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 SIZE EFFECTS
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`Attorney Docket No. AGP-002
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`Confirmation No. 5393
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`Dear Sir:
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`RESPONSE
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`This Response is being filed in response to the outstanding Office Action, mailed October
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`21, 2009 in connection with the above-identified application, together with a Declaration of
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`William Sasiela, Ph.D., under 37 C.F.R § 1.132. A petition for a Three Month Extension of
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`Time and a Supplemental Information Disclosure Statement accompanies this response.
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`Applicant submits the following remarks:
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`CFAD Ex. 1009 (1 of 9)
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`

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`In the claims:
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`1.
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`(Currently Amended) A method of treating a subject suffering from a eliseFEier asseeiateel
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`with hyperlipidemia ftfi:Eikr hypercholesterolemia, the method comprising administering to the
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`subject an effective am(:>Unt of an MTP inhibitor effeetive te amelierate the elisereler, wherein
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`said administration comprises at least three step-wise, increasing dose levels elesages of the MTP
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`inhibitors wherein a first dose level is from about 2 to about 13 mg/day, a second dose level is
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`from about 5 to about 30mg/day. and a third dose level is from about 10 to about 50 mg/day; and
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`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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`(Currently Amended) The method of claim 1 wherein one or more of Total Cholesterol,
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`LDL, fasting triglycerides (TO), VLDL, lipoprotein (a) (Lp(a)), and BfJelifJeproteiAs A I, A H, B,
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`aftEI...e. lipoprotein B are reduced by at least 15%, compared to control levels.
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`- 2-
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`CFAD Ex. 1009 (2 of 9)
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`

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`4.
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`(Currently Amended)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 Bf!elij:Jef!Feteias A I, A II, B,
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`ftHEl-.6 lipoprotein B are reduced by at least 25%, compared to control levels.
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`5.
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`(Canceled)
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`6.
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`7.
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`(Original) The method of claim 1 wherein the MTP inhibitor is administered orally.
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`(Canceled)
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`8.
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`(Currently Amended) The method of claim l + wherein said increasing dose levels
`esealatiRg Eleses further comprise a fourth dose level.
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`9.
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`(Currently Amended) The method of claim l + wherein said increasing dose levels
`esealatiAg Eleses further comprise a fourth and a fifth dose level.
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`10.-15. (Canceled)
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`16.
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`(Currently Amended) The method of claim 1 wherein said MTP inhibitor is administered
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`to said subject in combination with a further lif!iEl meElifyiag 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 seguestrants, 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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`(Currently Amended) The method of claim 16 wherein the MTP inhibitor and the further
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`compound lif!iEl meElifyiHg eemfJel:lAEls are present in the same dosage unit.
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`19. -25. (Canceled).
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`CFAD Ex. 1009 (3 of 9)
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`26. (New) The method of claim 1, wherein the increasing dose levels comprise a fourth dose
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`level from about 20 to about 60 mg/day and a fifth dose level from about 30 to about 75mg/day.
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`27. (New) A method of treating hyperlipidemia or hypercholesterolemia in a subject in need
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`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
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`compound represented by:
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`or a pharmaceutically acceptable salt thereof or the piperidine N-oxide thereof, for about 1 week
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`to about 4 weeks,
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`administering an increasing second and third dose level of the compound for about I
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`week to about 4 weeks each, wherein said second and third dose level are no more than 50% of
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`the immediately following dose level.
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`28. (New) The method of claim 16, wherein the further compound is ezetimibe.
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`-4-
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`CFAD Ex. 1009 (4 of 9)
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`REMARKS
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`Claims 1-25 are pending. Claims 5, 7, 10-15, 17, and 19-25 have been canceled. Claims
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`3, 4, 8, 9 and 18 have been amended for clarity. Claim 1 has been amended to recite limitations
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`of original claims 13 and 17, and the MTP inhibitor of original claim 21. Claim 16 has been
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`amended to particularly point out further compounds, as previously recited in original claim 23.
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`No new matter has been added.
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`Claims 26-28 are new. Support for claim 26 may be found for example, on page 17,
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`paragraph 58 of the instant specification. Support for claim 27 may be found throughout the
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`specification and claims as originally filed, for example, on page 17, paragraph 58; page 18,
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`paragraph 63; page 16, paragraph 53, and page 26, Example 8. Support for claim 28 may be
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`found throughout the specification and claims as originally filed, for example, original claim 16.
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`Amendment of the originally filed claims, or cancellation of any claims should in no way
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`be construed as an acquiescence, narrowing, or surrender of any subject matter. The
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`amendments are being made not only to point out with particularity and to claim the present
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`invention, but also to expedite prosecution of the present application. Applicant reserves the
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`option to prosecute the originally filed claims further, or similar ones, in the instant or
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`subsequently filed patent applications.
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`Claim Rejections under 35 U.S.C. § 112, first paragraph
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`Claim 1, 3-18,20,24 and 25 stand rejected under 35 U.S.C. 112, first paragraph, as
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`failing to comply with the written description requirement because "the specification as original
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`filed fails to provide sufficient written bases of any the agents demonstrating wherein possession
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`of the use of the broad terms: a disorder associated with hyperlipidemia and/or
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`hypercholesterolemia and a further lipid modifying agent." Applicant respectfully traverses this
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`rejection.
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`However, solely to expedite prosecution of this application, claim 1 has been amended to
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`recited a method of treating hyperlipidemia or hypercholestermia, diseases that are well known
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`to those of skill in the art. Further, claim 16 has been amended to recite particular further
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`CFAD Ex. 1009 (5 of 9)
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`compounds. Support for such amendment may be found in e.g., original claim 23. Claims 20
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`and 24-25 have been canceled. Applicant therefore requests withdrawal of this rejection.
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`Claim Rejections under 35 U.S.C. § 102
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`Claims 1-4,6-8,14, 15, 17, 19and22standrejectedunder35U.S.C.l02(b)asbeing
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`anticipated by Biller et al., US 5,739,135. Applicant notes that independent claim 1 has been
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`amended to include limitations of claim 5 and claim 13, which do not stand rejected under 35
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`U.S.C. 102(b) by Biller. Applicant therefore respectfully requests withdrawal of this rejection.
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`Claims 1-8, 14-16, and 18-23 stand rejected under 35 U.S.C. 102(b) as being anticipated
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`by Gregg et al., US 5,883,109. Applicant notes that independent claim 1 has been amended to
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`include limitations of claim 13, which do not stand rejected under 35 U.S.C. 102(b) by Gregg.
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`Applicant therefore respectfully requests withdrawal of this rejection.
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`Claim Rejections under 35 U.S.C. § 103(a)
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`Claims 9-13, 17,24 and 25 stand rejected under 35 U.S.C. 103(a) as being unpatentable
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`over Biller (U.S. 5, 739,135) ("Biller") or Gregg, U.S. Patent No. 6,057,339 ("Gregg") in view
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`of Dow U.S. 6, 194,454 ("Dow"). Applicant respectfully traverses this rejection in view of the
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`following comments.
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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 first notes that claim 1 has been amended to recite a method that includes a
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`specific dosing regimen. Neither Gregg nor Biller 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, for about 1 to
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`- 6 -
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`CFAD Ex. 1009 (6 of 9)
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`about 4 weeks, and then an increasing second dose, and a third dose, as recited in claim 1.
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`Rather, Biller, for example, teaches "5 to about 500 mg per day in single or divided doses of one
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`to four times daily," with no teaching of an initial low dose level of 2 to 13 mg for 1 to 4 weeks
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`as recited in claim 1.
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`Importantly, neither Gregg or Biller recognize that the disclosed MTP inhibitor would
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`cause two significant adverse effects, gastrointestinal related disorders and increase in hepatic
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`fat, when administered to patients only at a constant level. As a consequence, previous phase II
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`trials in human patients, initially administering 25 mg/day of the claimed compound, were
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`discontinued because of such adverse events. (See e.g. instant specification at e.g., paragraph
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`115; Example 8, and the accompanying Declaration of William Sasiela Ph.D. (the
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`"Declaration"). Further, neither the Gregg or Biller reference recognize that the instantly
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`claimed method would result in the reduced incidence of both of these adverse events, while still
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`being efficacious. There is no guidance in Biller or Gregg to select, without undue
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`experimentation, the claimed low initial dose from the very broad range of disclosed dose levels
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`-a range that spans 1 to 2 orders of magnitude-, and then a step-wise increase in dose levels,
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`to arrive at the instantly 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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`disclosure recognizes that the method provides for possible adaptation by the liver to the claimed
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`MTP inhibitor once administered at a low dose level of the claimed MTP inhibitor, and such an
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`initial low dose may continue to limit e.g. hepatic steatosis (fatty liver) even when the patient is
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`ultimately administered a higher dose, as described in the instant specification for example, at
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`page 26 paragraph 115. Further, as noted in the specification, it had been previously concluded,
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`after a patient study using constant dose levels of 25 mg per day, (that the claimed MTP inhibitor
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`could not be developed as a drug for large scale use in the treatment of hypercholesterolemia.
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`(Specification, paragraph 33).
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`The accompanying Declaration indicates that others of skill in the art, including the
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`scientists and investigators of the failed trial, did not appear to arrive at any solution these
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`adverse events, and that the instant invention is non-obvious as to these prior art teachings.
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`CFAD Ex. 1009 (7 of 9)
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`Further, Applicants note, as described in the accompanying Declaration, that the instantly
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`claimed method, e.g. with an initial administration of about 5 mg/day for four weeks, and then
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`step-wise increases to larger doses, results in dramatic difference in the rate of gastrointestinal
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`(GI) effects as compared to a constant dose level administration of the claimed inhibitor- even
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`when the constant dose level is substantially less than the dose administered after several step
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`wise increases as instantly claimed. This significant reduction in GI effects is obtained even
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`when patients also receive a further lipid modifying compound such as ezetimibe.
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`In contrast, Gregg teaches starting with low dose combinations of MTP inhibitors and
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`other cholesterol lowering agents, effectively teaching away from the claimed method of the low
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`step wise dose levels of the MTP inhibitor and a constant level of another agent, e.g. 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 notes that claims 24 and 25 have been canceled. The Dow reference appears to
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`be cited as possibly relevant only to those claims. Applicants assert that nothing in the Dow
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`reference teaches or suggests any element of the instant claims.
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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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`CFAD Ex. 1009 (8 of 9)
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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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`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 02109
`Customer No. 051414
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`April 14, 2010
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`Tel. No.: (617) 570-8743
`Fax No.: (617) 523-1231
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`LIBC/3785036.3
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`CFAD Ex. 1009 (9 of 9)