`Filed: April 16, 2017
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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 INDUSTIRES, LTD., SUN
`PHARMACEUTICAL INDUSTRIES, INC., AND SUN PHARMA GLOBAL
`FZE,
`Petitioners,
`
`v.
`
`NOVARTIS A.G.,
`Patent Owner.
`_____________________________
`
`IPR2017-008541
`Patent No. 9,187,405
`_____________________________
`
`PETITIONERS’ MOTION FOR OBSERVATIONS REGARDING THE
`CROSS-EXAMINATION OF DR. WILLIAM JUSKO
`
`
`1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
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`with this proceeding.
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`Petitioners hereby submit observations on the deposition testimony of
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`Novartis's declarant Dr. William Jusko given on April 10, 2018 (EX1064).
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`1.
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`
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`In EX1064 at 17:18-18:10, 128:11-129:25, Dr. Jusko agreed that the average
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`weights of American women he used were "in concordance" regardless of their
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`time-frame. This is relevant because Dr. Jusko's abandonment of his previous
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`reliance on lower weights (e.g., 70 kg) for fingolimod animal to human
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`conversions is not justified by a change in average weight over time. EX2095 (4th
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`Jusko Decl), ¶20; EX2024 (2nd Jusko Decl), ¶50.
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`2.
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`In EX1064 at 34:7-36:8, Dr. Jusko testified that he often uses mathematics.
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`This is relevant to Dr. Jusko's credibility based on his refusal during the deposition
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`to confirm simple calculations or use a calculator when asked. See e.g., id., 72:7-
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`90:19; EX2095, ¶¶25, 41; Paper 63, 8; EX2005 (1st Jusko Decl), ¶¶4, 21-22;
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`EX2024, ¶¶14, 83.
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`3.
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`In EX1064 at 49:10-51:4, Dr. Jusko agreed that he relied upon the FDA
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`Guidance (EX1049) at page 10 as discussing the impact on animal scaling of steep-
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`dose response curves for efficacy, acknowledged that the Guidance was instead
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`"talking about steep dose-response curve for significant toxicities," and admitted
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`that caveats regarding steep dose response for significant toxicities "would not
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`apply for toxicity of fingolimod." Id., 52:6-56:7. This is relevant to Dr. Jusko's
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`assertion that the FDA Guidance scaling factors Dr. Benet relied upon should not
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`be used because fingolimod allegedly had a steep dose response curve for efficacy.
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`EX2095, ¶16; Paper 63, 7-8; Paper 56, 15; EX1047, ¶¶59-60, 104-05.
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`4.
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`In EX1064 at 58:18-60:5, Dr. Jusko testified that direct conversion of rodent
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`to human doses, when accounting for the difference in bioavailability between
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`species, would result in a 0.1 mg/kg dose in a mouse being about 14 mg in a
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`human. This is relevant to Dr. Jusko's assertions that "primates would thus need an
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`oral dose twice as large as rats to receive the same amount of drug." EX2095, ¶16.
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`It is relevant because it demonstrates that many of Dr. Jusko's animal conversion
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`arguments lead to human equivalent doses that are much higher than the doses
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`already found maximally efficacious in humans in Kappos 2005. Id., ¶¶20, 25, 40-
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`41; Paper 63, 7-8; see also, Paper 56, 15; EX1047, ¶¶60, 70, 104-05.
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`5.
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`In EX1064 at 60:6-16, Dr. Jusko agreed that the use of 70 kg human in his
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`Fourth Declaration (EX2095, ¶20) was "a place where [he] hadn't updated the
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`weights from 70 to 75 [kg]." This is relevant to Dr. Jusko's assertions that Dr.
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`Benet's human equivalent dose calculations were inadequate because they did not
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`focus exclusively on a 75 kg person. It is relevant because it indicates Dr. Jusko
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`selected the 75 kg weight to achieve a predetermined outcome. Id., ¶¶24-25, 31,
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`39-41; Paper 63, 7-8; EX2024, ¶50 (70 kg); EX1047, ¶¶69-70; Paper 56, 15.
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`6.
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`In EX1064 at 62:6-66:14, 67:15-69:6, Dr. Jusko agreed that his clearance
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`methodology for converting 0.1 mg/kg in rats to human doses resulted in a human
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`-2-
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`equivalent dose of 1.43 mg, that this suggested that 1.43 milligrams "should be an
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`effective dose in humans" and would be "a reasonable effective dose in humans,"
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`that this "is not about [the] lowest effective dose," and that "one needs more
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`information to get to a question like lowest effective dose." This is relevant to
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`Novartis's arguments that 0.1 mg/kg in rats was "their" lowest effective dose that
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`Kataoka tested. Id., 69:15-70:12. This is relevant because Thomson (EX1005) and
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`Kappos 2005 (EX1007) had already shown that 1.43 mg was not the lowest
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`effective dose in humans and that the efficacy of an even lower dose, 1.25 mg, was
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`still on the plateau of the dose-response curve. EX2095, ¶¶20, 25, 40-41; Paper 63,
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`7-8; see also, e.g., Paper 56, 15; EX1047, ¶¶60, 70, 104-05.
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`7.
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`In EX1064 at 72:7-16, 75:18-76:7, 86:2-21, Dr. Jusko agreed that the FDA
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`Guidance's standard rat conversion factor of 0.162 is roughly double its standard
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`mouse conversion factor of 0.081, that using these factors to convert from 0.1
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`mg/kg in mice to a human equivalent dose and from a human equivalent dose to
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`rats results in 0.05 mg/kg in rats, and that this conversion illustrates the
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`consequence of the standard rat conversion factor being roughly double the
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`standard mouse conversion factor. This is relevant to Dr. Jusko's argument that he
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`did not know why Dr. Benet did not adopt 0.1 mg/kg in rats as the lowest dose of
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`fingolimod proven to be effective in any animal. EX2095, ¶¶3, 33-36; Paper 63, 7-
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`8; see also, e.g., EX2024, ¶¶68-70; EX2096, ¶¶70-74; EX2098 (Chun
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`-3-
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`Decl), ¶¶18-21; EX1047, ¶¶67-70, 102-05; Paper 56, 14-15.
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`8.
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`In EX1064 at 91:21-92:13, Dr. Jusko testified that he selected a human
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`clearance value for fingolimod for converting rat doses to human doses by first
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`excluding an "extreme outlier" of 23.7 L/hr, then "pick[ing] a simple number that
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`was in the middle of all those" remaining values (7.7, 7.4, 9.5, 13.4, 9.4). When Dr.
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`Jusko was confronted with the fact that the simple arithmetic mean of these values
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`was 9.48 L/hr, he said at first that one would do this "more precisely" by
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`multiplying the clearance values "by the number of subjects, " but then said that he
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`selected 10 L/hr as the coalesced value by performing a "weighted average
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`calculation" mentally, that the value of 10 "would be the equivalent of" doing the
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`weighted arithmetic average, and that his mental calculation of the weighted
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`arithmetic average was his explanation for how he arrived at that number. Id.,
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`94:21-95:17, 98:4-25, 100:15-101:10. Dr. Jusko subsequently confirmed that the
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`weighted arithmetic average was the method he described using in his declaration
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`and that it yielded a value of 9.44 L/hr. Id., 123:11-22. This is relevant to Dr.
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`Jusko's credibility. It is also relevant to his assertion that the Board should reject
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`Dr. Benet's use of the FDA Guidance's standard conversion factors for generating a
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`human equivalent dose from mice and rat data because Dr. Jusko's testimony
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`validates Dr. Benet's use of the FDA Guidance's standard conversion factors as
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`being appropriate for fingolimod. EX2095, ¶¶22-26; Paper 63, 7-8; see also, e.g.,
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`EX1031, 1082 & Table 2; EX1047, ¶¶49-53, 104-05; Paper 56, 15.
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`9.
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`In EX1064 at 102:12-105:13, 112:2-113:6, Dr. Jusko testified that it "would
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`be reasonable" to calculate the clearance per kg for the fingolimod patients in
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`Kahan 2003 using their average weight (80.7 kg) instead of using the average
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`weight of adult females in the United States, and that doing so would result in his
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`conversion ratio from rat to human doses going down from 0.19 to about 0.17. This
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`is relevant to Dr. Jusko's assertion the Board should reject Dr. Benet's use of the
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`FDA Guidance's standard conversion factors for generating a human equivalent
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`dose from mice and rat data because it validates Dr. Benet's use of the FDA
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`Guidance's standard conversion factors as being appropriate for fingolimod.
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`EX2095, ¶¶22-26, 31, 39-41; Paper 63, 7-8; EX1031, 1082 & Table 2; EX1047,
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`¶¶49-53, 69-70, 104-05; Paper 56, 15.
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`10.
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`In EX1064 at 110:18-111:15, Dr. Jusko testified that all patients in Kahan
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`2003 were treated with corticosteroids that could increase water and fat retention,
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`but that there was still a difference in weight between the fingolimod-treated
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`patients and the placebo patients. This is relevant to Dr. Jusko's post-hoc argument
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`(Id., 108:14-109:2) that he would no longer use the weight of the fingolimod-
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`treated patients when converting the clearance of those same patients to clearance
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`per kg once he realized it would make his conversion ratio more like the FDA
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`Guidance standard conversion factor. It is relevant because it undermines Dr.
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`Jusko's credibility and his post-hoc argument. EX2095, ¶¶22-25, 31, 39-41; Paper
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`63, 7-8; EX1031, 1081-82; EX1047, ¶¶49-53; Paper 56, 15.
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`11.
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`In EX1064 at 114:17-120:20, 123:11-22, 124:4-126:12, Dr. Jusko testified
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`about how to calculate the weighted arithmetic average of the clearance values
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`from Kahan 2003, confirmed that the weighted arithmetic average of those
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`clearance values was 9.44 L/hr, and confirmed that using the weighted arithmetic
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`average clearance value of 9.44 L/hr and the average weight (80.7 kg) of
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`fingolimod-treated patients from whom that clearance value was derived resulted
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`in a rat-to-human conversion factor of 0.167 that was very similar to the standard
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`FDA conversion factor of 0.162. This is relevant to Dr. Jusko's assertion the Board
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`should reject Dr. Benet's use of the FDA Guidance's standard conversion factors
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`for generating a human equivalent dose from mice and rat data because it validates
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`Dr. Benet's use of the FDA Guidance's standard conversion factors as being
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`appropriate for fingolimod. EX2095, ¶¶24-25, 31, 39-41; Paper 63, 7-8; see also,
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`e.g., EX1031, 1082 & Table 2; EX1047, ¶¶49-53; Paper 56, 15.
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`12.
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`In EX1064 at 120:21-124:3, Dr. Jusko testified when he realized that the
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`weighted average clearance was 9.44 L/hr, and not 10 L/hr as he initially thought,
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`he wanted to include the 23.7 L/hr " extreme outlier" that he previously excluded
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`back in the data set in order to get a number that was closer to the number he
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`originally chose, but that a clearance of 9-12 L/hr was " more reflective." This is
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`relevant to Dr. Jusko's credibility. It is relevant because it indicates Dr. Jusko
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`selected a clearance value of 10 L/hr to achieve a predetermined outcome to
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`benefit Novartis's case. EX2095, ¶¶24-25, 31, 39-41; Paper 63, 7-8; see also, e.g.,
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`EX1031, 1082 & Table 2; EX1047, ¶¶49-53; Paper 56, 15.
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`13.
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`In EX1064 at 130:2-16, Dr. Jusko testified he used average adult female
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`weights when converting doses from mg/kg to kg in humans because it was his
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`understanding that women are the predominant victims of MS and he was using
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`women as a proxy for the average weight of a person with MS. This is relevant to
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`Dr. Jusko's later argument that he wanted to include the weight of men in his
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`calculation when he realized that MS patients may have lower-than-average adult
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`weight due to glycocorticoid (e.g., prednisone and/or prednisolone) treatment in
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`order to keep the average weight closer to the 75 kg value he selected in his Fourth
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`Declaration. Id., 164:17-165:8; EX1058, 130-11. This is relevant to Dr. Jusko's
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`credibility. It is relevant because it indicates Dr. Jusko selected 75 kg to achieve a
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`predetermined outcome to benefit Novartis's case. EX2095, ¶¶24-25, 31, 39-41;
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`Paper 63, 7-8; EX2024, ¶50; EX1047, ¶¶69-70; Paper 56, 15.
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`14.
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`In EX1064 at 130:17-24, Dr. Jusko testified that he could not recall doing
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`any research to determine if there were studies that reported average weights for
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`MS patients. This is relevant to Dr. Jusko's credibility. It is relevant because it
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`indicates Dr. Jusko selected a weight of 75 kg to achieve a predetermined outcome
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`that he thought would benefit Novartis's case. EX2095, ¶¶24-25, 31, 39-41; Paper
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`63, 7-8; see also, e.g., EX2024, ¶50; EX1047, ¶¶69-70; Paper 56, 15.
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`15.
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`In EX1064 at 130:25-132:21, 134:24-135:9, Dr. Jusko testified that the
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`Matarese paper (EX1057) published in 2005 in Proceedings of the National
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`Academy of Science and that it reported an average weight for 126 RRMS patients
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`of 65.9 kg. This is relevant because it undermines Dr. Jusko's assumption that the
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`weight of RRMS patients would not be lower than the average weight of all adult
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`American females. EX2095, ¶¶24-25, 31, 39-41; Paper 63, 7-8.
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`16.
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`In EX1064 at 135:11-137:11, 139:3-10, Dr. Jusko testified that the Formica
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`paper (EX1058) published in 1997 in the Journal of Calcified Tissue and that the
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`average weight of the MS patients from the United States reported in Table 1 was
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`63.0 kg. This is relevant because it contradicts Dr. Jusko's assumption that the
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`weight of RRMS patients would not be lower than the average weight of adult
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`American females. EX2095, ¶¶24-25, 31, 39-41; Paper 63, 7-8.
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`17.
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`In EX1064 at 139:12-141:22, Dr. Jusko postulated that MS patients in the
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`Formica paper (EX1058) had lower weights because they had been treated for MS
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`with corticosteroids and testified that Formica teaches that management of MS
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`includes intermittent or continuous treatment with corticosteroids. When asked
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`whether corticosteroid use is a major feature of MS treatment, Dr. Jusko testified,
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`"Obviously I'm not a clinician…I don't have expertise. There's multiple forms or
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`ways that MS is described, and I would expect it's used during certain acute attacks
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`but not exactly entirely." EX1064, 142:23-143:20. This is relevant because Dr.
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`Jusko did not account for the effect of corticosteroid use on weight of MS patients
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`when he decided to use the average weight of all adult American females for his
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`dose conversion calculations. EX2095, ¶¶24-25, 31, 39-41; Paper 63, 7-8.
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`18.
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`In EX1064 at 143:23-144:24, 146:11-23, 148:4-150:11, Dr. Jusko testified
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`that the Ghadirian paper (EX1059) published in 1998 in the International Journal
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`of Epidemiology and that it reported an average weight of 60 kg for female MS
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`patients, and the data provided an average weight of about 65 kg for male and
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`female MS patients together. This is relevant because it undermines Dr. Jusko's
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`assumption that the weight of RRMS patients would not be lower than the average
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`weight of all adult American females. EX2095, ¶¶24-25, 31, 39-41; Paper 63, 7-8.
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`19.
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`In EX1064 at 158:8-160:7, Dr. Jusko testified that the Stepan paper
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`(EX1060) was published in 2004 in Clinica Chimica Acta and that it reported an
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`average weight of female MS patients of 60.4 kg and an average weight of all MS
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`patients in the study of 65.8 kg. This is relevant because it undermines Dr. Jusko's
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`assumption that the weight of RRMS patients would not be lower than the average
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`weight of all adult American females. EX2095, ¶¶24-25, 31, 39-41; Paper 63, 7-8.
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`20.
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`In EX1064 at 161:16-163:7, Dr. Jusko agreed that the MS patients treated
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`with glucocorticosteroids in America and in Europe had about the same average
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`-9-
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`weight. This is relevant to Dr. Jusko's argument that European MS patients' weight
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`is lower on average than American MS patients' weight. Id., 161:8-15. It is relevant
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`because it undermines Dr. Jusko's argument regarding the weight difference.
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`EX2095, ¶¶24-25, 31, 39-41; Paper 63, 7-8.
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`21.
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`In EX1064 at 163:19-164:17, 165:9-24, 166:16-168:6, Dr. Jusko testified
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`that his calculation of the human equivalent dose for 0.1 mg/kg in mice using the
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`body surface area exponent of 0.67 would be 0.4875 mg if he used 65 kg and that
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`the difference between a 0.4875 mg dose of fingolimod in humans and a 0.56 mg
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`fingolimod dose in humans was trivial and very small. This is relevant to Dr.
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`Jusko's credibility because it indicates Dr. Jusko selected a weight of 75 kg to
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`achieve a predetermined outcome to benefit Novartis's case. EX2095, ¶¶24-25, 31,
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`38-41; Paper 63, 7-8; see also, e.g., EX2024, ¶50; EX1047, ¶¶69-70; Paper 56, 15.
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`Date: April 16, 2016
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`Respectfully submitted,
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`/ Steven W. Parmelee /
`Steven W. Parmelee
`Reg. No. 31,990
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`CERTIFICATE OF SERVICE
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`This is to certify that I caused to be served a true and correct copy of the
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`foregoing Motion for Observations, on this 16th day of April, 2018, on the Patent
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`Owner at the correspondence address of the Patent Owner as follows:
`
`Jane M. Love, Ph.D.
`Robert W. Trenchard
`GIBSON, DUNN & CRUTCHER LLP
`200 Park Avenue, 47th Floor
`New York, NY 10166
`Email: jlove@gibsondunn.com
`Email: rtrenchard@gibsondunn.com
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`
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`Dated: April 16, 2018
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`Respectfully submitted,
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`/ Steven W. Parmelee /
` Steven W. Parmelee, Lead Counsel
` Reg. No. 31,990
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`-11-
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