Docket No.: AGP-002C2
`(PATENT)
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re Patent Application of:
`Daniel J. Rader
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`Application No.: 13/046,118
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`Confirmation No.: 4237
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`Filed: March 11, 2011
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`Art Unit: 1629
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`For: METHODS FOR TREATING DISORDERS OR
`DISEASES ASSOCIATED WITH
`HYPERLIPIDEMIA AND
`HYPERCHOLESTEROLEMIA WHILE
`MINIMIZING SIDE EFFECTS
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`Examiner: K. E. Weddington
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`AMENDMENT AND RESPONSE TO OFFICE ACTION
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`MS Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`This Response is being filed in response to the outstanding Office Action, mailed
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`October 2, 2012, in connection with the above-identified application, together with a terminal
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`disclaimer and a copy of the Declaration ofWilliam Sasiela, Ph.D., under 37 C.P.R.§ 1.132, which
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`was filed in the parent application, U.S. Application No. 10/591,923. Applicant also submits
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`herewith an Information Disclosure Statement, a form used in lieu of a PTO/SB/08, copies of the
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`references cited thereon, and a petition for a Two Month Extension of Time.
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`Amendments to the Claims begin on page 2 of this paper.
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`Remarks begin on page 5 of this paper.
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`CFAD Ex. 1009 (1 of 9)
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`

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`Application No. 13/046,118
`Attorney Docket No.: AGP-002C2
`Amendment and Response to Office Action
`Page2of9
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`AMENDMENTS TO THE CLAIMS
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`What is claimed is:
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`1.
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`(Currently amended) A method of treating a subject suffering from a disorder associated
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`with hyperlipidemia andtor hypercholesterolemia, the method comprising administering to the
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`subject an effective amount of an MTP inhibitor effective to ameliorate the disorder, wherein said
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`administration comprises at least three step-wise, increasing dose levels dosages of the MTP
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`inhibitor wherein a first dose level is from about 2 to about 13 mg/day, a second dose level is from
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`about 5 to about 30 mg/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 about 5 weeks.
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`2.
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`(Original) The method of claim 1 wherein the disorder is severe hypercholesterolemia.
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`CFAD Ex. 1009 (2 of 9)
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`

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`Application No. 13/046,118
`Attorney Docket No.: AGP-002C2
`Amendment and Response to Office Action
`Page3 of9
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`3.
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`(Original) The method of claim 1 wherein one or more of Total Cholesterol, LDL, fasting
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`triglycerides (TG), VLDL, lipoprotein (a) (Lp(a)), and apolipoproteins A-I, A-II, B, and E are
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`reduced by at least 15%, compared to control levels.
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`4.
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`(Original) The method of claim 1 wherein one or more of Total Cholesterol, LDL, fasting
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`triglycerides (TG), VLDL, lipoprotein (a) (Lp(a)), and apolipoproteins A-I, A-II, B, and E are
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`reduced by at least 25%, compared to control levels.
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`5.
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`6.
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`7.
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`(Cancelled)
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`(Original) The method of claim 1 wherein the MTP inhibitor is administered orally.
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`(Cancelled)
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`8.
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`(Currently amended) The method of claim 1 [[7]] wherein said increasing dose levels
`escalating doses further comprise a fourth dose level.
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`9.
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`(Currently amended) The method of claim 1 [[7]] wherein said increasing dose levels
`escalating doses further comprise a fourth and a fifth dose level.
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`10-12. (Cancelled)
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`13.
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`(Currently amended) The method of claim 9 wherein said first dose level is from about 2 to
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`about 13 mg/day, said second dose level is from about 5 to about 30mg/day, and said third dose
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`level is from about 10 to about 50 mg/day, said fourth dose level is from about 20 to about 60
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`mg/day, and said fifth dose level is from about 30 to about 75_mg/day.
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`14-25. (Cancelled)
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`CFAD Ex. 1009 (3 of 9)
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`Application No. 13/046,118
`Attorney Docket No.: AGP-002C2
`Amendment and Response to Office Action
`Page4of9
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`26.
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`(New) A method of treating a subject suffering from hyperlipidemia or
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`hypercholesterolemia, the method comprising administering to the subject an effective amount of an
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`MTP inhibitor, wherein said administration comprises at least three step-wise, increasing dose
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`levels of the MTP inhibitor wherein a first dose level is from about 2 to about 13 mg/day,
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`administered to the subject for about 2 weeks; a second dose level is from about 5 to about 30
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`mg/day, administered to the subject for about 2 weeks to about 4 weeks; and a third dose level is
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`from about 10 to about 50 mg/day, administered to the subject for about 2 weeks to about 4 weeks;
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`and wherein the MTP inhibitor is represented by:
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`or a pharmaceutically acceptable salt thereof or the piperidine N-oxide thereof.
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`CFAD Ex. 1009 (4 of 9)
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`

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`Application No. 13/046,118
`Attorney Docket No.: AGP-002C2
`Amendment and Response to Office Action
`PageS of9
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`REMARKS
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`Claim 1-4, 6, 8, 9, 13, and 26 are pending. Claims 5, 7, 10-12, and 14-25 have been
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`cancelled. Claims 8, 9 and 13 have been amended for clarity. Claim 1 has been amended to recite
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`limitations of original claims 13 and 17, and the MTP inhibitor of original claim 5. Further support
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`for the amendments to claim 1 are found throughout the application as filed, including, for example,
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`at paragraphs 56 and 63. New claim 26 has been added. Support for new claim 26 is found
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`throughout the application as filed, including, for example, in original claims 1, 5, 13, and 17 and in
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`paragraphs 56 and 63. No new matter has been added.
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`Amendment of the originally filed claims, or cancellation of any claims should in no way be
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`construed as an acquiescence, narrowing, or surrender of any subject matter. The amendments are
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`being made not only to point out with particularity and to claim the present invention, but also to
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`expedite prosecution of the present application. Applicant reserves the option to prosecute the
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`originally filed claims further, or similar ones, in the instant or subsequently filed patent
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`applications.
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`Double Patenting
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`Claims 2-9 and 11-13 stand rejected on the ground of nonstatutory obviousness-type double
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`patenting as being unpatentable over claims 2-8 of U.S. Patent No. 7,932,268. Applicant submits
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`herewith a terminal disclaimer over U.S. Patent No. 7,932,268. Applicant respectfully requests the
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`rejection be reconsidered and withdrawn.
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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 failing
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`to comply with the written description requirement because "the specification as original filed fails
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`to provide sufficient written bases of any the agents demonstrating wherein possession of the use of
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`the broad terms: a disorder associated with hyperlipidemia and/or hypercholesterolemia and a
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`further lipid modifying agent." Applicant respectfully traverses this rejection.
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`CFAD Ex. 1009 (5 of 9)
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`

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`Application No. 13/046,118
`Attorney Docket No.: AGP-002C2
`Amendment and Response to Office Action
`Page6of9
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`However, solely to expedite prosecution of this application, claim 1 has been amended to
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`recite a method of treating hyperlipidemia or hypercholestermia, diseases that are well known to
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`those of skill in the art. Claims 20, 24, and 25 have been cancelled. Applicant therefore requests
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`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, 19 and 22 stand rejected under 35 U.S.C. 102(b) as being
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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) as anticipated by Biller. In addition, new independent claim 26 includes the
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`limitations of original claims 5 and 13, which do not stand rejected under 35 U.S.C. 102(b) as
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`anticipated 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 by
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`Gregg et al., US 5,883,109. Applicant notes that independent claim 1 has been amended to include
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`limitations of claim 13, which do not stand rejected under 35 U.S.C. 1 02(b) as anticipated by Gregg.
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`In addition, new independent claim 26 includes the limitations of original claims 5 and 13, which do
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`not stand rejected under 35 U.S.C. 102(b) as anticipated by Gregg. Applicant therefore respectfully
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`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 over
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`Biller (U.S. 5, 739,135) ("Biller") or Gregg, U.S. Patent No. 6,057,339 ("Gregg") in view of Dow
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`U.S. 6,194,454 ("Dow"). Applicant respectfully traverses this rejection in view of the following
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`comments.
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`Applicant submits that the standard of obviousness requires a consideration of whether the
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`subject matter, taken as a whole, would have been obvious at the time the invention was made to a
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`person skilled in the art. As the Examiner knows, combining prior art methods to reach a
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`conclusion of obviousness requires: (i) a finding that the prior art included each element claimed,
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`CFAD Ex. 1009 (6 of 9)
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`Application No. 13/046,118
`Attorney Docket No.: AGP-002C2
`Amendment and Response to Office Action
`Page7 of9
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`(ii) a finding that one of ordinary skill in the art could have combined the elements by known
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`methods and that in combination each element merely would have performed the same function as it
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`did separately; and (iii) a finding that one of ordinary skill in the art would have recognized that the
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`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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`about 5 weeks, and then an increasing second dose, and a third dose, as recited in claim 1. Rather,
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`Biller, for example, teaches "5 to about 500 mg per day in single or divided doses of one to four
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`times daily," with no teaching of an initial low dose level of 2 to 13 mg for 1 to 5 weeks as recited
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`in claim 1.
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`Importantly, neither Gregg or Biller recognize that the disclosed MTP inhibitor would cause
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`two significant adverse effects, gastrointestinal related disorders and increase in hepatic fat, when
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`administered to patients only at a constant level. As a consequence, previous phase II trials in
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`human patients, initially administering 25 mg/day of the claimed compound, were discontinued
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`because of such adverse events. (See e.g. instant specification at e.g., paragraph 115; Example 8,
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`and the Declaration of William Sasiela Ph.D. (the "Declaration"), filed in parent application no.
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`10/591,923, now U.S. Patent No. 7,932,268, a copy of which is submitted herewith for the
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`convenience of the Examiner. Applicant submits that the Declaration is also directly relevant to the
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`instant claims.) Further, neither the Gregg nor Biller reference recognizes 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 Biller or Gregg to select, without undue experimentation, the
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`claimed low initial dose from the very broad range of disclosed dose levels -a range that spans 1
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`to 2 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 the
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`art at the time of the instant invention would arrive at the claimed method. For example, the
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`CFAD Ex. 1009 (7 of 9)
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`Application No. 13/046,118
`Attorney Docket No.: AGP-002C2
`Amendment and Response to Office Action
`Page 8of9
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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 page
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`26, paragraph 115. Further, as noted in the specification, it had been previously concluded, after a
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`patient study using constant dose levels of 25 mg per day, that the claimed MTP inhibitor could not
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`be developed as a drug for large scale use in the treatment of hypercholesterolemia. (Specification,
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`paragraph 33).
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`The Declaration indicates that others of skill in the art, including the scientists and
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`investigators of the failed trial, did not appear to arrive at any solution to these adverse events, and
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`that the instant invention is non-obvious as to these prior art teachings.
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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 two to four weeks or more,
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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. This significant reduction in GI effects is obtained
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`even 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 other
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`cholesterol lowering agents, effectively teaching away from the claimed method of the low step
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`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 the
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`subject matter, taken as a whole, would have been obvious at the time the invention was made to a
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`person skilled in the art. Without conceding any prima facie case of obviousness, Applicant
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`believes that the Office must consider any rebuttal evidence, including showings that the claimed
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`invention possesses superior properties, as described in the Declaration.
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`CFAD Ex. 1009 (8 of 9)
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`Application No. 13/046,118
`Attorney Docket No.: AGP-002C2
`Amendment and Response to Office Action
`Page9of9
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`Applicant notes that claims 24 and 25 have been canceled. The Dow reference appears to be
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`cited as possibly relevant only to those claims. Applicants assert that nothing in the Dow reference
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`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 or
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`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 element
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`of the claims merely perform the same function as it does separately. Further, there is no finding
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`that one of ordinary skill in the art would have recognized that the results of the combination were
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`predictable. Therefore, Applicant respectfully requests withdrawal of this rejection.
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`In addition, Applicant notes that new independent claim 26 is directed to a method similar to
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`that of claim 1, but that each dose level of the MTP inhibitor is administered to the subject for about
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`2 weeks to about 4 weeks. Accordingly, Applicant believes that the above arguments also apply to
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`claim 26, and that the cited references fail to teach or suggest the subject matter of claim 26.
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`Any questions raised by this submission may be directed to the undersigned at (617) 570-
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`3917. 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-002C2.
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`Dated: Monday, March 4, 2013
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`Respectfully submitted,
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`/Megan A. Gustafson/
`Megan A. Gustafson
`Registration No.: 65,847
`GOODWIN PROCTER LLP
`Exchange Place
`Boston, Massachusetts 021 09
`(617) 570-1000
`Attorney for Applicant
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`CFAD Ex. 1009 (9 of 9)