`Date Filed: December 20, 2016
`
`Filed On Behalf Of: Novartis AG
`
`By: Nicholas N. Kallas
`
`NKallas@fchs.com
`
`ZortressAfinitorIPR@fchs.com
`
`(212) 218-2100
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`PAR PHARMACEUTICAL, INC.,
`BRECKENRIDGE PHARMACEUTICAL, INC. AND
`ROXANE LABORATORIES, INC.
`Petitioners,
`
`v.
`
`NOVARTIS AG,
`Patent Owner
`
`
`
`Case IPR2016-000841
`U.S. Patent 5,665,772
`
`
`
`PATENT OWNER’S MOTION FOR OBSERVATIONS ON
`CROSS-EXAMINATION OF MARK J. RATAIN, M.D.
`
`
`
`
`1 Breckenridge Pharmaceutical, Inc. was joined as a party to this proceeding
`via a Motion for Joinder in IPR2016-01023; Roxane Laboratories, Inc. was
`joined as a party via a Motion for Joinder in IPR2016-01102.
`
`
`
`I.
`
`A POSA Would Not Have Reasonably Expected Everolimus’s
`Observed Antitumor Activity
`
`In Ex. 2223, page 11, lines 15-24, Dr. Ratain testified that his “opinions
`
`relate only to secondary considerations.” Dr. Ratain also admitted that he
`
`“can’t come up with any independent firsthand opinions related to the
`
`chemical modifications and the impact of such” because he is “not a
`
`chemist.” Ex. 2223 at 14:19-15:6. This testimony is relevant because Dr.
`
`Jorgensen did not address whether a POSA would have reasonably expected
`
`everolimus’s antitumor activity; thus, Drs. Burris’s and Roush’s opinions
`
`that a POSA would not have reasonably predicted what effect the difference
`
`in structure between rapamycin and everolimus would have on antitumor
`
`activity are unrebutted. Ex. 2095, Burris ¶¶ 86-89; Ex. 2093, Roush ¶ 156.
`
`In Ex. 2223, page 18, line 9 to page 19, line 23, Dr. Ratain testified that
`
`all of the references he cited in support of his opinions in Ex. 1119, Ratain
`
`¶¶ 101-106 were published after 1992. Dr. Ratain also admitted that mTOR
`
`“had not yet been identified” in 1992. Ex. 2223 at 21:18-20; Ex. 1102, p.527
`
`(“mTOR was identified in 1994”). This testimony is relevant because it
`
`confirms that Petitioners improperly rely on post-invention date information
`
`to try to rebut Patent Owner’s evidence that a POSA would not have had a
`
`reasonable expectation that everolimus would have its observed antitumor
`
`activity. Paper No. 46 (“Reply”) at 17-18 FN 6.
`
`
`
`1
`
`
`
`II.
`
`Petitioners Have Failed To Establish That Co-Administration
`Of Everolimus And Cyclosporine, And Everolimus’s Half-Life
`Do Not Provide Unexpected Clinical Benefits
`
`At Ex. 2223, page 204, line 20 to page 205, line 21, Dr. Ratain admitted
`
`that he is not an immunologist or a transplant nephrologist and has not
`
`prescribed immunosuppressants to transplant patients to induce
`
`immunosuppression. This testimony is relevant because it undermines the
`
`credibility and weight of Dr. Ratain’s opinions, especially when compared to
`
`those of Dr. Stefan Tullius—Petitioners’ transplant and immunosuppression
`
`expert in the related District Court litigation—who admitted that co-
`
`administration increases the likelihood that patients will adhere to an
`
`immunosuppressive drug regimen and provides clinical benefits. Paper No.
`
`27 (“Response”) at 57; Ex. 2132, Tullius Trial 1205:11-23, 1308:8-17.
`
`At Ex. 2223, page 206, line 22 to page 207, line 5, Dr. Ratain admitted
`
`that he did not know the recommended dosing regimen for cyclosporine in
`
`renal transplant patients. This testimony is relevant because it undermines
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`the credibility and weight of Dr. Ratain’s opinions regarding whether
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`physicians would prefer to prescribe everolimus to be taken once a day, or
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`twice a day on the same schedule as cyclosporine, and medication adherence
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`in transplant patients taking either rapamycin or everolimus with
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`cyclosporin. Reply at 25-26 (citing Ex. 1118, Jorgensen ¶¶ 49-50).
`
`
`
`2
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`
`
`At Ex. 2223, page 205, line 22 to page 206, line 17, Dr. Ratain admitted
`
`that the Rapamune (rapamycin) label (Ex. 2053) at page 5, section 2.1,
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`recommends that “Rapamune be taken 4 hours after administration of
`
`cyclosporine.” This testimony is relevant because it contradicts Petitioners’
`
`assertion that there is no evidence that rapamycin and cyclosporine cannot
`
`be co-administered. Reply at 25.
`
`At Ex. 2223, page 212, line 25 to page 215, line 8, Dr. Ratain admitted
`
`that none of the references cited in Ex. 1119, Ratain ¶ 47 disclosed the half-
`
`lives of rapamycin analogs, and that a POSA would not have reasonably
`
`predicted the effect of chemical modification on rapamycin’s half-life or
`
`whether the half-life of any derivative would be shorter or longer, rather its
`
`half-life would have to be determined experimentally. This testimony is
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`relevant because it contradicts Petitioners’ assertion that everolimus’s half-
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`life, which is significantly shorter than that of rapamycin, would not have
`
`been unexpected. Reply at 25-26. There is no evidence of what a POSA
`
`would have reasonably expected everolimus’ half-life to be, or that a POSA
`
`would have reasonably expected chemical modification to rapamycin to
`
`result in a half-life that provides clinical benefits.
`
`At Ex. 2223, page 207, lines 6-22, Dr. Ratain admitted that Ex. 1055
`
`“was not looking at the medical adherence in patients taking cyclosporine
`
`
`
`3
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`
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`with either everolimus or rapamycin.” At Ex. 2223, page 211, lines 8 to page
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`212, line 24, Dr. Ratain further admitted that the clinical trial reported in Ex.
`
`1057 was not completed and results for the trial were not reported. At Ex.
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`2223, page 207, lines 10 to page 211, line 7, Dr. Ratain also admitted that
`
`Ex. 1056 stated that in a study comparing mycophenolate mofetil (MMF)
`
`twice-daily and rapamycin once-daily adherence rates, “there was no
`
`statistically significant difference between once-daily and twice-daily
`
`dosing.” This testimony is relevant because it demonstrates that none of the
`
`cited references support Dr. Ratain’s assertion that rapamycin’s longer half-
`
`life allows for once-daily dosing, which leads to improved adherence and
`
`clinical outcomes. Ex. 1119, Ratain ¶¶ 49-50; Reply at 26.
`
`III. Compelling Objective Indicia Further Support Non-Obviousness
`
`In Ex. 2223, page 12, line 11 to page 13, line 2, Dr. Ratain admitted that
`
`he has not offered any opinions regarding failure of others, industry praise,
`
`or commercial success. This is relevant because it confirms that Dr. Burris’s
`
`following opinions are unrebutted: (a) prior to 1992, numerous other
`
`therapies had failed for both advanced RCC and breast cancer (Response at
`
`62-63), (b) numerous physicians have praised everolimus (Response at 66),
`
`and (c) Afinitor® has achieved significant commercial success due to its
`
`active ingredient, everolimus (Response at 66). Likewise, Patent Owner’s
`
`
`
`4
`
`
`
`evidence that others tried and failed to develop rapamycin derivatives for
`
`preventing transplant rejection is unrebutted. Response at 67.
`
`A. Everolimus Satisfied Long-Felt But Unmet
`Medical Needs In Advanced RCC And Breast Cancer
`
`In Ex. 2223, page 187, lines 15-25, Dr. Ratain agreed that a long-felt
`
`need existed in October 1992 for new safe and effective therapies for
`
`advanced RCC and breast cancer. And Dr. Ratain admitted that everolimus
`
`is safe and effective for advanced RCC and breast cancer. Ex. 2223 at 188:2-
`
`11. Dr. Ratain further admitted that temsirolimus was developed after 1992
`
`(Ex. 2223 at 196:11-18) and cabozantinib and nivolumab were approved for
`
`RCC after everolimus (Ex. 2223 at 192:10-12, 192:23-193:2). This is
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`relevant because the long-felt need must only be unmet at the invention date
`
`and need to be unmet when the invention becomes available on the market.
`
`In Ex. 2223, page 190, line 19 to page 191, line 8, Dr. Ratain agreed that
`
`rapamycin was only tested and approved as an immunosuppressant before
`
`everolimus. Dr. Ratain further admitted that still today, rapamycin is not
`
`approved for any anticancer indication. Ex. 2223 at 130:17-21. This is
`
`relevant because it contradicts Dr. Ratain’s opinion that “any long-felt need
`
`met by everolimus in regard to advanced RCC or advanced breast cancer
`
`was first met by rapamycin.” Ex. 1119, Ratain ¶ 109.
`
`
`
`5
`
`
`
`B.
`
`Everolimus Has Demonstrated Unexpected Results
`
`1.
`
`Everolimus Unexpectedly Has Antitumor Activity
`
`In Ex. 2223, page 198, lines 9-12, Dr. Ratain admitted that “prior to
`
`October of 1992, there was no data on the antitumor activity of rapamycin
`
`from testing in humans.” This is relevant because Dr. Ratain admitted that
`
`activity in the in vivo tumor models did not predict activity in humans. Ex.
`
`2145, Ratain Trial 1000:8-12; Ex. 2095, Burris ¶¶ 82-84.
`
`In Ex. 2223, page 67, lines 14-21, Dr. Ratain admitted that the source of
`
`the information in Houchens regarding the believed mechanism of in vivo
`
`antitumor activity of rapamycin was from a “well-regarded pharmaceutical
`
`scientist.” This is relevant because Houchens suggested that rapamycin
`
`exerted its antitumor activity by inhibiting DNA synthesis, which is different
`
`from rapamycin’s suggested mechanism of immunosuppressive activity. Ex.
`
`2095, Burris ¶ 85; Ex. 2157, Houchens p.803; Ex. 2160, Baumann p.4. Thus,
`
`a POSA would not have reasonably expected everolimus to have antitumor
`
`activity because of the different mechanisms of action. Response at 59.
`
`In Ex. 2223, page 27, line 17 to page 28, line 7, Dr. Ratain admitted that
`
`“cytostatic” describes a mechanism of action distinct from “cytotoxic.” See
`
`also Ex. 2223 at 70:7-19 (confirming the understanding of “cytotoxic” in
`
`1992). This is relevant because, as of October 1992, the literature suggested
`
`
`
`6
`
`
`
`that rapamycin exerted its antitumor activity by inhibiting DNA synthesis,
`
`i.e., a “cytotoxic” mechanism, whereas the literature suggested rapamycin
`
`exerted its immunosuppressive activity by preventing cell cycle progression,
`
`i.e., a “cytostatic” mechanism. Ex. 2095, Burris ¶ 85; Ex. 2157, Houchens
`
`p.803; Ex. 2160, Baumann p.4; Ex. 1034, Fiebig p.116 (reporting that
`
`rapamycin “inhibits DNA synthesis by interference with thymidine
`
`incorporation” and has “high cytotoxic potency” in in vitro antitumor tests).
`
`In Ex. 2223, page 37, lines 6-10 and page 41, lines 3-8, Dr. Ratain
`
`admitted that he has published a paper in which “information [was] included
`
`that was received by one of the authors by personal communication.” Dr.
`
`Ratain also admitted that he cited exhibits—Ex. 1058 p.516 (endnote 28);
`
`Ex. 1103 p.627; Ex. 1046 p.8 (endnote 16), p.9 (endnote 55)—that included
`
`information received by personal communication. Ex. 2223 at 43:3-11,
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`52:21-24, 62:21-63:23, 64:2-66:17. And Dr. Ratain considered such exhibits
`
`reliable. Ex. 2223 at 9:13-16. This is relevant because it confirms that the
`
`information in Houchens on rapamycin’s mechanism of antitumor activity
`
`was not unreliable because it was received by personal communication.
`
`In Ex. 2223, page 28, lines 9-14 and page 29, lines 14-20, Dr. Ratain
`
`admitted that he co-authored a paper reporting that “as of 1977, the
`
`inhibitory effect of rapamycin on the immune system had been recognized in
`
`
`
`7
`
`
`
`rats.” This is relevant because it contradicts Dr. Ratain’s opinion that the
`
`immunosuppressive activity of rapamycin was not reported until 1989, i.e.,
`
`after Houchens was published. Ex. 1119, Ratain ¶ 34.
`
`In Ex. 2223, page 88, lines 4-10 and page 89, lines 7-15, Dr. Ratain
`
`admitted that he did not “see anything directed towards anticancer
`
`properties” in Schreiber (Ex. 1012). This is relevant because it demonstrates
`
`that Houchens reflects the understanding in the art as of October 1992 as to
`
`the believed mechanism of rapamycin’s antitumor activity. Thus, Dr.
`
`Ratain’s criticism of Dr. Burris’s reliance on Houchens because of the time
`
`gap between its publication and the ’772 patent invention date is meritless.
`
`Ex. 1119, Ratain ¶ 35; Ex. 2223 at Ex. 67:22-69:8.
`
`In Ex. 2223, page 91, lines 11-16, and page 92, lines 6-13, Dr. Ratain
`
`admitted that, prior to October 1992, it had been reported that FK506 (a
`
`known immunosuppressant agent (Ex. 2223 at 88:6-89:6; Ex. 1012,
`
`Schreiber at Abstract)) bound to FKBP in calf thymus and the human T cell
`
`line Jurkat. This is relevant because, as of October 1992, FK506 was
`
`reported to be “immunosuppressive but not to inhibit tumor growth in vivo.”
`
`Ex. 1005, Morris at 52. Thus, contrary to Dr. Ratain’s assertion (Ex. 1119,
`
`Ratain ¶ 36; Ex. 2223 at 22:5-15, 23:19-24:16), a POSA would not have
`
`believed rapamycin’s antitumor activity was mediated by FKBP binding.
`
`
`
`8
`
`
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`Indeed, Dr. Ratain does not cite any publication suggesting that FKBP
`
`binding was believed to mediate rapamycin’s antitumor activity.
`
`In Ex. 2223, page 72, lines 6-18; page 80, lines 3-25; page 81, lines 3-24;
`
`page 82, lines 3-6; page 86, lines 15-21; page 86, line 23 to page 87, line 3;
`
`and page 87, line 16 to page 88, line 2, Dr. Ratain admitted that none of the
`
`patents disclosing C40 modified rapamycin derivatives on which he relied—
`
`Exs. 1011, 2130, 2075, 2046 (Ex. 1119, Ratain ¶ 43)—contains “any data
`
`from any tests that are used to determine antitumor or anticancer activity.”
`
`This is relevant because it supports Dr. Burris’s and Dr. Roush’s opinions
`
`that the antitumor properties of everolimus are unexpected. Ex. 2095, Burris
`
`¶¶ 73-99, 100-133; Ex. 2093, Roush ¶ 229, 155-156.
`
`In Ex. 2223, page 70, lines 4-6, Dr. Ratain admitted that esorubicin is
`
`an analog of doxorubicin. Dr. Ratain also admitted that, as of October 1992,
`
`doxorubicin was known to be effective for breast cancer. Ex. 2223 at 70:20-
`
`23. But esorubicin was reported to be “not an effective agent for the
`
`treatment of advanced breast cancer.” Ex. 1039, Rankin p.1080. This is
`
`relevant because it confirms that a POSA would not have expected
`
`everolimus to have antitumor activity just because it is a rapamycin analog.
`
`Ex. 2095, Burris ¶¶ 95-97.
`
`
`
`9
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`
`
`2.
`
`Everolimus Unexpectedly Has FDA
`Approval For Six Antitumor Indications
`
`In Ex. 2223, page 186, lines 13-23, Dr. Ratain testified that unexpected
`
`results require an analysis of “whether or not [any] difference would have
`
`been unexpected to a POSA in October 1992.” This is significant because
`
`whereas everolimus is FDA approved for six antitumor indications (Ex.
`
`2095, Burris ¶ 24), Dr. Ratain admitted that rapamycin is not approved for
`
`any anticancer indication. Ex. 2223 at 130:17-21. And Ratain previously
`
`conceded, a POSA “could not have predicted that everolimus would achieve
`
`its approved indications in 1992.” Ex. 2145, Ratain Trial 971:3-9.
`
`In Ex. 2223, page 187, lines 4-7, Dr. Ratain testified that FDA approval
`
`could be an unexpected result, if it is due to a difference in properties. This
`
`is relevant because there have been at least 10 Phase I and II clinical trials of
`
`rapamycin (Ex. 2182), the Acevedo rapamycin “clinical trial was funded by
`
`Genentech” (Ex. 2177 p.165), and the Gonzalez nab-rapamycin trial was
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`“sponsored by Celgene” (Ex. 2173 p.5483). Thus, there has been ample
`
`funding for the development of rapamycin as an antitumor agent, including
`
`from large pharmaceutical companies. Contrary to Dr. Ratain’s assertions
`
`(Ex. 1119, Ratain ¶¶ 52, 61, 63, 70, 108; Ex. 2223 at 215:16-23), the
`
`absence of FDA approval of rapamycin for the same antitumor indications as
`
`everolimus is not simply due to a lack of funding.
`
`
`
`10
`
`
`
`In Ex. 2223, page 159, lines 15-19, Dr. Ratain admitted that Acevedo
`
`(Ex. 2177) did not demonstrate effectiveness2 of rapamycin in the treatment
`
`of breast cancer. Dr. Ratain also admitted that the (a) Chan clinical trial
`
`(Ex. 1086) was not “designed to demonstrate effectiveness” of temsirolimus
`
`in breast cancer (Ex. 2223 at 159:20-24, 162:14-17); (b) Duran clinical trial
`
`(Ex. 2174) “was not a trial that demonstrates effectiveness” of temsirolimus
`
`in neuroendocrine carcinomas (Ex. 2223 at 141:20-25); and (c) Gonzalez
`
`(Ex. 2173) did not “demonstrate effectiveness of nab-rapamycin in any
`
`particular type of cancer,” including RCC (Ex. 2223 at 153:15-20). This is
`
`significant because it confirms that neither rapamycin nor temsirolimus has
`
`demonstrated the same clinical efficacy as everolimus. Ex. 2095, Burris ¶¶
`
`105-133. In fact, Sabitini confirms that temsirolimus did not show “good
`
`
`2 Dr. Ratain testified that he uses the terms “efficacy” and “activity”
`
`interchangeably. Ex. 2223 at 100:16-101:15. In his opinion, if a drug causes
`
`a tumor to get smaller or prevents the tumor from growing in one patient,
`
`that is sufficient for evidence of antitumor activity. Ex. 2223 at 104:19-
`
`105:6. Effectiveness is a different concept from efficacy or activity; it refers
`
`to whether a drug will work in large populations and it generally requires a
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`Phase III randomized clinical trial. Ex. 2223 at 119:7-120:17.
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`
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`
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`11
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`
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`anti-tumor activity against...breast cancers.” Ex. 1105, Sabitini p.731.
`
`In Ex. 2223, page 142, lines 2-14, Dr. Ratain admitted that in support of
`
`his opinions that temsirolimus has activity in neuroendocrine carcinomas
`
`(Ex. 1119, Ratain ¶ 81), he compared the everolimus clinical trial and the
`
`Duran temsirolimus clinical trial results. This is relevant because Dr. Ratain
`
`previously testified that such interstudy comparisons are problematic
`
`“because you have no idea whether the patients in the other study resemble
`
`the patients in the current study.” Ex 2145, Ratain Trial at 1010:10-19.
`
`In Ex. 2223, page 32, lines 13-18, Dr. Ratain admitted that the peer
`
`review process “increases the probability that something is reliable.” He
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`further admitted that “[a]bstracts, with rare exception, are generally
`
`published as submitted;” they are not peer-reviewed. Ex. 2223 at 36:5-9.
`
`This is relevant because the Bhattacharyya rapamycin breast cancer clinical
`
`trial has only been reported as an abstract and Dr. Ratain admitted that he
`
`does not know the final results of the trial. Ex. 2223 at 168:5-11.
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`In Ex. 2223, page 154, lines 5-25, Dr. Ratain admitted that the
`
`Bhattacharyya clinical trial enrolled patients from 2004 to 2010, identified
`
`two primary end points, and drew conclusions on pharmacoeconomics and
`
`safety. This is relevant because Dr. Burris opined that there are numerous
`
`reasons to be skeptical of the Bhattacharyya results including (a) patients
`
`
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`12
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`
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`were enrolled over an unusually long period during which the standard of
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`care for breast cancer may have changed, (b) statisticians usually require one
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`primary endpoint, not two, and there is no statistical analysis of the results,
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`and (c) the conclusions do not relate to efficacy. Ex. 2095, Burris ¶ 127.
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`In Ex. 2223, page 141, lines 15-19, Dr. Ratain admitted that “mTOR
`
`inhibitors are not agents where you would expect to see a high response
`
`rate.” This is relevant because Dr. Ratain opines Bhattacharyya reported
`
`“that breast cancer patients who received rapamycin and tamoxifen (an
`
`estrogen receptor inhibitor) showed significant response rates.” Ex. 1119,
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`Ratain ¶ 64. Thus, the reported response rates are another reason to be
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`skeptical of the Bhattacharyya abstract.
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`In Ex. 2223, page 162, lines 22-25; page 163, line 14 to page 164, line 5;
`
`and page 165, line 20 to page 166, line 24, Dr. Ratain admitted that Ex.
`
`1081, Arena states that “larger trials are necessary before sirolimus can be
`
`used to treat patients with advanced breast cancer” and Ex. 1082, Palmieri
`
`states that “final results of this trial are awaited.” This is relevant because
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`Dr. Ratain cited these references in support of his opinion that “a variety of
`
`different publications have favorably cited the Bhattacharyya study.” Ex.
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`1119, Ratain ¶ 71. His admissions confirm that rapamycin has not
`
`demonstrated confirmed clinical efficacy in advanced breast cancer and the
`
`
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`13
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`
`
`results in the Bhattacharyya study are preliminary. Arena further states that
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`“[e]verolimus represents the first and only targeted agent approved for
`
`combatting endocrine resistance.” Ex. 1081 at Abstract. See also Ex. 1084,
`
`p.9 (recommending the use of everolimus, not rapamycin); Ex. 1085, p.27
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`(identifying everolimus as an agent with proven activity, not rapamycin).
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`In Ex. 2223, page 178, line 25 to page 179, line 20 and page 184, line 25
`
`to page 185, line 19, Dr. Ratain admitted that he does not have the expertise
`
`to opine on whether the rapamycin clinical trials in TSC patients with SEGA
`
`or renal angiomyolipoma—Lam (Ex. 1099), Franz (Ex. 1098) and Bissler
`
`NEJM (Ex. 1093)—demonstrate effectiveness. This is significant because
`
`Dr. Bissler, an expert in TSC (Ex. 1094, Bissler Trial at 583:22-584:6),
`
`testified that rapamycin has not shown effectiveness in the treatment of
`
`SEGAs (Ex. 1094, Bissler Trial at 610:17-611:7) or the reduction of
`
`angiomyolipoma volume (Ex. 1094, Bissler Trial 653:20-654:1) and that
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`Bissler NEJM reported “important limitations, including the open label
`
`design and the lack of control group and the small number of patients” (Ex.
`
`1094, Bissler Trial 651:7-13; Ex. 1093, Bissler NEJM p.150-151). Dr.
`
`Ratain admitted that he did not discuss any of the trial limitations reported in
`
`Bissler NEJM. Ex. 2223 at 176:19-177:2. He also mischaracterized Dr.
`
`Bissler’s opinions (Ex. 1119, Ratain ¶ 90). Consistent with Dr. Bissler’s
`
`
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`14
`
`
`
`opinions, each of Lam, Franz and Bissler NEJM reports the need for further
`
`trials to demonstrate the effectiveness of rapamycin in TSC; Dr. Ratain cited
`
`no such studies. Ex. 1099, Lam p.479; Ex. 1098, Franz p.498; Ex. 1093,
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`Bissler NEJM p.151; Ex. 2223 at 179:21-180:20, 18:2-11.
`
`In Ex. 2223, page 71, lines 9-12, Dr. Ratain admitted that esorubicin and
`
`doxorubicin are both members of the same class of drugs, anthracyclines.
`
`This is relevant because esorubicin and doxorubicin have different clinical
`
`activity. Ex. 2223 at 70:20-23; Ex. 1039, Rankin p.1080. Thus, contrary to
`
`Dr. Ratain’s assertions (Ex. 1119, Ratain ¶¶ 101-102), the fact that
`
`rapamycin and everolimus are both mTOR inhibitors does not mean that
`
`they have the same clinical efficacy. Indeed, Dr. Ratain admitted that the
`
`mechanism of action of the mTOR inhibitors is not completely understood
`
`and there is still more to learn. Ex. 2223 at 170:12-171:15.
`
`In Ex. 2223, page 71, lines 20-23, Dr. Ratain admitted that esorubicin
`
`and its parent doxorubicin were reported to have comparable in vivo
`
`antitumor activity. However, esorubicin and doxorubicin have different
`
`clinical activity. Ex. 2223 at 70:20-23; Ex. 1039, Rankin at 1080. This is
`
`relevant because it contradicts Dr. Ratain’s assertion (Ex. 1119, Ratain ¶¶
`
`59-60) that comparable in vivo antitumor activity is evidence of similar
`
`clinical efficacy.
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`15
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`Dated: December 20, 2016
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`Respectfully submitted,
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`
`
`/Nicholas N. Kallas/
`Nicholas N. Kallas
`Registration No. 31,530
`Lead Counsel for Patent Owner
`FITZPATRICK, CELLA,
`HARPER & SCINTO
`1290 Avenue of the Americas
`New York, NY 10104-3800
`Tel. 212-218-2100
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`CERTIFICATE OF SERVICE
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`I certify that a copy of the foregoing Patent Owner’s Motion for
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`Observations on Cross-Examination of Mark J. Ratain, M.D. was served on
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`December 20, 2016 by causing it to be sent by email to counsel for
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`Petitioners at the following email addresses:
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`Daniel G. Brown (dan.brown@lw.com)
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`Robert Steinberg (bob.steinberg@lw.com)
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`Brenda L. Danek (Brenda.danek@lw.com)
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`Jonathan M. Strang (jonathan.strang@lw.com)
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`Matthew L. Fedowitz (mfedowitz@merchantgould.com)
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`B. Jefferson Boggs (jboggs@merchantgould.com)
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`Daniel R. Evans (devans@merchantgould.com)
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`Keith A. Zullow (kzullow@goodwinlaw.com)
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`Marta Delsignore (mdelsignore@goodwinprocter.com)
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`Dated: December 20, 2016
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`/Nicholas N. Kallas/
`Nicholas N. Kallas
`Registration No. 31,530
`Lead Counsel for Patent Owner
`FITZPATRICK, CELLA,
`HARPER & SCINTO
`1290 Avenue of the Americas
`New York, NY 10104-3800
`Tel. 212-218-2100