UNITED STATES DISTRICT COURT
`DISTRICT OF NEVADA
`BEFORE THE HONORABLE MIRANDA DU, DISTRICT JUDGE
`---o0o---
`
`No. 2:16-cv-02525-MMD-NJK
`January 28, 2020
`Reno, Nevada
`Volume 7
`
`::::::::::::
`
`:
`
`AMARIN PHARMA, INC., and
`AMARIN PHARMACEUTICALS
`IRELAND LIMITED,
`Plaintiffs,
`
`-vs-
`HIKMA PHARMACEUTICALS USA
`INC., et al.,
`Defendants.
`
`TRANSCRIPT OF BENCH TRIAL
`
`APPEARANCES:
`FOR THE PLAINTIFFS:
`
`FOR DEFENDANT HIKMA:
`
`Reported by:
`
`MEAGAN P. KEANE, CHRISTOPHER N.
`SIPES, MICHAEL KENNEDY, JEFFREY
`ELIKAN, JOSEPH KENNEDY, ELAINA M.
`WHITT, BARBARA KURYS, HAN PARK,
`DANIEL J. FARNOLY and ERIC R.
`SONNENSCHEIN
`Attorneys at Law,
`Washington, D.C.
`
`CHARLES B. KLEIN and
`CLAIRE A. FUNDAKOWSKI,
`Attorneys at Law
`Washington, D.C.
`
`Kathyrn M. French, CCR #392, RPR
`Official Reporter
`U.S. District Court
`Reno, Nevada
`
`(Appearances continue on next page.)
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`Appx2551
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1018, p. 1 of 280
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`
`DISTRICT OF NEVADA
`BEFORE THE HONORABLE MIRANDA DU, DISTRICT JUDGE
`---o0o---
`
`No. 2:16-cv-02525-MMD-NJK
`January 28, 2020
`Reno, Nevada
`Volume 7
`
`::::::::::::
`
`:
`
`AMARIN PHARMA, INC., and
`AMARIN PHARMACEUTICALS
`IRELAND LIMITED,
`Plaintiffs,
`
`-vs-
`HIKMA PHARMACEUTICALS USA
`INC., et al.,
`Defendants.
`
`TRANSCRIPT OF BENCH TRIAL
`
`APPEARANCES:
`FOR THE PLAINTIFFS:
`
`FOR DEFENDANT HIKMA:
`
`Reported by:
`
`MEAGAN P. KEANE, CHRISTOPHER N.
`SIPES, MICHAEL KENNEDY, JEFFREY
`ELIKAN, JOSEPH KENNEDY, ELAINA M.
`WHITT, BARBARA KURYS, HAN PARK,
`DANIEL J. FARNOLY and ERIC R.
`SONNENSCHEIN
`Attorneys at Law,
`Washington, D.C.
`
`CHARLES B. KLEIN and
`CLAIRE A. FUNDAKOWSKI,
`Attorneys at Law
`Washington, D.C.
`
`Kathyrn M. French, CCR #392, RPR
`Official Reporter
`U.S. District Court
`Reno, Nevada
`
`(Appearances continue on next page.)
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`Appx2551
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`Hikma Pharmaceuticals
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`Ex. 1018, p. 1 of 280
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`APPEARANCES CONTINUED:
`
`
`FOR DEFENDANT HIKMA:
`
`FOR DEFENDANT DR.
`REDDY'S LABORATORIES:
`
`
`
`ALISON M. HEYDORN
`Attorney at Law
`Chicago, Illinois
`EIMERIC REIG-PLESSIS
`Attorney at Law
`San Francisco, California
`
`W. WEST ALLEN
`Attorney at Law
`Las Vegas, Nevada
`
`CONSTANCE S. HUTTNER and
`JAMES BARABAS
`Attorneys at Law
`Madison, New Jersey
`MICHAEL D. ROUNDS
`Attorney at Law
`Reno, Nevada
`
`1758
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`RENO, NEVADA, TUESDAY, JANUARY 28, 2020, 8:30 A.M.
`--o0o--
`THE COURT: Good morning. Please be seated.
`MR. ELIKAN: Your Honor, good morning.
`THE COURT: Good morning. Are you ready?
`MR. ELIKAN: May I proceed?
`THE COURT: Yes. Thank you.
`PETER PAUL TOTH, M.D.,
`recalled as a witness on behalf of the plaintiffs,
`previously sworn, testified further as follows:
`DIRECT EXAMINATION RESUMED
`
`BY MR. ELIKAN:
`Yesterday we were discussing the JELIS trial when we
`Q
`broke. I want to turn now to PX 272, the publication by
`Dr. Bhatt the REDUCE-IT study we looked at before.
`MR. ELIKAN: Can we have Figure 4 on page 10.
`BY MR. ELIKAN:
`How do these results compare to the JELIS results?
`Q
`Well, what we see here, counsel, are across-the-board
`A
`significant reductions in all of the cardiovascular endpoints
`evaluated, whereas within JELIS, the primary composite
`endpoint.
`
`And the endpoint unstable angina, only those two are
`
`reduced.
`And you explained yesterday that unstable angina is the
`Q
`driver of the other endpoint, right?
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`Yes.
`A
`And these differences, all of the cardiovascular
`Q
`differences, those are all statistically significant?
`Yes.
`A
`
`MR. ELIKAN: Can we pull up the second full
`paragraph in the right-hand column on page 9 and highlight the
`first sentence.
`BY MR. ELIKAN:
`What does Dr. Bhatt state here about how Vascepa results
`Q
`stand apart from other results achieved with other drugs?
`"The results of REDUCE-IT stand apart from
`A
`the negative findings of several contemporary trials
`of other agents that also lower triglyceride levels,
`including other omega-3 fatty acids, extended release
`niacin, fenofibrate, and cholesterol ester transfer
`protein inhibitors."
`Do you recall that Dr. Heinecke testified that there was
`Q
`not a failure of others to reduce cardiovascular risk with a
`triglyceride-lowering agent?
`Yes.
`A
`Is Dr. Heinecke's position consistent with Dr. Bhatt's
`Q
`observations?
`No.
`A
`Proceeding to the next sentence, does Dr. Bhatt offer a
`Q
`clear explanation for why clinical trials fail to demonstrate
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`a cardiovascular benefit or was it for him still a matter of
`uncertainty? What did he have to say?
`He reflects some uncertainty. He states,
`A
`"It is not known whether the lack of benefit
`Q
`from omega-3 fatty acids in previous trials may be
`attributable to the low dose or the low ratio of EPA
`to DHA."
`Still looking at the same paragraph I'm going to ask you
`Q
`about an additional sentence further down the paragraph
`beginning with "although the dose."
`What does Bhatt have to say here about how the dose
`in JELIS compared to the dose in REDUCE-IT?
`Dr. Bhatt notes,
`A
`"Although the dose of EPA administered in
`Q
`JELIS (1.8 grams daily) was lower than the
`EPA-equivalent dose used in REDUCE-IT (4 grams
`daily), it resulted in a plasma EPA level
`(170 micrograms per milliliter in a Japanese
`population) similar to that attained in a previous
`12-week lipid study in which a total daily dose of 4
`grams of icosapent ethyl was used in a Western
`population (183 micrograms per milliliter) and
`similar to that attained in the current trial."
`So my question was how does the dose in JELIS compare to
`Q
`the dose administered in REDUCE-IT.
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`1762
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`In terms of attained EPA levels in serum --
`A
`Before we get to the serum, what was the dose
`Q
`administered in the two trials?
`Okay. In REDUCE-IT, it was 4 grams, in JELIS, it was
`A
`1.8 grams.
`Now, let's turn to the serum. Maybe you can unpack the
`Q
`passage you read. What is this saying about the serum levels?
`That they were very close, 170 micrograms per milliliter
`A
`of EPA in JELIS, and 183 micrograms per milliliter in the
`MARINE trial, and similar to what was seen in REDUCE-IT.
`Do you see a reference to -- citation to references 25
`Q
`and 26?
`I do.
`A
`
`MR. ELIKAN: Let's take a look at those for a
`second as they're listed at the end the article.
`Can we pull up those references on page 12.
`BY MR. ELIKAN:
`Based on the dates of publication, would these references
`Q
`have been available to the person of ordinary skill in the art
`in March 2008?
`They were published in 2011 and 2016, so the answer is
`A
`no.
`Do you recall that yesterday we looked at the Yokoyama
`Q
`article?
`Yes.
`A
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`Where it acknowledged that an exclusively Japanese
`Q
`population was studied?
`Yes.
`A
`
`MR. ELIKAN: I want to turn back to that. Can
`we go to DX 1553 and page 8, and I want to pull up on the
`screen the last paragraph of the paper and highlight the
`second to last sentence.
`BY MR. ELIKAN:
`What did the author state here about the consequence of
`Q
`the study population being exclusively Japanese?
`Dr. Yokoyama notes that,
`A
`"Because our population was exclusively
`Q
`Japanese, we cannot generalize our results to other
`populations."
`MR. ELIKAN: And I want to go now to page 7 and
`highlight the statement at the bottom of the left-hand column
`which carries over to the top of the right-hand column.
`BY MR. ELIKAN:
`What did the author state here about how the average
`Q
`Japanese diet compares to the diet of people in other
`countries?
`A
`
`"In Japan, death from coronary artery disease
`is rare, and the average dietary intake of fish is
`about five times higher than that in other
`countries."
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`Does fish contain DHA?
`Q
`Yes.
`A
`If a person of ordinary skill in the art wanted to
`Q
`formulate an omega-3 for other populations that don't eat as
`much fish, and believed it was necessary to mimic the
`composition of omega-3 fatty acids that Japanese people
`consume throughout the day, would that person have included
`substantial amounts of DHA?
`Yes.
`A
`And why is that?
`Q
`Because they would try to mimic -- is a good word -- the
`A
`dietary reconditions of the people in Japan who participated
`in this study.
`The supplement was EPA alone, but because they eat
`five times as much fish as people in other countries, they're
`still taking in a very substantial amount of DHA daily.
`Have you prepared a slide showing the doses used for
`Q
`omega-3 fatty acid cardiovascular outcome trials underway as
`of March 2008?
`Yes.
`A
`
`MR. ELIKAN: Can we have PDX 6-31.
`BY MR. ELIKAN:
`Before we walk through the specifics, are these the same
`Q
`trials you discussed earlier, that is, yesterday, the omega-3
`fatty acid cardiovascular outcome trials underway as of March
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`2008?
`Yes, counsel.
`A
`And are the source materials the same?
`Q
`Yes.
`A
`And what were the doses that were being studied as of
`Q
`March 2008?
`Well, you see five trials used one gram daily, one trial
`A
`used 400 milligrams daily, one used 600 milligrams daily, and
`another used 2.4 grams daily.
`Did any of the outcome trials underway as of March 2008
`Q
`on omega-3 fatty acids use 4 grams?
`No.
`A
`
`MR. ELIKAN: We move for the admission of PDX
`6-31 under Federal Rule of Evidence 1006.
`MR. KLEIN: No objection.
`THE COURT: PDX 6-31 is admitted.
`(Plaintiffs' Exhibit 6-31 received in
`evidence.)
`
`BY MR. ELIKAN:
`What, if anything, do the doses used in these
`Q
`cardiovascular outcome trials suggest about whether it would
`have been obvious to use 4 grams of EPA to lower
`cardiovascular risk?
`Well, it suggests that no one believed that 4 grams was
`A
`the magic bullet here. People were using different doses
`because, as I said, they were feeling their way through the
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`dark.
`
`MR. ELIKAN: Let's go back to PDX 6-32, and
`
`skepticism.
`BY MR. ELIKAN:
`In your work on this case, did you review materials that
`Q
`reflected skepticism about whether or not omega-3 fatty acids
`would provide a cardiovascular benefit?
`Yes.
`A
`Do you recall yesterday we looked at a statement in the
`Q
`Cochrane collaboration, PX 953, that Omega-3s, and I'm
`quoting, "probably are not useful for preventing or treating
`cardiovascular disease"?
`Yes.
`A
`And do you recall looking at a statement in an article by
`Q
`Dr. Aung, PX 954, that there is, quote,
`"No support for current recommendations for
`the use of such supplements in people with a history
`of coronary heart disease"?
`Yes.
`A
`Do you consider these examples of skepticism?
`Q
`Yes.
`A
`Were you, Dr. Toth, as skeptical as some other people
`Q
`were?
`No, I was more optimistic. I was more hopeful. And I
`A
`was still hoping that the omega-3s would be able to
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`demonstrate benefit.
`And in being hopeful, do you believe you were in the
`Q
`majority or the minority?
`Oh, I was in the minority.
`A
`Are there other materials you have reviewed in this case
`Q
`that reflect skepticism about the potential of omega-3 fatty
`acids to lower cardiovascular risk before REDUCE-IT?
`Yes.
`A
`Let's turn to PX 951. And what is this?
`Q
`This is an article by Adam Feuerstein entitled "Amarin
`A
`Fish Oil Capsule Shows Dramatic Benefit For Cardiovascular
`Patients, Potentially Upending Market."
`What's the date of the article?
`Q
`September 24th, 2018.
`A
`MR. ELIKAN: Your Honor, we move for admission
`
`of PX 951.
`
`MR. KLEIN: No objection.
`BY MR. ELIKAN:
`Let's turn to --
`Q
`THE COURT: 951?
`MR. ELIKAN: Yes, I'm sorry, Your Honor.
`THE COURT: Exhibit 951 is admitted.
`(Plaintiffs' Exhibit 951 received in
`evidence.)
`
`BY MR. ELIKAN:
`Turning to the sixth paragraph on page 2, what did
`Q
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`Dr. Ethan Weiss, the cardiologist at UCSF, have to say about
`the Vascepa study?
`"I thought the Vascepa study would be
`A
`negative, colored by all the prior failed studies, so
`I'm surprised. I'm willing to eat my shoe on this
`one. This could be really beneficial to people."
`And in the last paragraph on page 3, what did Dr. Norman
`Q
`Lepor of Cedars-Sinai Medical Center have to say?
`"I went into this study not convinced that
`A
`Vascepa would make a difference, but these results
`will definitely change my practice and the way I
`treat patients."
`Do you consider these examples of skepticism?
`Q
`Yes.
`A
`In general, have the REDUCE-IT trial results now been
`Q
`embraced by the medical community?
`Yes.
`A
`Do you recall that Dr. Heinecke testified that there was
`Q
`no relevant skepticism that EPA would reduce cardiovascular
`risk?
`Yes.
`A
`And in light of all the materials that you've reviewed,
`Q
`do you agree with Dr. Heinecke that there was no relevant
`skepticism that EPA would reduce cardiovascular risk?
`No.
`A
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`MR. ELIKAN: Let's turn back to PDX 6-33. I
`want to turn now to Unexpected Results.
`BY MR. ELIKAN:
`You testified earlier that the REDUCE-IT results apply
`Q
`equally to a population with severe hypertriglyceridemia
`because, among other things, we knew from MARINE there would
`be no substantial rise in LDL-C.
`Do you recall that testimony?
`
`Yes.
`A
`Was there any parallel study that existed in March 2008
`Q
`that would have told the person of ordinary skill in the art
`that when Epadel is given to a patient population with severe
`hypertriglyceridemia, there will be no substantial rise in
`LDL-C?
`No.
`A
`Do you recall that Dr. Heinecke testified that JELIS
`Q
`reported a 19 percent reduction in cardiovascular risk?
`Yes.
`A
`And accepting that risk reduction at face value, would
`Q
`the person of ordinary skill in the art have expected -- would
`they have had reason to expect that this risk reduction
`reported in patients with, I believe you said a mean baseline
`triglyceride level of 153?
`Yes.
`A
`-- that it would apply to patients with severe
`Q
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`hypertriglyceridemia?
`No.
`A
`Triglycerides over 500.
`Q
`No.
`A
`And why not?
`Q
`Because a person of ordinary skill in the art as of March
`A
`2008 would have understood that the response in LDL for
`patients below 500 on their triglycerides and above 500 were
`distinctly different.
`MR. ELIKAN: I'd like to pull up, again, PX 272,
`the Bhatt publication, and go to page 10 and back to Figure 4.
`And, Mr. Brooks, can you highlight Fatal Or
`Nonfatal Stroke.
`BY MR. ELIKAN:
`What's the risk reduction shown for stroke?
`Q
`Twenty-eight percent, and it is statistically
`A
`significant.
`Would this result have been expected after JELIS?
`Q
`No.
`A
`
`MR. ELIKAN: Let's look at JELIS on stroke. Can
`we have -- DX 1553, please, and Figure 3 on page 5, and I want
`to look at the analysis on stroke. It starts at the bottom.
`And, Mr. Brooks, can you highlight the stroke
`
`line.
`
`
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`BY MR. ELIKAN:
`What was reported in terms of risk reduction for stroke
`Q
`in the JELIS study?
`Well, the hazard ratio is 1.02, statistically not
`A
`significant, and you'll notice that the point is virtually
`straddling unity, that vertical bar. So there was no impact
`on stroke in the JELIS trial.
`What does it mean that it's a number that's higher than
`Q
`1?
`Well, if it's higher than 1, that means there's hazard
`A
`that it would increase that specific endpoint. But we can't
`conclude here that stroke went up by 2 percent because it's
`not statistically significant.
`Is a statistically significant reduction in stroke of
`Q
`28 percent an important clinical benefit?
`Counsel, it is enormously important because it's over and
`A
`above that observed with statin therapy.
`And if we think about this, stroke is one of the
`most dreaded cardiovascular complications of all because it
`can leave a loved one with the inability to speak, walk,
`think, it could change their personality.
`Yes, it's of enormous, enormous importance.
`Do you consider this difference, 28 percent and zero, one
`Q
`of degree or one of kind?
`Well, I think it speaks for itself. It's one of kind.
`A
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`And for patients who don't experience a stroke, who would
`Q
`have without Vascepa, is that a difference in kind or in
`degree?
`It's a difference in kind.
`A
`Let's go back to PX 272 and back to Figure 4. I'm going
`Q
`to look at the cardiovascular death endpoint.
`What did REDUCE-IT report with respect to the effect
`of Vascepa on cardiovascular death?
`REDUCE-IT reported a 20 percent relative risk reduction
`A
`in cardiovascular death that was statistically significant at
`P equal to .03.
`Would that result have been expected based on JELIS?
`Q
`No, counsel.
`A
`MR. ELIKAN: I'd like to go back to Yokoyama,
`DX 1553, and page 5, Figure 3, and can we highlight the
`coronary death entry.
`BY MR. ELIKAN:
`What did JELIS report in terms of the risk of
`Q
`cardiovascular death?
`There was a 6 percent trend for reduction. There's a
`A
`slight leftward shift, left of unity. But, it didn't even
`come close to statistical significance with a P value of .81.
`It looks like this line through which the dot runs is
`Q
`very wide. What does that signify?
`That means there's great uncertainty about how accurate
`A
`
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`Ex. 1018, p. 16 of 280
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`that estimate is.
`Is REDUCE-IT significant reduction in cardiovascular
`Q
`death a difference in kind or in degree compared to JELIS'
`nonsignificant risk reduction on cardiovascular death?
`It is a difference in kind. This has never been shown
`A
`before when using an adjutant therapy over and above a statin.
`We've seen numerous trials with adjutant therapies
`on top of a statin and none of them have been able to
`demonstrate an incremental reduction in mortality over and
`above a statin.
`This is a profound difference in kind. Death is it,
`there is no second chance. Reducing death by 20 percent for
`cardiovascular events over and above a statin is a landmark
`achievement.
`In summary, do you agree with Dr. Heinecke that the
`Q
`cardiovascular benefits shown in REDUCE-IT were expected?
`No, they were not expected. I think the evidence speaks
`A
`for itself.
`And do you agree with him in summary that the results of
`Q
`REDUCE-IT were merely a difference in degree as compared to
`JELIS rather than one -- than a difference in kind?
`No, I do not agree with that assessment.
`A
`I want to go back to PDX 6-34. Are you ready to discuss
`Q
`praise?
`Yes, counsel.
`A
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`Hikma Pharmaceuticals
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`IPR2022-00215
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`Ex. 1018, p. 17 of 280
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`1774
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`MR. ELIKAN: Can we pull up PDX 6-10 that we
`discussed earlier.
`BY MR. ELIKAN:
`In your opinion, are the references listed in PDX 6-10
`Q
`that you testified about yesterday, PX 952, PX 902, and PX
`714, examples of praise for REDUCE-IT?
`Yes.
`A
`You testified earlier that the cardiovascular benefits in
`Q
`REDUCE-IT were independent of the triglyceride levels of the
`participants and that severely hypertriglyceridemic patients
`enjoy the same benefits. Do you recall that?
`Yes.
`A
`So my question to you is do you read the praise in these
`Q
`articles as equally applicable to patients with severe
`hypertriglyceridemia?
`Yes.
`A
`Do you recall that Dr. Heinecke testified that there is
`Q
`no nexus between the benefits observed in REDUCE-IT and the
`asserted claims?
`Yes.
`A
`Do you agree with him?
`Q
`No.
`A
`Do you recall that Dr. Heinecke first disputed nexus on
`Q
`the ground that the asserted claims are directed to a method
`of reducing triglycerides, but that cardiovascular risk
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`IPR2022-00215
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`Ex. 1018, p. 18 of 280
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`
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`1775
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`reduction in REDUCE-IT was not the result of triglyceride
`lowering?
`Yes.
`A
`So I want to now turn to the Bhatt article again, PX 272
`Q
`at page 10, starting at the bottom of the left-hand column and
`carrying over to the right-hand column.
`Does this passage beginning with "these
`observations," does it rule out the possibility that some of
`the cardiovascular reduction may be the result of triglyceride
`lowering?
`No.
`A
`
`"These observations suggest that at least
`some of the effect of icosapent ethyl that resulted
`in a lower risk of ischemic events than that with
`placebo may be explained by metabolic effects other
`than the reduction of triglycerides,"
`but he doesn't rule it out.
`And setting aside whether triglyceride lowering explains
`Q
`any of the cardiovascular benefits observed in REDUCE-IT, will
`administering the claimed treatment method of 4 grams of high
`purity EPA result in patients receiving the cardiovascular
`benefits observed in REDUCE-IT?
`Yes.
`A
`Do you recall that Dr. Heinecke also testified that
`Q
`there's no nexus between the REDUCE-IT findings and the
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`IPR2022-00215
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`Ex. 1018, p. 19 of 280
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`1776
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`asserted claims because REDUCE-IT did not begin to show a
`divergent of reduction in cardiovascular events until year one
`rather than at 12 weeks?
`Yes.
`A
`In your opinion, does the fact that there was no
`Q
`statistically significant reduction in cardiovascular events
`in REDUCE-IT at 12 weeks mean that there is no cardiovascular
`advantage to a patient who has taken Vascepa for 12 weeks
`compared to a patient who hasn't?
`Well, as a clinician, I have to say you have to start
`A
`somewhere. You have to initiate treatment if you want to
`expect benefit downstream.
`We know from MARINE that within three months you
`will most certainly induce biochemical metabolic changes in
`that patient's lipoprotein physiology that are beneficial,
`reducing triglycerides, keeping LDL neutral, reducing apo B.
`And MARINE also demonstrated that multiple different
`inflammatory mediators also decrease. These would all be seen
`as beneficial and all have been tied to cardiovascular
`benefit.
`You said that these benefits were observed at three
`Q
`months. Were they observed at 12 weeks in MARINE?
`Yes, I'm sorry, 12 weeks.
`A
`Does that mean that the patient is getting closer to a
`Q
`point where there will be -- where that patient will be at the
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`Ex. 1018, p. 20 of 280
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`point in a study in which there are observable differences?
`Yes, we know that with any drug it takes time to accrue
`A
`enough benefit, enough physiologic change or anatomical change
`so that you can reserve reductions in cardiovascular events.
`Do you also need a study to have enough events occur in
`Q
`order to see a divergence --
`Yes.
`A
`-- between two arms?
`Q
`You do.
`A
`Now, do you recall that Dr. Heinecke testified that the
`Q
`patients in REDUCE-IT were on statin therapy while some of the
`asserted claims specify that the medication is administered
`without concomitant lipid-altering therapy?
`Do you recall that testimony?
`
`A
`Q
`
`Yes.
`I want to ask you some questions about that.
`What's the primary mechanism by which statins lower
`cardiovascular risk?
`LDL cholesterol reduction.
`A
`Does Vascepa lower cardiovascular risk by lowering LDL-C?
`Q
`No.
`A
`Is it the case, then, that Vascepa and statins lower
`Q
`cardiovascular risk through different mechanisms?
`Yes, that is the best explanation.
`A
`And what, if anything, does that suggest about whether
`Q
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`Ex. 1018, p. 21 of 280
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`patients taking Vascepa will derive a benefit, even if they're
`not on statins?
`It would strongly suggest that they would derive benefit
`A
`even if they're not on statins.
`Given that fact, do you agree with Dr. Heinecke that
`Q
`there's no nexus between the REDUCE-IT benefits and the claims
`that require patients not to be on concurrent statin therapy?
`No.
`A
`I want to turn to the remaining asserted claims.
`Q
`Do the reasons you've testified that claim 1 of the
`'728 patent would not have been obvious apply to the other
`asserted claims as well?
`Yes.
`A
`Some of the asserted claims other than claim 1 of the
`Q
`'728 patent specify that the claimed treatment must effect a
`reduction in apo B. Have you prepared a slide that identifies
`the claims that discuss reductions in apo B?
`Yes.
`A
`Can we have PDX 6-35.
`Q
`What are the claims and limitations relating to apo
`
`B?
`A
`
`Claim 8 of the '677 patent states "to.
`Effect a reduction in apolipoprotein B compared to
`placebo control."
`Claim 5 of the '929 patent states "effective to
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`Ex. 1018, p. 22 of 280
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`reduce apolipoprotein B."
`And claim 14 of the '715 patent states "to effect a
`statistically significant reduction in apolipoprotein B."
`You testified yesterday that Lovaza did not reduce apo B
`Q
`in patients with very high triglycerides. In your opinion,
`would a person of ordinary skill in the art have reasonably
`expected that administering 4 grams of EPA in March 2008,
`would reduce apo B in patients with very high triglycerides?
`No, they have no foundation for that.
`A
`Do you recall that Dr. Heinecke testified that a person
`Q
`of ordinary skill in the art would have reasonably expected
`that 4 grams of EPA would reduce apo B in patients with very
`high triglycerides based on Grimsgaard and Kurabayashi?
`No.
`A
`I'm sorry, I'm just asking you if you recall. You said
`Q
`no?
`A
`Q
`
`I'm sorry.
`Let me read --
`THE COURT: It's all right if you don't recall.
`THE WITNESS: No, I do.
`MR. ELIKAN: If you don't recall --
`THE WITNESS: Please repeat the question.
`MR. ELIKAN: I will.
`BY MR. ELIKAN:
`Do you recall that Dr. Heinecke testified that a person
`Q
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`IPR2022-00215
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`Ex. 1018, p. 23 of 280
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`of ordinary skill in the art would have reasonably expected
`that 4 grams EPA would reduce apo B in patients with very high
`triglycerides based on Grimsgaard, Nozaki, and Kurabayashi?
`Yes.
`A
`Did any of those references report reductions in apo B --
`Q
`No.
`A
`-- in patients -- hold on, Doctor.
`Q
`Did any of those references report mechanism --
`report reductions in apo B in patients with very high
`triglycerides?
`No.
`A
`Would the person of ordinary skill in the art have looked
`Q
`to those references in forming an expectation about the effect
`of EPA on apo B in patients with very high triglycerides?
`No.
`A
`Why not?
`Q
`Because they didn't look at apo B in patients with very
`A
`high triglycerides.
`Did Dr. Heinecke cite a single prior art reference
`Q
`reporting that any omega-3 fatty acid formulation reduced apo
`B in patients with very high triglycerides?
`No.
`A
`Beyond apo B some of the other asserted claims have
`Q
`limitations that do not appear in claim 1 of the '782 patent.
`I want to go through those now.
`
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`Ex. 1018, p. 24 of 280
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`Claim 1 the '728 patent claims a dose of about 4
`grams of EPA a day, whereas claims 4 and 17 of the '560 patent
`cover a daily dose of about 3.6 to 4 grams per day.
`Do you have a different opinion or different
`reasoning about the nonobviousness of those claims that have a
`slightly different dose limitation or do you believe that the
`same opinion and reasoning applies with equal force to those
`claims?
`I believe the latter.
`A
`And turning to concurrent lipid altering therapy.
`Q
`Whereas claim 1 of the '782 patent specifies that
`the EPA is administered without concurrent lipid altering
`therapy, other claims are silent on whether the subject
`receives concurrent lipid altering therapy.
`Do you have a different opinion or different
`reasoning about the nonobviousness of those claims that are
`silent on whether the subject is on concurrent lipid altering
`therapy, or do you believe the same opinion and reasoning
`applies with equal force to those claims?
`I believe the latter.
`A
`Some of the claims use different language than claim 1 of
`Q
`the '782 patent to describe the effects of administering
`Vascepa on LDL-C levels. I want to walk through that now.
`MR. ELIKAN: Can we have PDX 6-36.
`
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`IPR2022-00215
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`Ex. 1018, p. 25 of 280
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`1782
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`BY MR. ELIKAN:
`And can you walk us through the claims and limitations.
`Q
`These are variations on LDL-C limitation in claims other
`A
`than claim 1 of the '728 patent.
`Claim 1 of the '677 patent states "without
`substantially increasing LDL-C compared to placebo control."
`Claim 14 of the '715 patent states "without
`effecting a statistically significant increase of [LDL-C] in
`the subject."
`Claims 4 and 17 of the '560 patent state "without
`increasing LDL-C by more than 5 percent in the subject," and
`"without increasing LDL-C in the subject compared to placebo
`control."
`
`And claim 1 of the '652 patent stating "without
`substantially increasing LDL-C compared to baseline."
`And as to those claims, do you have a different opinion
`Q
`or different reasoning about their nonobviousness, or do you
`believe the same opinion and reasoning applies with equal
`force to those claims?
`The latter.
`A
`Let's talk about the two asserted claims that don't
`Q
`mention LDL-C, claims 1 and 5 of the '929 patent.
`MR. ELIKAN: Can we pull up PDX 6-37.
`BY MR. ELIKAN:
`Do you have a different opinion or different reasoning
`Q
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`Ex. 1018, p. 26 of 280
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`
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`about the nonobviousness of these two claims, claim 1 of the
`'929 patent and 5 of the '929 patent, or do you believe the
`same opinion and reasoning applies with equal force to these
`claims?
`The latter.
`A
`In sum, then, what's your opinion on whether any of the
`Q
`asserted claims would have been obvious?
`None of them would have been obvious.
`A
`MR. ELIKAN: Your Honor, can you give me one
`
`moment?
`
`THE COURT: Yes.
`MR. ELIKAN: Your Honor, I have no further
`questions at this time.
`We have a technical issue. The screens at
`counsel table, at least on our side, are not working. I don't
`know whether you're experiencing --
`MR. KLEIN: Ours are okay.
`MR. ELIKAN: Yours are okay? Ours are not.
`MR. SIPES: We're hoping when we flip over the
`screens will come back. That's it.
`THE COURT: Why don't we see if we can address
`that issue before cross-examination, maybe, perhaps.
`THE CLERK: I just flipped it over. Did it
`
`change?
`
`MR. SIPES: It did change.
`
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`IPR2022-00215
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`Ex. 1018, p. 27 of 280
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`THE CLERK: Is it coming up on all of the
`
`screens?
`
`MR. SIPES: Now it is.
`THE COURT: Okay.
`MR. ELIKAN: Thank you very much.
`MR. KLEIN: May I proceed?
`THE COURT: Yes.
`MR. KLEIN: Good morning, Dr. Toth.
`THE WITNESS: Good morning, Mr. Klein. Good to
`see you again.
`MR. KLEIN: You and I met at your deposition,
`
`right?
`
`THE WITNESS: Yes, we did.
`MR. KLEIN: For the record, I'm Charles Klein.
`I'll be asking you questions for the defendants.
`Mr. Gross, can you put on DDX 10.1, please.
`CROSS-EXAMINATION
`
`BY MR. KLEIN:
`Dr. Toth, were you here for Dr. Heinecke's direct?
`Q
`I was not present for it, no.
`A
`Okay. Did you read his testimony?
`Q
`Yes.
`A
`Okay. This -- I will represent to you that this slide
`Q
`was used during Dr. Heinecke's direct. It was DX 6.75. Have
`you seen this slide before?
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`IPR2022-00215
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