from which each of these
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`claims depend, is novel and nonobvious.
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`For at least the foregoing, Applicants submit that all of the pending claims are
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`nonobvious over the cited art. Reconsideration and withdrawal of the outstanding § 103 rejection
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`is respectfully requested.
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`IV.
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`Final Remarks
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`Applicants respectfully request entry of the above amendment, favorable reconsideration,
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`of this application, and the timely allowance of the pending claims. If a telephone conversation
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`with Applicants’ agent would help expedite the prosecution of the above—identified application,
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`the Examiner is urged to call the undersigned agent at (617) 449-6585.
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`Please charge any fee(s) required for entry of this response, and any and all additional
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`fee(s) to our Deposit Account No. 50-4876, under Docket No. 122184-02804, from which the
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`undersigned is authorized to draw.
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`Dated: April 24, 2013
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`Respectfully submitted,
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`/Michael J. DeGrazia/
`Electronic signature:
`Michael J. DeGrazia, Ph.D.
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`Registration No.: 68,901
`McCarter & English, LLP
`265 Franklin Street
`
`Boston, MA 02110
`
`(617)-449-6585 (Tel)
`(617)-607-9200 (Fax)
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