Paper No. ___
`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. FRED LUBLIN
`
`
`1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`
`with this proceeding.
`
`
`Filed: April 16, 2017
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`
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`
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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. FRED LUBLIN
`
`
`1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`
`with this proceeding.
`
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`
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`Petitioners hereby submit observations on the deposition testimony of
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`Novartis's declarant Dr. Fred Lublin given on April 6, 2018 (EX1062).
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`1.
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`In EX1062 at 31:12-33:12, 35:12-36:8, Dr. Lublin testified that
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`Novartis paid him to make presentations at the company as far back as 2010 or
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`2011, that they paid him to make presentations at conferences sponsored by
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`Novartis, and that he has "a long history" of consultation and presentations related
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`to Novartis. This is relevant to establishing that Dr. Lublin's testimony is
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`influenced by his long-term association with Novartis. EX2097 (4th Lublin Decl),
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`¶¶1, 20; Paper 63 (PO Sur-Reply), 9-11; see also, e.g., EX2003 (1st Lublin Decl),
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`¶¶17-18; EX2025 (2nd Lublin Decl), ¶¶2, 10; Paper 27 (POR), 6-7.
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`2.
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`In EX1062 at 106:24-107:15, 108:20-109:3, Dr. Lublin testified that
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`the percentage of his income coming from consulting for pharmaceutical
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`companies has increased over time and that he receives a larger proportion of his
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`income from consulting for pharmaceutical companies than the time he spends
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`working for them. This is relevant to establishing that Dr. Lublin's testimony is
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`influenced by his financial ties to Novartis and the pharmaceutical industry.
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`EX2097, ¶¶1, 20; Paper 63, 9-11; see also, e.g., EX2003, ¶¶17-18; EX2025, ¶¶2,
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`10; Paper 27 (POR), 6-7.
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`3.
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`In EX1062 at 44:22-46:5, Dr. Lublin testified that Novartis agreed to
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`include the 0.5 mg dose of fingolimod in its Phase III trials because there was
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`some chance of efficacy based on studies showing the dose could suppress
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`lymphocyte levels in circulating blood to some degree. This is relevant to Dr.
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`Lublin's assertion that a person of ordinary skill in the art would have ignored the
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`0.5 mg dose of fingolimod unless it had been shown to achieve at least 70%
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`lymphopenia. EX2097, ¶¶2, 6, 12-17; Paper 63, 5-7, 9-11; see also, e.g., Paper 27,
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`1-3, 11-12; EX2025, ¶62; EX2003, ¶¶33, 39; EX1042 (12/15/2017 Lublin Depo),
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`171:21-175:6, 209:2-215:25; EX2024 (2nd Jusko Decl), ¶¶70-75; EX2096, ¶26;
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`Paper 56 (Pet. Reply), 11-12; EX1047 (Benet Decl), ¶¶38-48.
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`4.
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`In EX1062 at 46:6-16, 49:10-55:19, Dr. Lublin testified that he was
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`unaware of any other hospital other than Mt. Sinai that declined to participate in
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`any of the Phase III clinical trials of fingolimod because of the 0.5 mg dose, that
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`138 centers in 22 countries cooperated in enrolling 1,272 patients in the
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`FREEDOMS I trial that included 0.5 mg fingolimod, that 172 centers in 18
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`countries agreed to enroll 1,292 patients in the TRANSFORMS trial in which 0.5
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`mg fingolimod was administered, and that 117 centers agreed to enroll 1,083
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`patients in the FREEDOMS II trial in which 0.5 mg fingolimod was administered.
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`This is relevant to Dr. Lublin's testimony that there was industry skepticism of the
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`0.5 mg dose of fingolimod. EX2097, ¶¶3, 14-16; Paper 63, 9-12; see also, e.g.,
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`Paper 27, 2-3, 25-27, 40-41; EX2025, ¶¶50-57; Paper 56, 20-23; EX1047, ¶84.
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`5.
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`In EX1062 at 58:8-61:13, 63:19-65:11, Dr. Lublin testified that, in the
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`-2-
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`second-to-last sentence of paragraph 8 of his declaration (EX2097), he was
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`providing his opinion of what he believed the expectation of a person of skill in the
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`art would have been for the results of the Phase III trials of fingolimod before the
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`results came out, that he was not suggesting that were the trial repeated today the
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`drug would fail, that the trials provided evidence that established that the dose was
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`efficacious, that it would be his expectation that testing the same dose in an
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`equivalent group of patients today would still find a result of efficacy, that
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`fingolimod's mechanism of action did not change because of the publication of the
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`Phase III results, and that fingolimod's mechanism of action is just the way the
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`drug works and is just something intrinsic in the drug for the people that you're
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`giving it to. This is relevant to Novartis's argument in its sur-reply that efficacy in
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`treating RRMS is not inherent to the 0.5 mg dose of fingolimod. EX2097, ¶¶2, 8;
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`Paper 63, 4-5, 9-11; see also, e.g., EX1042, 43:21-46:5, 94:9-15; EX2024, ¶¶46-
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`47; EX2003, ¶36; Paper 56, 17-20; EX1047, ¶¶28-29.
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`6.
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` In EX1062 at 65:12-67:20, Dr. Lublin testified that prior art
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`publications, including Budde (EX1008), Kahan 2003 (EX1031) and Park
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`(EX1019) showed that 0.5 mg daily of fingolimod would suppress lymphocytes to
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`some extent and that this was enough to justify testing the dose. This is relevant to
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`Dr. Lublin's assertion that a person of ordinary skill in the art would ignore the 0.5
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`mg dose of fingolimod unless it had been shown to achieve at least 70%
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`-3-
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`lymphopenia. EX2097, ¶¶2, 6, 12-17; Paper 63, 5-7, 9-11; see also, e.g., Paper 27,
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`1-3, 11-12; EX2025, ¶62; EX2003, ¶¶33, 39; EX1042, 171:21-175:6, 209:2-
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`215:25; EX2024, ¶¶70-75; EX2096, ¶26; Paper 56, 11-12; EX1047, ¶¶38-48.
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`7.
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`In EX1062 at 67:21-73:3, Dr. Lublin testified that Budde (EX1008)
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`provides baseline lymphocyte counts for the placebo and each of the six
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`fingolimod doses ranging from 2,284 to 3,002 cells per microliter, that Budde
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`teaches that 2,590 cells per microliter was the average baseline count for all
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`treatment groups and was "very near" the normal average lymphocyte count of
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`2,500 cells per microliter, that the normal average lymphocyte count "depends on
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`the laboratory" because "different laboratories have different normal values"
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`because of the way they do the assessments, and that Budde (EX1008) excluded
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`patients from the study if they had lymphocyte counts below 1,500, and that Budde
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`(EX1008) reports nadir average lymphocyte counts for the placebo and each of the
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`fingolimod treatment groups. This is relevant to Dr. Lublin's assertion that a person
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`of ordinary skill in the art would ignore the 0.5 mg dose of fingolimod unless it had
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`been shown to achieve at least 70% lymphopenia. It is relevant because Budde
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`reported that 0.5 mg suppressed lymphocyte levels in circulating blood to some
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`degree and below normal levels. EX2097, ¶¶2, 6, 12-17; Paper 63, 5-7, 9-11; see
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`also, e.g., Paper 27, 1-3, 11-12; EX2025, ¶62; EX2003, ¶¶33, 39; EX2024, ¶¶70-
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`-4-
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`75; EX2096, ¶26; Paper 56, 11-12; EX1047, ¶¶38-48; EX1002 (Giesser Decl),
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`¶¶97-98, 139-40.
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`8.
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`In EX1062 at 73:4-74:6, Dr. Lublin testified Budde (EX1008) teaches
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`that, as has been described for nonhuman primates, the lymphopenic effects of
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`FTY has no linear dose response relationship, that, in baboons, the maximal
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`peripheral lymphodepletion was similar within the large dose range (0.03 to 0.3
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`mg/kg) administered, and that Budde stated that its results supported the
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`conclusion that the degree of lymphopenia showed only minor differences. This is
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`relevant to Dr. Lublin's assertion that a person of ordinary skill in the art would
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`have ignored the 0.5 mg dose of fingolimod unless it had been shown to achieve
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`maximal efficacy. EX2097, ¶¶2, 6, 12-17; Paper 63, 5-7, 9-11; see also, e.g., Paper
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`27, 1-3, 11-12; EX2025, ¶62; EX2003, ¶¶33, 39; EX2024, ¶¶70-75; EX2096,
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`¶26; Paper 56, 11-12; EX1047, ¶¶38-48; EX1002, ¶¶97-98, 139-40.
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`9.
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`
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`In EX1062 at 78:6-79:10, 84:25-87:4, Dr. Lublin testified that the
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`Park reference teaches that 5 mg fingolimod per day probably produces maximum
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`percent reduction of lymphocyte counts, that the predicted maximum percent
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`reduction of lymphocyte counts in Park was 87.8%, that the maximum percent
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`reduction in lymphocyte counts referenced in Park is the 87.8% Emax from Park
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`Figure 7, and that the 2.5 mg dose in Table 3 of Park achieved a lymphocyte
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`reduction of 80%, that the doses lower than 2.5 mg had even lower reductions in
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`-5-
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`lymphocyte counts, and that the Park reference does not teach that a 1.25 mg dose
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`of fingolimod per day achieves a maximum percent reduction of lymphocyte
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`counts. This is relevant to Dr. Lublin's assertion that he thought that a person of
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`ordinary skill in the art would have understood that maximal suppression of
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`lymphocytes was essential to efficacy of fingolimod for all treatments. Id., 74:9-
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`75:4. It is relevant because it undermines Dr. Lublin's assertion. EX2097, ¶¶2, 6,
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`12-17; Paper 63, 5-7, 9-11; see also, e.g., Paper 27, 1-3, 11-12; EX2025, ¶62;
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`EX2003, ¶¶32-33, 39; EX1042, 217:11-219:19; EX2024, ¶¶8-11, 60-64; EX2096,
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`¶¶3, 47-52; Paper 56, 11-12; EX1047, ¶¶54-58; EX1002, ¶57.
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`10.
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`In EX1062 at 89:18-25, Dr. Lublin testified that he was not aware of
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`any prior art printed publications discussing clinical trials administering
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`fingolimod to primary progressive MS (PPMS) patients. This is relevant to Dr.
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`Lublin's argument that his decision not to include 0.5 mg fingolimod in the
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`INFORMS trial demonstrates skepticism of the efficacy of the dose against RRMS.
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`It is relevant because no treatment had been shown to be effective against PPMS,
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`and doubt as to efficacy against PPMS was not informative of efficacy against
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`RRMS. EX2097, ¶¶14-17; Paper 63, 9-12; see also, e.g., Paper 27, 2-3, 25-27, 40-
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`41; EX2025, ¶¶50-57, 61; Paper 56, 20-23; EX1047, ¶84; EX1002, ¶¶87, 107.
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`11.
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`In EX1062 at 90:2-19, Dr. Lublin testified that the desire to identify
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`the lowest effective dose in the RRMS context is driven by safety concerns and
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`that one would prefer a lower dose that is also effective that is safer, all else being
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`equal. This is relevant to Novartis's experts' arguments that there would be no
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`motivation to administer the 0.5 mg dose because the 1.25 mg dose was safe and
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`effective. It is relevant because it contradicts that argument. EX2097, ¶¶8-10, 19;
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`Paper 63, 9-12, 14; see also, e.g., EX1042, 85:12-22; EX2096, ¶¶75-77; Paper 27,
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`52-53, 56.
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`12.
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`In EX1062 at 95:2-24, 102:16-19, 102:24-103:17, 106:14-23, Dr.
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`Lublin testified that no interim efficacy analysis was performed in the
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`TRANSFORMS study, that a futility analysis was only included in the
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`FREEDOMS I study, that the futility analysis provided a certain level of comfort
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`to facilities participating in the FREEDOMS I study, that the futility analysis in the
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`FREEDOMS I study did not motivate Mt. Sinai hospital to participate in the
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`TRANSFORMS study in which there was no futility analysis, that "other hospitals
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`might have had a different point of view" than Mt. Sinai regarding the
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`TRANSFORMS trial because they decided to participate in it, and that the results
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`of the FREEDOMS I and TRANSFORMS trials were published at the same time.
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`This is relevant to Dr. Lublin's assertion the futility analysis in the FREEDOMS I
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`Trial establishes industry skepticism of the 0.5 mg dose. It is relevant because it
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`undermines Dr. Lublin's assertion. EX2097, ¶¶3-4, 14-15; Paper 63, 10-12; see
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`also, e.g., Paper 27, 26, 40; EX2025, ¶¶6, 50-57; Paper 56, 20-23.
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`-7-
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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:
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`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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`-9-
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