Paper No. ___
`Filed: April 16, 2017
`
`
`
`
`
`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. LAWRENCE STEINMAN
`
`
`1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`
`with this proceeding.
`
`
`Filed: April 16, 2017
`
`
`
`
`
`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. LAWRENCE STEINMAN
`
`
`1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`
`with this proceeding.
`
`
`
`
`
`Petitioners hereby submit observations on the deposition testimony of Novartis's
`
`declarant Dr. Lawrence Steinman given on April 5, 2018 (EX1061).
`
`1.
`
`
`
`In EX1061 at 37:2-39:7, Dr. Steinman testified that the "standard of care"
`
`"often" used for treating relapses in RRMS patients is using corticosteroids to blunt
`
`the relapse and "alleviate the variety of different manifestations of a relapse." He
`
`also testified that "if they did have a relapse, I would be giving steroid as well" as
`
`fingolimod. This is relevant to Dr. Jusko's assertion that MS patients treated with
`
`corticosteroids provided a skewed weight average. EX1064 (04/10/2017 Jusko
`
`Depo), 139:12-141:22; see also EX2022 (1st Steinman Decl), ¶¶33-34, 38.
`
`2.
`
`
`
`In EX1061 at 39:24-41:20, 44:18-48:4 Dr. Steinman testified that one cannot
`
`know when administering fingolimod whether it will be effective in a particular
`
`patient, that he "can't provide any guarantees," that "it would be hard" to talk in a
`
`scientific manner about slowing progression of RRMS in an individual patient.
`
`This is relevant to Novartis's proposed construction that the original and proposed
`
`amended claims require actual efficacy as a claim element because it demonstrates
`
`that their proposed construction is unreasonable, indefinite, and lacks support and
`
`enablement in the '405 patent. EX2096, ¶¶5, 7, 9-17; Paper 63, 2-5.
`
`3.
`
`
`
`In EX1061 at 48:5-23, 52:4-56:16, 57:20-58:14, Dr. Steinman testified that
`
`treating RRMS is broad enough to include each of slowing progression and
`
`preventing relapses but broader than just those two and described a Venn diagram
`
`
`
`-1-
`
`
`
`
`
`illustrating how different categories can have overlapping subject matter without
`
`being co-extensive. He disagreed that "all patients whose relapses are under control
`
`are no longer in need of slowing progression of RRMS," and agreed that "an
`
`RRMS patient whose relapses are controlled may still be in need of slowing
`
`progression of RRMS." Id., 57:20-58:14. This is relevant to Novartis's argument
`
`that the claims require an intention of efficacy because the independent claims
`
`otherwise would allegedly be rendered duplicative. Dr. Steinman's testimony
`
`establishes that each independent claim has a different scope. EX2096, ¶¶11-17;
`
`Paper 63, 2-5; Paper 61, 8; Paper 64, 2-3, 7-8; Paper 2, 24-25; EX1002, ¶¶43-47.
`
`4.
`
`
`
`In EX1061 at 112:5-113:18, 114:15-117:22, Dr. Steinman agreed it was
`
`known fingolimod was being developed as a DMT, that DMTs had only been
`
`approved to treat RRMS, not PPMS, that the default understanding of a POSA was
`
`that a DMT for treating MS referred to RRMS, and that he "would probably think
`
`yes, it was about RRMS” prior to June 2006 if discussing treatment of MS using
`
`fingolimod. This is relevant to Dr. Steinman's assertion that a POSA would not
`
`understand Kovarik's 0.5 mg daily maintenance dose for treating an autoimmune
`
`disease (e.g., MS) as relevant to RRMS. EX2096, ¶¶57-66; Paper 63, 13-14.
`
`5.
`
`
`
`In EX1061 at 118:7-23, Dr. Steinman agreed that a POSA would have been
`
`more skeptical of a fingolimod clinical trial for PPMS than RRMS. This is relevant
`
`to Novartis's assertion that the failure to include a 0.5 mg dose of fingolimod in the
`
`-2-
`
`
`
`
`
`INFORMS trial for PPMS indicates skepticism that the 0.5 mg dose of fingolimod
`
`would be effective against RRMS. Paper 63, 9-12; EX2097, ¶¶14-17.
`
`6.
`
`
`
`In EX1061 at 121:19-122:16, Dr. Steinman agreed that the '405 patent
`
`discloses a 200-fold dose range for fingolimod (0.1-20 mg/kg) in rats for
`
`significant inhibitory activity and 0.3 mg/kg to fully inhibit activity. This is
`
`relevant to Novartis’s assertion that the animal data in the specification supports
`
`efficacy against RRMS of the 0.5 mg dose in humans. EX2096, ¶¶53-54, 65;
`
`Paper 63, 2-5, 7-8. It is relevant because Dr. Jusko converts 0.1 mg/kg in rats to
`
`1.43 mg in humans, not 0.5 mg. EX2095, ¶¶22-26, 31, 39-41. This is also relevant
`
`to Dr. Steinman's assertion that a POSA should ignore the Chiba reference's
`
`disclosure of a range of effective doses encompassing 0.5 mg because it is in a
`
`"thousand-fold range" of 0.01 mg to 10 mg. EX2022, ¶179.
`
`7.
`
`
`
`In EX1061 at 122:17-128:17, Dr. Steinman testified that the '405 patent's
`
`only discussion of lymphopenia addresses 50% lymphopenia and that "I don't think
`
`it addresses the Webb threshold at all." This is relevant to Novartis's argument that
`
`"at least" 70% lymphopenia was required to see any efficacy. See, e.g., EX2096,
`
`¶¶25-40, 72-73; Paper 63, 5-6, 9-12. It is relevant because the patent reflects the
`
`same understanding as the prior art (e.g., Kovarik (EX1004), 2) that lymphopenia
`
`of at least 70% was not a threshold for any efficacy. EX2096, ¶¶3, 62, 65; Paper
`
`63, 5-6, 9; see also, e.g., Paper 56, 11-12; EX1047, ¶¶38-48, 99.
`
`-3-
`
`
`
`
`
`8.
`
`
`
`In EX1061 at 128:18-132:7, 203:5-13, Dr. Steinman argued that the claims
`
`of the '405 patent are where it allegedly teaches that the 0.5 mg dose is effective
`
`and agreed that the specification only describes administering that dose in the
`
`prophetic clinical trial for investigating clinical benefit in an experimental setting.
`
`This is relevant to Novartis's argument that the claims require at least intended
`
`efficacy as a claim element. It is relevant because the pre-2011 patent specification
`
`does contain the claim language Dr. Steinman relies upon. EX1009, 0188-89.
`
`9.
`
`
`
`In EX1061 at 157:11-158:20, 264:18-268:13, Dr. Steinman agreed that
`
`scientists in June 2006 believed that fingolimod did not work exclusively by
`
`sequestering lymphocytes and that Webb teaches that its non-lymphopenia
`
`mechanism of action may produce the therapeutic benefit. This is relevant to
`
`Novartis’s argument that "at least" 70% lymphopenia was required to see any
`
`efficacy. See, e.g., EX2096, ¶¶3-5, 25-40, 50, 52, 72-73; Paper 63, 5-7.
`
`10.
`
`
`
`In EX1061 at 190:17-191:25, Dr. Steinman testified that the claims of the
`
`'405 patent are complete once the steps are performed regardless of whether the
`
`steps results in an effect on the subject. This is relevant to Novartis's arguments
`
`that the claims require efficacy because it demonstrates there is no efficacy
`
`element. See, e.g., EX2096, ¶¶5, 7, 9-17; Paper 63, 2-5.
`
`11.
`
`
`
`In EX1061 at 209:24-210:17, 213:6-215:222, Dr. Steinman testified that the
`
`'405 patent claims provide no limitation for the number of days of administration
`
`-4-
`
`
`
`
`
`and do not require administration over an extended period of time. This is relevant
`
`to Novartis's argument that the claims require efficacy. It is relevant because
`
`Novartis argues a POSA would understand the claims as providing a complete
`
`instruction for administering fingolimod but the claims do not specify a duration of
`
`administration. EX2096, ¶¶5, 7, 9-17, 22-24; Paper 63, 2-5.
`
`12.
`
`
`
`In EX1061 at 228:8-236:11, 240:15-241:3, Dr. Steinman testified that "you
`
`don't usually talk about animals with replicates in an [EAE] experiment," that "I've
`
`never heard an EAE experiment called a replicate," and after fingolimod dosing
`
`ceased, he saw "some pretty big error bars, making me think that they only really
`
`did have four [mice] per group." This is relevant to Dr. Steinman's argument that a
`
`POSA would expect wide variation in the granular data underlying Webb Fig. 5
`
`including at least one death and clinical score of 5. It is relevant because it is
`
`impossible for one out of 4 mice to have a 5 and the average to be less than 1 (0.75
`
`for 0.03 mg/kg). Id., 242:6-245:19; EX2096, ¶¶33-35; Paper 63, 6-7.
`
`13.
`
`
`
`In EX1061 at 240:25-241:3, 262:25-264:16, Dr. Steinman agreed that the
`
`standard errors in Fig. 5A of Webb and in Figure 6B at day 25 are "very small" for
`
`each of the fingolimod groups during treatment, indicating low variation. This is
`
`relevant because it contradicts Novartis’s argument that a POSA would expect
`
`wide variation in the granular data underlying Webb Figure 5, including at least
`
`one death resulting in a clinical score of 5 and widespread lymphopenia
`
`-5-
`
`
`
`
`
`percentages. EX2096, ¶¶33-35; Paper 63, 6-7.
`
`14.
`
`
`
`In EX1061 at 24:5-25, 30:23-31:11, Dr. Steinman agreed that making
`
`relapses milder or lessening severity counts as alleviating. This is relevant to
`
`Novartis’s argument that at least 70% lymphopenia was required to see any
`
`efficacy. EX2096, ¶¶26-29. It is relevant because Dr. Steinman agreed Webb Fig.
`
`5 shows reduced severity of the EAE attack when using the lowest 0.03 mg/kg
`
`dose. EX1061, 236:18-239:19 (fingolimod doses made remission more profound
`
`than control); id., 245:20-246:18 (agreeing page 109 describes efficacy for all three
`
`doses in Fig. 5A and noting "a trend for all three" in Fig. 5B); EX2039, 70:18-86:8.
`
`15.
`
`
`
`In EX1061 at 246:22-248:3, 307:4-308:16, Dr. Steinman agreed that Section
`
`3.1 of Webb describes the results in the EAE model without fingolimod treatment.
`
`This is relevant to Dr. Steinman's argument that a POSA would expect at least one
`
`death in each fingolimod-treated group in Fig. 5 because 10-30% of mice allegedly
`
`died in every experiment in Webb. EX2096, ¶¶31-32; Paper 63, 6-7. It is relevant
`
`because it demonstrates this mortality rate applies only to FTY-untreated mice.
`
`16.
`
`
`
`In EX1061 at 250:21-256:23, 268:14-274:6, 301:5-304:13, Dr. Steinman
`
`agreed that Webb measured lymphocytes in mice differently than Kahan 2003 and
`
`Park, that each of Webb and Park do not disclose what they counted as
`
`lymphocytes, that all three papers may have counted different cells types as
`
`lymphocytes, that the lymphocyte counts were not directly comparable, and that
`
`-6-
`
`
`
`
`
`mouse and human lymphocytes have "different percentages." This is relevant to
`
`Novartis's argument that at least 70% lymphopenia was required to see any
`
`efficacy. See, e.g., EX2096, ¶¶3-5, 41, 44-48; Paper 63, 5-8.
`
`17.
`
`
`
`In EX1061 at 295:24- 301:4, Dr. Steinman agreed that Kahan 2003
`
`measured lymphocytes using flow cytometry, that the cells it included in its
`
`lymphocyte count included T cells, B cells, granulocytes, monocytes, and
`
`macrophages, that granulocytes and monocytes were not sequestered by
`
`fingolimod, and that including granulocytes and monocytes count could thus
`
`understate the percentage of lymphopenia. This is relevant to Novartis's argument
`
`that the prior art taught away from the 0.5 mg dose for allegedly failing to induce
`
`at least 70% lymphopenia. EX2096, ¶¶3-5, 41, 44-48; Paper 63, 5-8.
`
`18.
`
`
`
`In EX1061 at 274:7-282:2, 327:10-25, Dr. Steinman agreed that
`
`Park's control group reported baseline lymphocyte counts of 1,746, that control
`
`counts rose to 2,556 at week 8, that the average control count at each of weeks 4-
`
`12 was higher than at baseline, that many factors affect lymphocyte counts
`
`(including infection, rejection, natural daily variation depending on when the
`
`sample is taken, steroid use, stress, and physical activity), and that the sample size
`
`for 0.5 mg group was 4, half the sample size used in Kahan 2003. This is relevant
`
`to Novartis's argument that Park taught away from the 0.5 mg dose because of
`
`week-to-week variation because variation in lymphocytes over time is normal,
`
`-7-
`
`
`
`
`
`particularly with a very small sample size of 4. EX2096, ¶¶45-47, 50-51; Paper 63,
`
`7; see also, e.g., EX2022, ¶62; EX1047, ¶¶52-62; Paper 56, 11-12.
`
`19.
`
`
`
`In EX1061 at 283:21-285:25, Dr. Steinman testified that the average
`
`lymphocyte count for the four patients in the 0.5 mg fingolimod treatment group in
`
`Park was 675 at week 4 and was below 1,000 cells/µL for seven of the nine weeks
`
`reported in Park, and that the percent reduction for 0.5 mg was about 60% at week
`
`4. This is relevant to Novartis's argument that Park taught away from the 0.5 mg
`
`dose. It is relevant because it demonstrates that the dose reduced lymphocyte
`
`counts below the 1000 cells/µL threshold Dr. Steinman claimed was necessary for
`
`efficacy. EX2096, ¶¶45-47, 50-51; Paper 63, 7; EX2022, ¶65.
`
`20.
`
`
`
`In EX1061 at 291:17-292:4, Dr. Steinman agreed that Fig. 1 of Kahan
`
`2003 discloses that nadir average lymphocyte percentage reduction for 0.5 mg dose
`
`was about 60%. This is relevant to Novartis's argument that Kahan 2003 taught
`
`away from the 0.5 mg dose. It is also relevant because it demonstrates that the 0.5
`
`mg dose reduced lymphocytes by "about 70%." EX2096, ¶¶44-47; Paper 63, 5-8;
`
`see also, e.g., EX2022, ¶¶55-57, 138-39; EX1047, ¶¶49-53; Paper 56, 6-8; 11-12.
`
`21.
`
`
`
`In EX1061 at 292:5-297:23, Dr. Steinman agreed that each patient in
`
`Park (EX1019) and Kahan 2003 (EX1031) was being administered cyclosporin
`
`and prednisone and that this was real world for a transplant context but not for an
`
`RRMS context. This is relevant to Novartis's argument that Park and Kahan taught
`
`-8-
`
`
`
`
`
`away from the 0.5 mg dose because it demonstrates that the % reduction in Kahan
`
`2003 and Park may underestimate expected lymphopenia for the 0.5 mg dose in
`
`RRMS patients. EX2096, ¶¶44-47, 50-51; Paper 63, 5-8; EX2022, ¶51.
`
`22.
`
`
`
`In EX1061 at 308:19-312:13, Dr. Steinman agreed that he failed to
`
`discuss any of the mouse studies in Kataoka (including 9 out of 10 figures), that
`
`Dr. Benet had testified that the dose in the mice was approximately half that was
`
`used in the rat study, and that Dr. Steinman had no rebuttal response to Dr. Benet
`
`on this point. This is relevant to Dr. Steinman's argument that 0.1 mg/kg in rats
`
`was the lowest effective dose because it demonstrates that it was already known
`
`that a dose approximately one-half of the 0.1 mg/kg in rats (0.1 mg/kg in mice)
`
`was effective against EAE. Id., 328:12-329:2 (Kataoka demonstrated efficacy of
`
`the 0.1 mg/kg dose of fingolimod in mice). EX2096, ¶¶70-74; Paper 63, 7-8, 12.
`
`23.
`
`
`
`In EX1061 at 312:14-314:16, Dr. Steinman testified that Kataoka Figure 1
`
`on pg. 441 contains no measure of lymphopenia. Dr. Steinman agreed that Kataoka
`
`Fig. 3 on pg. 442 does not disclose data that would allow one to calculate total
`
`lymphocyte counts. EX1061, 328:2-10. This is relevant to Dr. Steinman's argument
`
`that pgs. 441 or 442 demonstrated that Kataoka's results show that effective doses
`
`met Webb's 70% lymphopenia threshold. EX2096, ¶¶70-74; Paper 63, 12.
`
`24.
`
`
`
`In EX1061 at 314:17-316:8, Dr. Steinman agreed that Kataoka (EX1029) at
`
`page 446 cites Webb, does not mention, discuss, or adopt any 70% lymphopenia
`
`-9-
`
`
`
`
`
`threshold, and instead points out Webb did not analyze T cell CNS infiltration.
`
`This is relevant to Novartis's argument that at least 70% lymphopenia was required
`
`to see any efficacy because subsequent prior art references did not read Webb as
`
`Novartis proposes. EX2096, ¶¶3-5, 41, 44-48; Paper 63, 5-8.
`
`25.
`
`
`
`In EX1061 at 321:11-16, 324:16-325:21, Dr. Steinman agreed that all
`
`statistical analysis in Kataoka and Webb Figure 5B are comparing the different
`
`FTY720 groups solely to the control and not to one another. Dr. Steinman testified
`
`that "trends are less important" than statistical significance, and that Kataoka
`
`Figure 1D showed that a lower dose (0.1 mg/kg) was statistically significant
`
`compared to the control to a greater degree than a larger dose (0.3 mg/kg). This is
`
`relevant to Novartis's argument that higher doses of fingolimod were significantly
`
`superior to lower doses. EX2096, ¶¶27-31, 70-74; Paper 63, 5-8.
`
`26.
`
`
`
`In EX1061 at 331:20-334:18, Dr. Steinman agreed a POSA would have
`
`thought that both 1.25 and 5 mg could have gone forward in the phase 3 trials and
`
`that the 0.5 mg dose was advanced to phase 3 instead of the 5 mg dose. This is
`
`relevant to Novartis's argument that a POSA would not consider a lower dose of
`
`fingolimod once a higher dose was believed to be safe and effective. EX2096, ¶75.
`
`
`
`Date: April 16, 2016
`
`
`
`Respectfully submitted,
`
`/ Steven W. Parmelee /
`Steven W. Parmelee
`Reg. No. 31,990
`
`
`
`
`
`
`
`-10-
`
`
`
`
`
`
`
`CERTIFICATE OF SERVICE
`
`This is to certify that I caused to be served a true and correct copy of the
`
`foregoing Motion for Observations, on this 16th day of April, 2018, on the Patent
`
`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
`
`
`
`Dated: April 16, 2018
`
`
`
`
`
`
`
`
`Respectfully submitted,
`
`/ Steven W. Parmelee /
` Steven W. Parmelee, Lead Counsel
` Reg. No. 31,990
`
`
`
`
`
`-11-
`
`
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