IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`In re Application of: Rader
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`Serial No:
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`10/591,923
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`Examiner: Weddington, Kevin E
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`Filed:
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`June 21, 2007
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`Art Unit:
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`1614
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`For: METHODS FOR TREATING
`DISORDERS OR DISEASES ASSOCIATED
`WITH HYPERLIPIDEMIA AND
`HYPERCHOLESTEROLIMIA WHILE
`MINIMIZING SIDE EFFECTS
`
`Attorney Docket No. AGP-002
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`Confirmation No. 5393
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`RESPONSE UNDER C.F.R. § 1.116
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`Dear Sir:
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`This Response is being filed in response to the outstanding Office Action, mailed July 26,
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`2010 in connection with the above-identified application. Applicant submits the following
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`remarks:
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`CFAD Ex. 1011 (1 of 9)
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`

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`In the claims:
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`I.
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`(Previously Presented) A method of treating a subject suffering hyperlipidemia or
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`hypercholesterolemia, the method comprising administering to the subject an effective amount of
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`an MTP inhibitor, wherein said administration comprises at least three step-wise, increasing dose
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`levels of the MTP inhibitors wherein a first dose level is from about 2 to about 13 mg/day, a
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`second dose level is from about 5 to about 30mglday, and a third dose level is from about 10 to
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`about 50 mg/day; and wherein the MTP inhibitor is represented by:
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`or a pharmaceutically acceptable salt thereof or the piperidine N-oxide thereof, and wherein each
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`dose level is administered to the subject for about 1 to 4 weeks.
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`2.
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`3.
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`(Original) The method of claim 1 wherein the disorder is severe hypercholesterolemia.
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`(Previously Presented) The method of claim 1 wherein one or more of Total Cholesterol,
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`LDL, fasting triglycerides (TG), VLDL, lipoprotein (a) (Lp(a)), and-lipoprotein Bare reduced by
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`at least 15%, compared to control levels.
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`4.
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`(Previously Presented) The method of claim I wherein one or more of Total Cholesterol,
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`LDL, fasting triglyceride·s {TG), VLDL, lipoprotein (a) (Lp(a)), and-lipoprotein B are reduced by
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`at least 25%, compared to control levels.
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`-2-
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`CFAD Ex. 1011 (2 of 9)
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`

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`5.
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`6.
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`7.
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`(Canceled)
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`(Original) The method of claim 1 wherein the MTP inhibitor is admin.istered orally.
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`(Canceled)
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`8.
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`(Previously Presented) The method of claim 1 wherein said increasing dose levels further
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`comprise a fourth dose level.
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`9.
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`(Previously Presented) The method of claim 1 wherein said increasing dose levels further
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`comprise a fourth and a fifth dose level.
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`10.-15. (Canceled)
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`16.
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`(Previously Presented) The method of claim 1 wherein said MTP
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`inhibitor is
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`administered to said subject in combination with a further compound selected from the group
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`consisting of: HMG CoA reductase inhibitors, cholesterol absorption inhibitors, ezetimibe,
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`squalene synthetase inhibitors, fibrates, bile acid sequestrants, statins, probucol, niacin,
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`thiazolidinediones, and cholesterol ester transfer protein (CETP) inhibitors.
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`17.
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`(Canceled)
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`18.
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`(Previously Presented) The method of claim 16 wherein the MTP inhibitor and the
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`further compound are present in the same dosage unit.
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`19. -25. (Canceled).
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`26. (Previously Presented) The method of claim 1, wherein the increasing dose levels comprise a
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`fourth dose level from about 20 to about 60 mg/day and a fifth dose level from about 30 to about
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`75mg/day.
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`- 3-
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`CFAD Ex. 1011 (3 of 9)
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`

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`27. (Previously Presented) A m~thod of treating hyperlipidemia or hypercholesterolemia in a
`subject in need thereof, comprising:
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`initially administering to the subject a first dose level of about 2 to about 13 mg/day of a
`compound represented by:
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`or a pharmaceutically acceptable salt thereof or the piperidine N-oxide thereof, for about 1 week
`to about 4 weeks,
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`administering an increasing second and third dose level of the compound for about 1
`week to about 4 weeks each, wherein said second and third dose level are no more than 50% of
`the immediately following dose level.
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`28. (Previously Presented) The method of claim 16, wherein the further compound is ezetimibe.
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`-4-
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`CFAD Ex. 1011 (4 of 9)
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`

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`REMARKS
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`Claims 1-4, 6, 8, 9, 16, 18, 26-28 are pending.
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`Applicants note that independent claim 27, which stands rejected as obvious under 35
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`U.S.C. 103, is directed to a specific method of treating hyperlipidemia or hypercholesterolemia
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`including administering the recited dosages of the claimed MTP inhibitor, and such methods
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`offer surprising and unexpected advantages, as was discussed in the previous response and the
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`previously submitted Declaration of William Sasiela, Ph.D. Because there is no mention of the
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`substantial effort and evidence of this previous submission in the instant Action, such evidence
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`does not appear to be considered by the Office. Applicants therefore respectfully request
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`reconsideration and withdrawal of the final rejection of these claims.
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`Further, as the Action notes, claim 1 was amended to include some limitations of original
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`claim 13, reciting the specific dosing of three claimed dosage levels. As is clear from the
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`pending claims, the claimed invention is directed in part to the recited dosage levels of claim 1 or
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`claim 27, which does not necessarily include a fifth dose level.
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`Claim Rejections under 35 U.S.C. § 102
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`Claims 1-4, 6, 8, 16 and 18 stand rejected under 35 U.S.C. 102(b) as being anticipated by
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`Gregg et al., US 5,883,109. Applicants respectfully disagree with the Office analysis of this
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`rejection on both a legal and factual basis.
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`Independent claim 1 recites a specific method that includes three step-wise, increasing
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`dose levels of the MTP inhibitors wherein a first dose level is from about 2 to about 13 mg/day, a
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`second dose level is from about 5 to about 30mg/day, and a third dose level is from about 10 to
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`about 50 mg/day. Nowhere in the Gregg et al. reference is there any teaching of such a method.
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`Rather, Gregg et al., for example, teaches oral dose forms containing "5 to about 500 mg,
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`preferably from about 10 to about 400 mg, and more preferably from about 20 to about 250 mg."
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`Gregg et al. col. 23 11. 17-19. As the Examiner knows, in order to anticipate claims, the claimed
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`subject matter must be disclosed in the reference with "sufficient specificity to constitute an
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`anticipation under the statute." M.P.E.P. 2131.03 (emphasis added). Applicant notes that the
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`first dose level in recited in instant claim 1 includes a narrow range that in part falls out of the
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`- 5-
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`CFAD Ex. 1011 (5 of 9)
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`

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`scope of any disclosure of Gregg et al. Further, while Gregg et al. recite that compositions that
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`may be administered "in single or divided doses of one to four times daily" there is no teaching
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`of the specific claimed step-wise claimed dosages. Applicant notes that, while Gregg et al. states
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`that it "may be advisable to start a patient on a low dose combination and work up gradually to a
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`high dose combination" such disclosure appears directed to a combination dose of HMG CoA
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`reductase inhibitor, not to the recited MTP inhibitor of instant claim 1, and there is no teaching
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`of the claimed step wise increase with the specific first, second and third dose levels of instant
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`claimed 1.
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`Further, as the Action notes and is noted above, claim 1 was amended to include some
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`limitations of original claim 13, reciting the specific dosing of three claimed dosage levels,
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`which as noted above, are not taught by Gregg et al. Appicant notes that independent claim 27,
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`reciting a specific first dose level and increasing second and third dose levels of the claimed
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`MTP inhibitor, does not stand rejected under 35 U.S.C. 102. Applicant therefore respectfully
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`requests reconsideration and withdrawal of this rejection.
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`Claim Rejections under 35 U.S.C. § 103(a)
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`Claims 9 and 26-28 stand rejected under 35 U.S.C. 103(a) as being unpatentable over
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`Gregg, U.S. Patent No. 6,057,339 ("Gregg") in view of Rosenblum et al. U.S5,767,115
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`("Rosenblum"). Applicant respectfully traverses this rejection in view of the following
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`comments.
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`The Action indicates that the "instant invention differs from the cited reference in the at
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`the cited reference does not teach a fifth dose level" and that "one skilled in the art would have
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`assumed that addition of a fifth administration is obvious since it is advisable to start a patient on
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`a low dose and work up gradually to a high dose ... in the absence of evidence to the contrary."
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`(Emphasis added). As discussed above, and as is clear from the pending claims, the claimed
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`invention is directed in part to the recited dosage levels of claim 1 or claim 27, which does not
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`necessarily include a fifth dose level.
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`Applicant respectfully requests reconsideration of this rejection in light of consideration
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`of all submitted evidence taken as a whole, including the previously submitted Declaration of
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`- 6 -
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`CFAD Ex. 1011 (6 of 9)
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`

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`William Sasiela, Ph.D., In particular, as noted in the previous response and below, there is no
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`teaching in Gregg et al. to select, without undue experimentation, the claimed low initial dose
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`from the very broad range of disclosed dose levels -a range that spans 1 to 2 orders of
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`magnitude-, and then a step-wise increase in dose levels, to arrive at the instantly claimed
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`method that is both effective in significantly reducing adverse effects, and effective in treating
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`hyperlipidemia or hypercholesterolemia.
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`Applicant submits that the standard of obviousness requires a consideration of whether
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`the subject matter, taken as a whole, would have been obvious at the time the invention was
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`made to a person skilled in the art. As the Examiner knows, combining prior art methods to
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`reach a conclusion of obviousness requires: (i) a finding that the prior art included each element
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`claimed, (ii) a finding that one of ordinary skill in the art could have combined the elements by
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`known methods and that in combination each element merely would have performed the same
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`function as it did separately; and (iii) a finding that one of ordinary skill in the art would have
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`recognized that the results of the combination were predictable.
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`Applicant notes that independent claim 27 recites a method that includes a specific
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`dosing regimen. Neither Gregg nor Rosenblum teach an effective method that includes, for
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`example, initially administering a low dose of about 2 mg/day to about 13 mg/day, fw about 1 to
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`about 4 weeks, and then an increasing second dose, and a third dose, as recited in claim 27.
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`Rather, as noted above, Gregg teaches only oral dose forms containing "5 to about 500 mg,
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`preferably from about 10 to about 400 mg, and more preferably from about 20 to about 250 mg."
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`Importantly, neither Gregg or Rosenblum recognize that the disclosed MTP inhibitor
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`would cause two significant adverse effects, gastrointestinal related disorders and increase in
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`hepatic fat, when administered to patients only at a constant level. As a consequence, previous
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`phase II trials in human patients, initially administering 25 mg/day of the claimed compound,
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`were discontinued because of such adverse events. (See e.g. instant specification at e.g.,
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`paragraph 115; Example 8, and the accompanying Declaration ofWilliam Sasiela Ph.D. (the
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`"Declaration"). Further, neither the Gregg or Rosenblum recognize that the instantly claimed
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`method would result in the reduced incidence ofboth of these adverse events, while still being
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`efficacious. There is no guidance in Gregg to select, without undue experimentation, the claimed
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`- 7 -
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`CFAD Ex. 1011 (7 of 9)
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`

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`low initial dose from the very broad range of disclosed dose levels -a range that spans 1 to 2
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`orders of magnitude-, and then a step-wise increase in dose levels, to arrive at the instantly
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`claimed method effective in significantly reducing adverse effects.
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`For example, Applicants note that there is no reasonable expectation that one skilled in
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`the art at the time of the instant invention would arrive at the claimed method. For example, the
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`instant disclosure recognizes that the method provides for possible adaptation by the liver to the
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`claimed MTP inhibitor once administered at a low dose level of the claimed MTP inhibitor, and
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`such an initial low dose may continue to limit e.g. hepatic steatosis (fatty liver) even when the
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`patient is ultimately administered a higher dose, as described in the instant specification for
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`example, at page 26 paragraph 115. Further, as noted in the specification, it had been previously
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`concluded, after a patient study using constant dose levels of25 mg per day, (that the claimed
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`MTP inhibitor could not be developed as a drug for large scale use in the treatment of
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`hypercholesterolemia. (Specification, paragraph 33). The previously submitted Declaration
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`indicates that others of skill in the art, including the scientists and investigators of the failed trial,
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`did not appear to arrive at any solution these adverse events, and that the instant invention is non(cid:173)
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`obvious as to these prior art teachings.
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`Further, Applicants note, as described in the previously submitted Declaration, that the
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`instantly claimed method, e.g. with an initial administration of about 5 mg/day for four weeks,
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`and then step-wise increases to larger doses, results in dramatic difference in the rate of
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`gastrointestinal (GI) effects as compared to a constant dose level administration of the claimed
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`inhibitor- even when the constant dose level is substantially less than the dose administered after
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`several step wise increases as instantly claimed. As noted in the Declaration, patients on a
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`regimen such as described in claim 1 and 27 have a surprisingly lower rate of gastrointestinal
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`adverse effects even when ultimately administered up to 60 mg/day of the claimed MTP inhibitor
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`as compared to patients administered a constant low level of 10 mg/day. This significant
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`reduction in GI effects is obtained even when patients also receive a further lipid modifying
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`compound such as ezetimibe.
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`In contrast, Gregg appears to teaches starting low dose combinations of MTP inhibitors
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`and other cholesterol lowering agents, effectively teaching away from the claimed method of the
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`- 8 -
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`CFAD Ex. 1011 (8 of 9)
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`

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`low step wise dose levels of the MTP inhibitor and a constant level of another agent, e.g.
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`ezetimibe.
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`Applicants submit that the standard of obviousness requires a consideration of whether
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`the subject matter, taken as a whole, would have been obvious at the time the invention was
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`made to a person skilled in the art. Without conceding any prima facie case of obviousness,
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`Applicant believes that the Office must consider any rebuttal evidence, including showings that
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`the claimed invention possesses superior properties, as described in the accompanying
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`Declaration.
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`Applicant submits that the above references, either alone or in combination, fail to teach
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`or suggest the claimed subject matter taken as a whole. In particular, the references alone or in
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`combination, do not teach every limitation of the claims. Nor does the combination of each
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`element of the claims merely perform the same function as it does separately. Further, there is
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`no finding that one of ordinary skill in the art would have recognized that the results of the
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`combination were predictable. Therefore, Applicant respectfully requests withdrawal of this
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`rejection.
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`Any questions raised by this submission may be directed to the undersigned at (617) 570-
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`8743. The Commissioner is hereby authorized to charge any underpayments, or credit any
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`overpayments, to our Deposit Account No. 07-1700, Reference: AGP-002.
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`September 13, 2010
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`Tel. No.: (617) 570-8743
`Fax No.: (617) 523-1231
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`LIBC/3875894.1
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`Respectfully submitted,
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`/Theresa C. Kavanaugh/
`Theresa C. Kavanaugh, Reg. No. 50,356
`Attorney for Applicants
`Goodwin Procter LLP
`Exchange Place
`Boston, Massachusetts 021 09
`Customer No. 051414
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`- 9 -
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`CFAD Ex. 1011 (9 of 9)