UNITED STATES PATENT AND TRADEMARK OFFICE
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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,
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`Petitioners
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`v.
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`ELI LILLY AND COMPANY,
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`Patent Owner.
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`Case IPR2016-003181
`U.S. Patent 7,772,209
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`PETITIONER SANDOZ INC.’S RESPONSE TO PATENT OWNER’S
`MOTION FOR OBSERVATIONS ON THE DEPOSITION OF EXPERT
`DAVID B. ROSS, M.D.
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`1 Cases IPR2016-01429, IPR2016-01393, and IPR2016-01340 have been joined
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`with the instant proceeding.
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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,
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`Petitioners
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`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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`PETITIONER SANDOZ INC.’S RESPONSE TO PATENT OWNER’S
`MOTION FOR OBSERVATIONS ON THE DEPOSITION OF EXPERT
`DAVID B. ROSS, M.D.
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`1 Cases IPR2016-01429, IPR2016-01393, and IPR2016-01340 have been joined
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`with the instant proceeding.
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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 David B.
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`Ross, M.D. (“Motion” or “Mot.”) and expunge its supporting exhibits because the
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`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 60, Mot. at
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`4, 6-7, 9. Moreover, many of Patent Owner’s arguments are new; they do not
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`match the positions taken on the portions of the prior briefing Patent Owner cites.
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`Sandoz discusses particularly egregious examples in further detail in its responses
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`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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`1
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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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`“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 observation misconstrues the relevance of Dr. Ross’s
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`testimony. Dr. Ross is not a POSA (i.e., an oncologist) and does not purport to be
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`2
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`one. Instead, Dr. Ross opined as an expert in FDA practice in the 1999 timeframe
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`and explained his disagreement with Lilly’s interpretation of FDA statements as
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`purported evidence of skepticism. Ex. 1093, Ross Decl., ¶¶ 11-12.
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`Further, Lilly’s observation omits Dr. Ross’s testimony concerning his
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`experience with oncology:
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`A. . . . . [C]ertainly, from the clinical perspective and, you
`know, I don't want to get into this now, but from the FDA perspective,
`I have the knowledge base that I think I need to accomplish the things
`that I -- I want to accomplish.
`Q. And when you say -- the -- the end of that answer was a
`little vague. When you say you have the knowledge base that you
`think you need to accomplish the things you want to accomplish, you
`mean -- what are those things? In -- in your – you mean in your role
`as -- as -- at VHA or here as an expert?
`A. Well, VHA, but I think -- and I know we're not discussing
`this now, but in terms of regulatory role, I think the same thing is true.
`So, you know, there's -- just to expand, there's some things where the
`clinic -- I'm only talking clinically – that I'm not -- there's things
`where this would not -- where this would not apply.
`Let's take, in general, for example, stage one melanoma. Okay.
`That's, in general, you know, not something -- if -- clinically, if I saw
`a patient with a mole that I thought was suspicious -- and I've done
`this -- I would send it to a dermatologist probably or, you know, if --
`if – you know, an oncologist if it was appropriate, but that doesn't
`mean that I don't know anything about it.
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`3
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`And so I'm not an oncologist, I don't hold myself out to be one,
`but what I'm saying is I do have some knowledge of it. It's -- that can
`apply, and I think the same is true in terms of my role as an expert
`witness, but not from a clinical perspective. I would not say, you
`know, here's the treatment for this, that, or the other thing.
`Q. What do you see your role as here as an expert witness?
`What -- what do you consider yourself to be an expert in for purposes
`of this proceeding?
`A. In FDA requirements for development of drugs and
`biologics, the practical implementation of those requirements with
`regard to clinical trials, and, from a practical sense, how these things
`play out in terms of getting a drug studied and seeing if it is safe and
`effective.
`Q. So in a -- in a broad sense, you're -- you're here as an expert
`in the issues in this case that relate to the FDA and to clinical trial
`design; is that fair?
`A. What I would say is I'm here with regard to a specific
`question I was asked to address involving interactions between Lilly
`and -- and the FDA during development of -- pemetrexed -- I'm sorry,
`pemetrexed.
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`Exhibit 2132, Ross Tr. at 35:7-37:12.
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`Additionally, Patent Owner ignores Dr. Ross’s extensive FDA experience,
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`which is relevant to his opinions:
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`Q. Could you describe your role at the FDA, please?
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`4
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`A. So I had a number of roles during my time at the FDA. As
`medical reviewer, primary reviewer, as a medical team leader, as
`deputy director of what was known at the time as the Office of Drug
`Evaluation VI, and then finally as associate director for regulatory
`science in the Office of Oncology Drug Products.
`And, in general, my responsibilities included, as I've set forth in
`my Declaration, reviewing scientific data for -- had been submitted in
`the form of either a New Drug Application or a Biological Licensing
`Application to the agency in support of an Application to Market a
`Drug or Biologic.
`Looking at the -- whether the trials or the studies that were
`conducted to garner those data met the statutory and regulatory
`standards, specifically adequate and well-controlled trials, reviewing
`protocols, clinical trial protocols, that companies would submit as part
`of a drug development program, various phases, being involved in
`policy discussions, being involved in drafting and reviewing
`guidances, supervising primary reviewers, drafting correspondence to
`companies involving any particular issue in their drug development
`program.
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`Id. at 38:9-39:11.
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`Response to Observation 2
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`Patent Owner misleadingly cites to Dr. Ross’s testimony concerning the
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`general role of a medical officer on the FDA team. Lilly’s observation omits Dr.
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`Ross’s testimony that the FDA ultimately found that there was no concern
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`5
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`sufficient to find the use of folic acid with pemetrexed unacceptable and instead
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`concluded that it was Lilly’s decision whether or not to use folic acid:
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`Q. And there was a -- there's a statement, if you look at the
`paragraph beginning with Dr. Walling(phonetic), "Dr. Walling
`provided some evidence that she believed tended to show that folic
`acid at a particular dosage does not affect efficacy."
`Do you see that?
`A. Yes.
`Q. And the FDA, then, expressed concern that folic acid might
`reduce efficacy?
`A. Well, actually, just to clarify, reading that paragraph starting
`with "Dr. Walling answered" –
`Q. Uh-huh.
`A. -- I think, after the description of Dr. Walling's presentation
`and her conclusion, the FDA did not say anything about risk. It
`simply -- it simply says the FDA responded that it was Lilly's decision
`whether or not to use folate. So there's -- there's not a statement about
`risk directly in that paragraph. The description of the word "risky" is
`in the paragraph B above.
`Q. Yeah. And I -- I don't think I was asking about risk. It – to
`focus you briefly on the -- the last sentence that you just highlighted.
`As we discussed earlier, it's always up to the sponsor rather than the
`FDA whether to make an alteration in a clinical trial design like this?
`A. Well, I guess what I would say is, though, that the FDA,
`you know, said, well, it's up to you, but let me contrast that with, in
`2C there is another question about the analysis plan and – and study --
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`6
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`"choice of primary and secondary end points and the analysis plan in
`study JMCH is acceptable." And there's -- the first word in caps is
`"NO."
`So, you know, and I think this is one of the good things about
`an end-of-phase 2 meeting, that if there's something where that is not
`going to be something that is going to be acceptable from a regulatory
`point of view, the FDA is going to say so. So I -- I think what I'm
`trying to say is the FD- -- it's not supposed to be an exercise in
`telepathy. The FDA is going to say, if it can, here is an unambiguous
`answer.
`So when it says here, there's no mention of the word risk in that
`-- going back to that paragraph, the FDA just said, it's up to you. And
`that's -- that's all it says. So it doesn't say I'm -- I'm saying, you know,
`if they -- in general, if they were going to say, no, that's not
`acceptable, I'd expect to see something akin to that very definitive
`statement down in 2C --
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`Ex. 2132, Ross Tr. at 104:3-106:6.
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`Patent Owner follows its citation with an improper argument that the
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`medical officer for pemetrexed was “concerned that [folic acid] would reduce
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`efficacy” of pemetrexed, which should be expunged. Paper 60, Mot. at 4 (citing
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`Paper 36, PO Resp. at 57-59). As noted above, argumentative observations are
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`improper. Lilly’s improper argument regarding efficacy is based on one sentence
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`in September 1998 minutes, which states that a medical officer raised an issue with
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`7
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`respect to folic acid. Id. at 6 (citing Ex. 2100, Sept. 1998 Minutes at
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`ELAP00008719).
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`Response to Observation 3
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`Patent Owner misleadingly cites to Dr. Ross’s testimony concerning the
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`general purpose of End of Phase II meetings. Lilly’s observation omits Dr. Ross’s
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`testimony that the FDA ultimately found that there was no concern sufficient to
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`find the use of folic acid with pemetrexed unacceptable and instead concluded that
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`it was Lilly’s decision whether or not to use folic acid. Ex. 2132, Ross Tr. at
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`104:3-106:6 (testimony reproduced above in response to Observation 2).
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`Patent Owner follows its citation with an improper argument that the FDA
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`expressed “concern at the pemetrexed End of Phase II meeting in September 1998
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`that Lilly’s addition of vitamin supplementation to the pemetrexed trials would
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`harm the efficacy of pemetrexed,” which should be expunged. Paper 60, Mot. at 6
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`(citing Ex. 2100 Sept. 1998 Minutes at ELAP00008719). As noted above,
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`argumentative observations are improper. Moreover, Lilly’s improper argument
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`regarding efficacy is based on one sentence in the September 1998 minutes, which
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`indicates that the medical officer raised an issue with respect to folic acid. Id.
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`Response to Observation 4
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`Patent Owner improperly excises select portions of Dr. Ross’s testimony and
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`draws conclusions that are not supported by his testimony as a whole. As noted
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`8
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`above, Lilly’s observation is improper because it is argumentative. Moreover,
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`contrary to Lilly’s argument that this testimony demonstrates that efficacy “was a
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`significant concern to the FDA during the development of pemetrexed,” Dr. Ross’s
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`testimony on this point concerned oncology drugs generally – not pemetrexed.
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`Paper 60, Mot. at 6 (emphasis added). Moreover, Lilly misleadingly leaves out the
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`fact that the 7% statistic Lilly cites was based on 2014 data that would not have
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`been available to a POSA in June 1999. Dr. Ross testified, “[T]he most
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`comprehensive survey I know in 2014 said that only seven percent of oncology
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`drugs got enter – phase 1 trials end up being approved.” Ex. 2132, Ross Tr. at
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`78:8-10 (emphasis added). Lilly also omits the explanation immediately following
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`Dr. Ross’s testimony that “most of the time it’s because they don’t work, or
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`because there’s not evidence that they work. Those are not the same thing.” Id. at
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`78:11-14 (omitted testimony underlined). Dr. Ross further explained that a drug
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`may not be approved because of lack of statistically sufficient proof of efficacy –
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`not simply because the drug does not work. Id. at 78:11-80:25.
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`Response to Observation 5
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`Patent Owner fails to include a subsequent portion of Dr. Ross’s testimony
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`where he disagrees that the FDA stated that folic acid would reduce efficacy:
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`Q. I mean, if -- if, in fact, folic acid reduces efficacy, then
`adding folic acid to the trial would make it less likely that the drug
`would be approved?
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`9
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`
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`*
`*
`*
`A. So I guess what I'm going to say is, when you say that it
`would reduce efficacy, it would depend on the details and, you know,
`like how much would it reduce it, whatever. You know, it – it didn't
`make it impossible. I think one thing the FDA is -- is not saying here
`is this will definitely reduce efficacy. I mean, they're just saying, we
`don't -- we don't know one way or the other.
`So they're -- they're not saying this is, you know, like other
`drugs where people have looked at this like, you know, we're -- we're
`sure this is going to do this. It's just we don't know what it's going to
`do, and that's -- that's what I would -- how I would read what they're
`saying.
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`Exhibit 2132, Ross Tr. at 116:10-117:5 (objection omitted).
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`Lilly’s observation also omits Dr. Ross’s earlier testimony that the FDA
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`ultimately found that there was no concern sufficient to find the use of folic acid
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`with pemetrexed unacceptable and instead concluded that it was Lilly’s decision
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`whether or not to use folic acid. Id. at 104:3-106:6.
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`Response to Observation 6
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`
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`Patent Owner’s observation includes improper argument concerning the
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`relevance of Worzalla’s mouse data – as noted above, that argument should be
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`expunged. Paper 60, Mot. at 9. Dr. Ross’s testimony did not concern Worzalla,
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`which was neither considered in preparing his declaration, nor shown to him at his
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`deposition. See Ex. 1093, Ross Decl. at Appendix B. Worzalla’s relevance is
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`10
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`discussed by Dr. Schiff and the Board’s Institution Decision. Ex. 1004, Schiff
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`Decl., ¶¶ 24, 53, 57-65; Paper 14, Institution at 17-18. Nothing in Dr. Ross’s
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`testimony about the use of animal studies is inconsistent.
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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.
`
`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
`
`John C. Demeter (Reg. No. 30,167)
`Eli Lilly and Company
`Lilly Corporate Center
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`
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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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