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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`SANDOZ INC.,
`APOTEX INC., APOTEX CORP.,
`EMCURE PHARMACEUTICALS LTD.,
`HERITAGE PHARMA LABS INC.,
`HERITAGE PHARMACEUTICALS INC.,
`GLENMARK PHARMACEUTICALS, INC., USA,
`GLENMARK HOLDING SA,
`GLENMARK PHARMACEUTICALS, LTD., MYLAN
`LABORATORIES LIMITED, TEVA PHARMACEUTICALS USA, INC.,
`FRESENIUS KABI USA, LLC, and WOCKHARDT BIO AG,
`
`Petitioners
`
`v.
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`ELI LILLY AND COMPANY,
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`Patent Owner.
`
`Case IPR2016-003181
`U.S. Patent 7,772,209
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`
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`
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`PETITIONER SANDOZ INC.’S RESPONSE TO PATENT OWNER’S
`MOTION FOR OBSERVATIONS ON THE DEPOSITION OF
`EXPERT PATRICK J. STOVER, PH.D.
`
`1 Cases IPR2016-01429, IPR2016-01393, and IPR2016-01340 have been joined
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`with the instant proceeding.
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`
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`I.
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`PATENT OWNER’S MOTION FOR OBSERVATIONS INCLUDES
`IMPROPER ARGUMENTS AND SHOULD BE EXPUNGED
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`Petitioner respectfully requests that the Board dismiss Patent Owner’s
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`Motion for Observations on the Deposition of Petitioner Sandoz’s Expert Dr.
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`Patrick Stover (“Motion” or “Mot.”) and expunge its supporting exhibits because
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`the purported observations in the Motion are a masked attempt to submit additional
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`argumentative sur-reply pages in contravention of the Board’s guidance and prior
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`decisions. Instead of a short statement of relevance, Patent Owner’s observations
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`include argument, some of which spans several sentences. E.g., Paper 61, Mot. at
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`2 and 3. Moreover, many of Patent Owner’s arguments are new; they do not match
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`the positions taken on the portions of the prior briefing Patent Owner cites. Sandoz
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`discusses particularly egregious examples in further detail in its responses below.
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`As the Office Patent Trial Practice Guide makes clear, “[a]n observation
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`should be a concise statement of the relevance of identified testimony to an
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`identified argument or portion of an exhibit . . . . [It] is not an opportunity to raise
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`new issues, re-argue issues, or pursue objections.” 77 Fed. Reg. 48,755, 48,767-68
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`(Aug. 14, 2012). The Board has further noted that “each item included as an
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`observation on cross-examination should be precise, preferably no more than one
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`short sentence in the explanation of relevance. Observations on cross-examination
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`are not meant to serve the purpose of an argumentative surreply.” Atrium Med.
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`Corp. v. Davol Inc., IPR2013-00189, Paper 48 at 2 (February 28, 2014).
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`1
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`
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`“The Board may refuse entry of excessively long or argumentative
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`observations (or responses),” such as the observations contained in Patent Owner’s
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`Motion. See 77 Fed. Reg. 48,755, 48,767-68 (Aug. 14, 2012). In fact, the Board
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`has previously considered proposed observations similar to the Patent Owner’s
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`submissions and dismissed them as containing improper argument. In Medtronic,
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`Inc. v. Nuvasive, Inc., the Board reviewed proposed observations that “cite[d]
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`several pages of [the witness’s] testimony, as opposed to one portion” and
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`“proceed[ed] to present an argument that the testimony is relevant . . . .” IPR2013-
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`00506, Paper 37 at 3-4 (October 15, 2014). The Board found the statements
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`improper, dismissed the Motion, and expunged the relevant exhibits. Id.; see also
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`LG Elecs., Inc. v. ATI Techs. ULC, IPR2015-00325, Paper 52 at 2-5 (January 25,
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`2016). While Petitioner maintains that the Board should dismiss the Motion
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`without considering Patent Owner’s proposed observations due to their inclusion
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`of argument, Petitioner has responded to the proposed observations below.
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`II.
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`SANDOZ’S RESPONSES TO PATENT OWNER’S OBSERVATIONS
`Response to Observation 1
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`Patent Owner’s observations introduce new arguments that are improper
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`because they misconstrue the relevance of Dr. Stover’s testimony, which is
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`inconsistent with Lilly’s own reliance upon the opinions of Dr. Zeisel and Lilly’s
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`definition of a POSA. Dr. Stover is not a POSA (i.e., an oncologist), and does not
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`2
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`purport to be one. His testimony is responsive to Dr. Zeisel who, like Dr. Stover,
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`is not an oncologist. Dr. Stover made clear that his opinions come from the
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`perspective of a nutritional scientist about knowledge available to a POSA in June
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`1999, which is consistent with Lilly’s definition that “[t]he POSA also would have
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`an understanding of how nutritional issues relate to the use of chemotherapy
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`agents . . . .” Paper 36 at 14. Dr. Stover testified:
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`A. I can tell you what information was available to that person at that
`time, but I can't tell you what any one individual would or would not have
`known. I can tell you what the state of knowledge was in terms of both
`biochemistry and nutrition at that time.
`Q. Right.
`A. And, but in particular you can speak to the state of knowledge in
`biochemistry and nutrition but not to the state of oncology; is that fair?
`A. I can tell you -- I don't think that's completely fair, no. I think that
`I can tell you what information would be available to an oncologist at that
`time.
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`*
`*
`*
`Q. Okay. And, but my question is: Have you -- have you made any
`effort in your mind to separate out, you know, what you know and what
`people with your type of expertise would have known from the standpoint of
`an expert in one-carbon metabolism and biochemistry from what the person
`of ordinary skill in the art for purposes of this case would have known?
`A. I don't see those as distinct, because I can tell you that many of the
`leading antifolate oncologists attend the same meetings I do. We speak in the
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`3
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`
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`same sessions. The focus of the talks is different, but there is a free sharing
`of information among those groups.
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`Ex. 2137, 25:2-26:22.
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`
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`Dr. Stover further explained the relevance of nutritional science to
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`oncologists and how nutritional scientists and oncologists work together both in a
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`research and clinical setting. He explained that “nutrition is an important part of
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`cancer treatment” (Ex. 2137 at 23:24-24:14), that he is in involved in “scientific
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`meetings, which are held annually, [where] we have a blend of people in nutrition,
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`people who are biochemists and clinicians” who “intermingl[e]” knowledge (id.
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`22:7-14), and that in a hospital setting, “a full clinical team that would include an
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`oncologist” would also “include someone understanding nutrition, if not the
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`oncologist him or herself” (id. at 108:7-109:25).
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`Dr. Stover also testified that he is qualified to opine on the topics related to
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`folate metabolism that are the subject of Dr. Zeisel’s testimony in this proceeding:
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`Q. And your declaration here today was done in response to
`Dr. Zeisel; correct?
`A. That's correct.
`Q. Is he an oncologist?
`A. Dr. Zeisel is not an oncologist.
`*
`*
`*
`Q. Do you know Dr. Zeisel?
`A. I know Dr. Zeisel well.
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`4
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`Q. Are you familiar with his background?
`A. I am very familiar with his background.
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`Exhibit 2137 at 220:25-221:19 (objections omitted).
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`Dr. Stover further testified:
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`Q. Let me ask you this way: Would you say that you are at
`least as qualified as Dr. Zeisel to opine on the nutritional issues in this
`case?
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`*
`*
`*
`A. I would say that, in my opinion, I'm abundantly more
`qualified than Dr. Zeisel to speak to folate metabolism. Dr. Zeisel
`does not have a research program that is focused on folate metabolism
`or DNA synthesis. His focus is on methylation, on choline and on
`liver disease, essentially.
`*
`*
`*
`A. I don't -- I am not aware of any work that Dr. Zeisel has
`done in the oncology field.
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`Id. at 222:19-223:20 (objections omitted).
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`Response to Observation 2
`Patent Owner’s observation misleadingly omits adjacent testimony
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`
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`demonstrating Dr. Stover’s knowledge of the mechanisms behind pemetrexed’s
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`toxicities. Just prior to the testimony excerpted by Patent Owner, Dr. Stover
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`explained:
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`Q. And how does pemetrexed cause toxicities?
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`5
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`
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`A. Pemetrexed is a multitargeted antifolate. So not only does it
`inhibit its primary target, or at least its highest affinity target, TYMS,
`but it targets other enzymes as well, as I indicated.
`Toxicities, depending on the nature of the toxicity, could
`originate from any off-target effect. Calling -- if we are referring to
`the target effect as the inhibition of TS.
`Ex. 2137, 15:10-20 (objection omitted).
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`Immediately after the testimony excerpted by Lilly, Dr. Stover further
`explained:
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`Q. Is the same true of other particular hematological toxicities?
`*
`*
`*
`A. Which would you be referring to, to a megaloblastic anemia
`or -- which -- which --
`Q. Any other hematologic toxicity.
`A. Rapidly dividing cells require DNA synthesis. So if you
`impair DNA synthesis, you will have -- you are more likely to have
`both chromosomal abnormalities in those cells as well as lower rates
`of cell division proliferation.
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`Exhibit 2137 at 16:12-23 (objection omitted).
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`Patent Owner also neglects to cite other testimony from Dr. Stover that
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`demonstrates his knowledge of the mechanics of pemetrexed’s toxicity and
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`efficacy. E.g., id. at 30:8-31:14. In particular, Dr. Stover further testified:
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`Q. Would there be differences, however, in how the
`pemetrexed overall interacted with the cells?
`*
`*
`*
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`6
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`
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`A. Yes. Context is really important.
`So if you look -- as we discussed, and as I stated in my
`declaration, there are fundamental differences in the way that folate
`metabolism functions as a unit in a normal cell as opposed to a cancer
`cell, and there is even differences among cancer cells.
`So one of the differences, for instance, is high rates of folate
`catabolism, for which, again, I have discussed in this declaration. So
`when you look at the interaction of pemetrexed in two different cells,
`and you consider other targets that it hits, including it is an effective
`inhibitor of dihydrofolate reductase, which is known to induce general
`increased rates in folate turnover, or catabolism, that effect is going to
`be very different in a cancer cell as opposed to a normal cell, because
`a cancer cell already has high rates of folate catabolism, and,
`therefore, one would predict that if you give more a substrate, like
`dihydrofolate, to that catabolism -- for that catabolism, that the folate
`deficiency would be felt more within the cancer cell than it would in
`the normal cell.
`Furthermore, if you wanted to attempt to ameliorate the
`deficiency, you -- the expectation is, and, in fact, you can actually see
`this in culture, that you would be able to replete a cell that was
`suffering from folate deficiency because of inhibited dihydrofolate
`reductase much more readily than you would a tumor cell, because of
`its active role in folate catabolism and having that machinery
`operative.
`So when you consider the effect of pemetrexed more broadly in
`different contexts, you would expect that some cells would be more
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`7
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`sensitized, some of the secondary and tertiary effects, than a normal
`cell would be.
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`Id. at 205:17-207:9 (objection omitted). Lastly, Lilly’s argument that Dr. Stover
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`lacks understanding of toxicities and that this undermines his opinions is an
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`improper argument for an observation as noted above.
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`Response to Observation 3
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`Patent Owner’s observation misleadingly omits the preceding testimony
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`setting the framework for the testimony Patent Owner cites in its observation. Dr.
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`Stover’s testimony was in response to a question regarding hypothetical normal
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`cells that have not been supplemented with folic acid or vitamin B12:
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`Q. And, similarly, pemetrexed may have an effect on rapidly
`dividing healthy cells through the inhibition of one or both of those
`enzymes?
`A. So you worry about toxicities in normal cells, absolutely.
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`Exhibit 2137 at 20:5-9.
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`Response to Observation 4
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`Patent Owner’s observation omits Dr. Stover’s explanation of the relevance
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`of his testimony regarding nutritional knowledge in June 1999 to the knowledge of
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`a POSA, which is summarized above in Sandoz’s response to Observation 1.
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`Response to Observation 5
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`8
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`Patent Owner cites to various incomplete portions of testimony, ignoring
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`relevant portions of Dr. Stover’s testimony regarding conversations with Dr. David
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`Goldman. The omitted testimony demonstrates that the conversations with Dr.
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`Goldman are not relevant because they occurred well after June 1999.
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`Q. Towards the end of your deposition there was a discussion
`of Dr. Goldman and some views that he had expressed. During -- I
`think they were concerns that he had expressed.
`A. Uh-hum.
`Q. During what time period did he express those concerns that
`were referenced during your -- your cross with Mr. Krinsky?
`A. Those concerns were expressed to me in Greece in the
`folate summer conference, both at a microphone following a
`presentation that was given, and then subsequently we talked about
`this over dinner at the Greece folate meeting, which I believe was
`2012, but I could verify that. It was either -- it was somewhere in the
`time period of 2012 to 2013 or '14.
`Q. So well after June 1999?
`A. Well after June 1999.
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`Exhibit 2137 at 217:21-218:14.
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`In addition, Patent Owner omitted testimony from Dr. Stover that these
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`discussions with Dr. Goldman did not reflect the prevailing view of the effect of
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`folate on cancer prior to June 1999:
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`Q. -- there was a school of thought among some oncologists
`anyway --
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`9
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`A. Yes.
`Q. -- that the levels of folate supplementation, even as low as I
`think you said 200 to 250 micrograms per day --
`A. Yeah.
`Q. -- could adversely impact either anticancer chemotherapy or
`could encourage cancer growth?
`*
`*
`*
`Q. I'm not saying you agree with that school of thought, but
`that was the school of thought that was out there?
`A. That was a school of thought that was out there. But again,
`this underwent extensive review by the Center of Disease Control
`prior to implementing -- or part of the federal government through the
`FDA implementing fortification through their labeling authority, that
`anything entitled enriched had folic acid added to it at these levels,
`and was also, again, subject to review in the 1998 dietary reference
`intakes where they looked at harm related to potential elevated levels
`of folic acid, and you won't find any evidence of that in there. This
`was something that was raised as a hypothesis, something that needed
`to be investigated, but something for which there were no data and for
`which there were counteractive – there were other data showing that if
`there was deficiency, you're actually creating risk, right. So there was
`-- it was a matter of academic debate, just as there were always issues
`of academic debate.
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`Id. at 195:9-196:20 (objection omitted).
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`Dr. Stover further testified:
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`10
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`
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`Q. We have talked about the FDA decision to fortify the diet
`with folic acid a few minutes ago. One follow-up questions on that.
`Are you aware of whether the FDA decision to ratify the
`fortification of the diet with folic acid, in making that decision
`whether they expressed any concern regarding the impact on
`antifolate administration to patients?
`A. That was a topic that was raised and that, my understanding,
`was considered. It was certainly debated and certainly was debated
`within discussions -- I actually went to the CDC to discuss these
`issues and there was not deemed to be evidence in support of a
`hypothesis that fortification would affect the efficacy of any antifolate
`chemotherapeutics.
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`Id. at 223:21-224:12.
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`
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`Dated: February 21, 2017
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`Respectfully submitted,
`/s/ Ralph J. Gabric
`Ralph J. Gabric (Reg. No. 34,167)
`Laura L. Lydigsen
`Bryan T. Richardson, Ph.D. (Reg. No.
`70,572)
`Joshua H. James (Reg. No. 72,568)
`Brinks Gilson & Lione
`NBC Tower – Suite 3600
`455 N. Cityfront Plaza Dr.
`Chicago, Illinois 60611
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`11
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`CERTIFICATE OF SERVICE
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`I hereby certify that true and correct copies of the foregoing document were
`served on February 21, 2017, via email to the following individuals at the email
`addresses below.
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`Dov P. Grossman (Reg. No. 72,525)
`Williams & Connolly LLP
`725 Twelfth St. NW
`Washington DC 20005
`Direct Phone: 202-434-5812
`Facsimile: 202-434-5029
`dgrossman@wc.com
`
`David M. Krinsky (Reg. No. 72,339)
`Williams & Connolly LLP
`725 Twelfth St. NW
`Washington DC 20005
`Direct Phone: 202-434-5338
`Facsimile: 202-480-8302
`dkrinsky@wc.com
`
`Adam L. Perlman
`Williams & Connolly LLP
`725 Twelfth St. NW
`Washington DC 20005
`Direct Phone: 202-434-5244
`aperlman@wc.com
`
`James P. Leeds (Reg. No. 35,241)
`Eli Lilly and Company
`Lilly Corporate Center
`Indianapolis, IN 46285
`Direct Phone: 317-276-1667
`Facsimile: 317-277-6534
`leeds_james@lilly.com
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`John C. Demeter (Reg. No. 30,167)
`Eli Lilly and Company
`Lilly Corporate Center
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`/s/ Ralph J. Gabric
`Ralph J. Gabric (Reg. No. 34,167)
`Laura L. Lydigsen
`Bryan T. Richardson, Ph.D. (Reg. No.
`70,572)
`Joshua H. James (Reg. No. 72,568)
`Brinks Gilson & Lione
`NBC Tower – Suite 3600
`455 N. Cityfront Plaza Dr.
`Chicago, Illinois 60611
`
`Indianapolis, IN 46285
`Direct Phone: 317-276-3785
`Facsimile: 317-276-3861
`Email: demeter_john_c@lilly.com
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