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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`APOTEX INC., APOTEX CORP., ARGENTUM PHARMACEUTICALS LLC,
`ACTAVIS ELIZABETH LLC, TEVA PHARMACEUTICALS USA, INC., SUN
`PHARMACEUTICAL INDUSTRIES, LTD., SUN PHARMACEUTICAL
`INDUSTRIES, INC., and SUN PHARMA GLOBAL FZE,
`Petitioners,
`v.
`NOVARTIS AG,
`Patent Owner.
`______________________
`Case IPR2017-008541
`U.S. Patent No. 9,187,405
`______________________
`PATENT OWNER NOVARTIS’S RESPONSE TO PETITIONERS’
`MOTION FOR OBSERVATIONS REGARDING THE CROSS-
`EXAMINATION OF DR. WILLIAM JUSKO
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
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`with this proceeding.
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`Patent Owner submits this response to Petitioners’ observations on the
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`deposition testimony of Novartis's declarant Dr. William Jusko given on April 10,
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`2018 (Ex. 1064). At the outset, Novartis objects to the observations because they are
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`excessively argumentative and thus not in compliance with the Patent Office Patent
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`Trial Practice Guide. Indeed, rather than simply cite or quote to the proffered
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`testimony, Petitioners often paraphrase it argumentatively and inaccurately. And
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`rather than succinctly state what issue the proffered testimony is purportedly relevant
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`to, Petitioners instead provide highly argumentative comments about what
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`conclusion the Board should draw from the testimony. The observations should be
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`struck in their entirety.
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`Response to Observation 1.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial. Dr. Jusko did not agree that “the average weight of American
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`women he used were ‘in concordance’ regardless of their time frame.” Rather, he
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`pointed counsel to the underlying CDC documents (Exhibits 2104 and 2109), which
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`do not speak to whether average weights changed from the 1990s to 2006. (Exhibit
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`1064 at 17:24–18:10.) Moreover, Dr. Jusko used 70 kg weights only in two places—
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`first when he was describing a reference that used that weight for a different purpose
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`(Ex. 2024 ¶ 50 (describing Budde 2002)), and second when using a hypothetical
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`calculation merely to illustrate that linear scaling based on weight over-estimates
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`doses (Ex. 2095 ¶ 20). Dr. Jusko never adopted 70 kg as the proper weight to use
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`when performing dose scaling for an RRMS drug in humans. After consultation
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`with MS expert Dr. Steinman, Dr. Jusko used 75 kg for that purpose. (Ex. 2108 ¶
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`3.)
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`Response to Observation 2.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial. Dr. Jusko explained that he was uncomfortable using a new
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`calculator; would accept counsel’s calculations unless he saw an error; and reserved
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`the option of using a calculator later in the deposition. (Ex. 1064 at 88:25–89:9; id.
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`at 150:9–18; id. at 153:17–154:23; id. at 156:16–157:19.)
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`Response to Observation 3.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial. Dr. Jusko’s Fourth Declaration identifies a drug’s steep dose
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`response as a “confounding factor” in scaling from animal to human doses (Ex. 2095
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`¶ 16), and none of the statements in this Observation are inconsistent with that point.
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`The entire FDA Guidance is focused on identifying a safe (non-toxic) first-in-human
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`dose. (Id. ¶¶ 5–6.) The FDA Guidance identifies a number of confounding factors
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`that can undermine that methodology, and Dr. Jusko shows that those factors existed
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`for fingolimod. (Id. ¶ 16.)
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`Response to Observation 4.
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial. To start, Dr. Jusko provided extensive caveats in his testimony that
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`this Observation omits. Moreover, Dr. Jusko testified repeatedly that counsel’s
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`human-to-rat conversion made no sense and would never be done by a real person
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`of skill. (Ex. 1064 at 83:10–94:5; id. at 86:2–13.) Moreover, that projected animal-
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`to-human doses might be higher than what had already been shown effective in
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`humans proves Dr. Jusko’s point: A person of skill would know that animal-to-
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`human dose projection is inherently uncertain and would never be used when human
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`PK/PD data and animal PD benchmarks already existed. (Ex. 2095 ¶¶ 5–18.)
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`Counsel never asked Dr. Jusko about that conclusion in his Fourth Declaration.
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`Response to Observation 5.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial for the reasons given above in response to Observation 1. Dr. Jusko
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`never used 70 kg to perform animal-to-human scaling for an RRMS drug.
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`Response to Observation 6.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial, for the reasons given in response to Observation 4. In addition, this
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`Observation omits Dr. Jusko’s numerous caveats about engaging in dose scaling at
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`all, such as those in Exhibit 2095 at Paragraphs 5–18 (a person of skill would not
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`use dose scaling when human PK/PD and animal PD data existed), and in Exhibit
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`1064 at 67:6–68:4 (explaining that extrapolation would depend on degree of
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`confidence in EAE efficacy as a predictor of MS efficacy). Lastly, this
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`Observation’s assertion that “1.25 mg . . . was still on the plateau of the dose-
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`response curve” is false, as shown in Dr. Steinman’s Third Declaration (Ex. 2096 ¶
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`77).
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`Response to Observation 7.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial, for the reasons given in response to Observation 4. In addition, this
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`Observation misrepresents Dr. Jusko’s criticism of Dr. Benet, which in fact was that
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`Dr. Benet selectively failed to consider the full range of doses that could be projected
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`from the data in Kataoka. (Ex. 2095 ¶¶ 32–43.)
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`Response to Observation 8.
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`This observation is improper as unduly long and argumentative. In addition,
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`this observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant and
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`prejudicial. Dr. Jusko explained in his Fourth Declaration (Ex. 2095 ¶ 24) and his
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`deposition testimony (Ex. 1064 at 97:18–98:16) that he selected a clearance value of
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`10 L/hr as an “appraisal” of where the values in Kahan 2003 “coalesce” based on his
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`professional judgment, and he cautioned that simple arithmetic means would be an
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`improper method for calculating clearance (id. at 122:12–123:10). If a more precise
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`average were sought, Dr. Jusko explained that all of the data in Kahan 2003 would
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`need to be considered. (Id. at 123:19–124:3.) Dr. Jusko further never validated Dr.
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`Benet’s use of the FDA Guidance, but instead criticized the use of that Guidance
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`when human PK/PD data and animal PD data existed, as was the case in June 2006.
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`(Ex. 2095 ¶¶ 5–18.) The testimony cited in this Observation illustrates the
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`imprecision of scaling methods and thus why a person of skill would have eschewed
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`them in June 2006.
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`Response to Observation 9.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial, for the reasons given in response to Observation 8.
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`Response to Observation 10.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial, for the reasons given in response to Observation 8.
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`Response to Observation 11.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial, for the reasons given in response to Observation 8.
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`Response to Observation 12.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial, for the reasons given in response to Observation 8.
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`Response to Observation 13.
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial. Dr. Jusko only considered including male weights when asked his
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`views on a more detailed analysis. (Ex. 1064 at 164:10-165:8.) In that context, Dr.
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`Jusko testified that it would be proper to consider male weights too. In addition, this
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`Observation misrepresents selected (and inadmissible) Exhibits as stating the weight
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`of “MS patients” generally, when in fact they do not as Dr. Jusko repeatedly
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`explained. (Ex. 1064 at 132:11–133:5; id. at 137:12–138:7; id. at 145:13–146:3; id.
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`at 160:23–161:15; see also Patent Owner’s Motion to Exclude (Paper 80) at 13–15.)
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`Response to Observation 14.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial. Dr. Jusko used the average weight of U.S. women in 2006 as
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`reflected in official government CDC reports. (Ex. 2095 ¶ 24; Ex. 2108 ¶¶ 2–3.)
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`Moreover, Dr. Jusko is not an MS expert. But as shown in his Fifth Declaration, Dr.
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`Jusko consulted with Dr. Lawrence Steinman, an MS expert, on Dr. Jusko’s weight
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`assumptions for MS patients. (Ex. 2108 ¶ 3) Counsel never asked Dr. Steinman
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`about the average weight of an RRMS patient. (Ex. 1061 passim)
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`Response to Observation 15.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial. Dr. Jusko pointed out that Exhibit 1057 reflects weights from an
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`Italian population. (Ex. 1064 at 134:24–135:9.) No evidence exists that the weights
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`in Exhibit 1057 are representative of all RRMS patients, or of U.S. patients in June
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`2006. To the contrary, Dr. Jusko confirmed his weight assumptions with MS expert
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`Dr. Lawrence Steinman (Ex. 2108 ¶ 3), and counsel never asked Dr. Steinman about
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`the average weights of MS patients (Ex. 1061 passim). For that reason among others,
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`Novartis has moved to exclude this exhibit. (Patent Owner’s Motion to Exclude
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`(Paper 80) at 13–15.)
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`Response to Observation 16.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial, for the reasons given in response to Observation 15 (except that
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`Exhibit 1058 does refer to U.S. patients, albeit from the 1990s). Moreover, Exhibit
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`1058 reports on “MS” patients generally, not “RRMS patients.” The mean weights
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`of “MS patients” are irrelevant to RRMS patients. As reported in Kappos 2010,
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`RRMS patients suffer relapses at a rate of 0.4 per year, and thus would receive only
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`occasional steroid treatment. (Ex. 1038 at 387.) Other forms of MS that are more
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`continuous have a different profile.
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`Response to Observation 17.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial, for the reasons given in response to Observation 16.
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`Response to Observation 18.
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial, for the reasons given in response to Observation 15 (except that
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`Exhibit 1059 refer to Canadian rather than U.S. patients from 1992-1995). In
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`addition, Exhibit 1059 supports Dr. Jusko’s use of general rather than RRMS-
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`specific weights, as the paper reports no statistically significant differences between
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`the mean weights of MS patients and controls. (Exhibit 1057 at 847, left col., 5th
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`paragraph.) Counsel did not point out this passage to Dr. Jusko in the deposition.
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`Response to Observation 19.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial, for the reasons given in response to Observation 15 (except that
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`Exhibit 1060 refer to Eastern European rather than U.S. patients)
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`Response to Observation 20.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial, for the reasons given in response to Observation 15.
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`Response to Observation 21.
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`This observation misrepresents Dr. Jusko’s testimony, and is thus irrelevant
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`and prejudicial. The Observation proves Dr. Jusko’s point that animal to human
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`dose scaling is inherently inexact and would not be used by a person of skill in June
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`2006. (Ex. 2095 ¶¶ 13–14.)
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`Dated: April 24, 2018
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`Respectfully submitted,
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`/Jane M. Love, Ph.D./
`Jane M. Love , Ph.D.
`Reg. No. 42,812
`Lead Counsel for Patent Owners
`Gibson, Dunn & Crutcher LLP
`200 Park Avenue
`New York, New York 10166-0193
`jlove@gibsondunn.com
`Tel: 212-351-3922
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`CERTIFICATE OF SERVICE
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`Pursuant to 37 C.F.R. § 42.6(e), I hereby certify that on April 24, 2018, a true
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`and accurate copy of PATENT OWNER’S RESPONSE TO PETITIONERS’
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`MOTION FOR OBSERVATIONS REGARDING THE CROSS-EXAMINATION
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`OF DR. WILLIAM JUSKO was served via electronic mail on the following counsel
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`of record for Petitioners:
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`For Apotex:
`
`Steven W. Parmelee: sparmelee@wsgr.com
`Michael T. Rosato: mrosato@wsgr.com
`Jad A. Mills: jmills@wsgr.com
`Wilson Sonsini Goodrich & Rosati
`701 Fifth Avenue, Suite 5100
`Seattle, WA 98104
`Telephone: 206-883-2542
`For Argentum:
`
`Teresa Stanek Rea: trea@crowell.com
`Deborah H. Yellin: dyellin@crowell.com
`Shannon M. Lentz: slentz@crowell.com
`Tyler C. Liu: TLiu@agpharm.com
`Crowell & Moring LLP
`Intellectual Property Group
`1001 Pennsylvania Ave, NW
`Washington, DC 20004-2595
`(202) 624-2620
`
`Samuel Park: SPark@winston.com
`Charles B. Klein: CKlein@winston.com
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`10
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`For Sun:
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`Winston & Strawn LLP
`35 W. Wacker Drive
`Chicago, IL 60601
`Telephone: (312) 558-7931
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`For Teva:
`
`Amanda Hollis: amanda.hollis@kirkland.com
`Eugene Goryunov: egoryunov@kirkland.com
`Gregory Springsted: greg.springsted@kirkland.com
`Kirkland & Ellis LLP
`300 North LaSalle
`Chicago, IL 60654
`Telephone: (312) 862-2000
`(202) 624-2620
`Dated: April 24, 2018
`
`
`
`
`
`/Jane M. Love, Ph.D./
`Jane M. Love , Ph.D.
`Reg. No. 42,812
`
`Lead Counsel for Patent Owners
`
`Gibson, Dunn & Crutcher LLP
`200 Park Avenue
`New York, New York 10166-0193
`jlove@gibsondunn.com
`Tel: 212-351-3922
`
`
`
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`11
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