494
`
`Civil Action
`
`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
`- - -
`SALIX PHARMACEUTICALS, INC. and )
`DR. FALK PHARMA GmbH,
`Plaintiffs,
`
`))
`
`))
`
`))
`
`))
`
`v.
`NOVEL LABORATORIES, INC.,
`Defendant.
`
`No. 14-213-GMS
`
`)
`- - -
`Wilmington, Delaware
`Wednesday, November 18, 2015
`9:00 a.m.
`Trial Day 3
`- - -
`BEFORE: HONORABLE GREGORY M. SLEET, U.S.D.C.J.
`APPEARANCES:
`MARY W. BOURKE, ESQ.,
`DANA KATHRYN SEVERANCE, ESQ.,
`DANIEL ATTAWAY, ESQ., and
`KRISTEN HEALEY CRAMER, ESQ.
`Womble Carlyle Sandridge & Rice, LLP
`-and-
`TRYN T. STIMART, ESQ.
`Womble Carlyle Sandridge & Rice, LLP
`(Tysons Corner, VA)
`-and-
`PRESTON W. HEARD, ESQ.
`Womble Carlyle Sandridge & Rice, LLP
`(Atlanta, Ga)
`
`Counsel for Plaintiffs
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`Dr. Falk Ex. 2024
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
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`
`
`Civil Action
`
`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
`- - -
`SALIX PHARMACEUTICALS, INC. and )
`DR. FALK PHARMA GmbH,
`Plaintiffs,
`
`))
`
`))
`
`))
`
`))
`
`v.
`NOVEL LABORATORIES, INC.,
`Defendant.
`
`No. 14-213-GMS
`
`)
`- - -
`Wilmington, Delaware
`Wednesday, November 18, 2015
`9:00 a.m.
`Trial Day 3
`- - -
`BEFORE: HONORABLE GREGORY M. SLEET, U.S.D.C.J.
`APPEARANCES:
`MARY W. BOURKE, ESQ.,
`DANA KATHRYN SEVERANCE, ESQ.,
`DANIEL ATTAWAY, ESQ., and
`KRISTEN HEALEY CRAMER, ESQ.
`Womble Carlyle Sandridge & Rice, LLP
`-and-
`TRYN T. STIMART, ESQ.
`Womble Carlyle Sandridge & Rice, LLP
`(Tysons Corner, VA)
`-and-
`PRESTON W. HEARD, ESQ.
`Womble Carlyle Sandridge & Rice, LLP
`(Atlanta, Ga)
`
`Counsel for Plaintiffs
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`Dr. Falk Ex. 2024
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
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`535
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`Golden - redirect
`physiologic approach, physiologic parameters.
`MS. CRAMER: Thank you, Dr. Golden.
`THE COURT: Thank you, Doctor. You're excused.
`THE WITNESS: Thank you.
`(Witness excused.)
`MR. BOURKE: The witness that I forgot about.
`Would you like to -- me to begin the examination or do you
`want to take a morning break?
`THE COURT: This witness is?
`MR. BOURKE: Dr. Roland Greinwald.
`THE COURT: On what subject?
`MR. BOURKE: He's testifying about the research
`that was done by Dr. Falk with their granulated mesalamine
`formulations.
`THE COURT: Let's take a quick stretch.
`(Short recess taken.)
`THE COURT: Take your seats. Let's have our
`next witness.
`MR. BOURKE: Plaintiffs call as their next
`witness Dr. Roland Greinwald.
`THE COURT: Okay.
`... DR. ROLAND GREINWALD, having been
`duly sworn as a witness, was examined and
`testified as follows ...
`THE COURT: Please take your seat, Doctor. Good
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`Dr. Falk Ex. 2024
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 2
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`
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`Greinwald - direct
`
`550
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`document.
`
`If you turn to Page 3 of the document. Are you
`with me? There is a Table 1?
`Yes.
`A.
`It says it's a Clinical Activity Index. Do you see
`Q.
`that?
`Yes.
`A.
`What is a clinical activity index?
`Q.
`So this is to describe the activity of ulcerative
`A.
`colitis. It is a tool, actually, to quantify the activity
`in clinical trials, a score.
`Have you heard of a disease activity index?
`Q.
`I have heard of this. This is another kind of
`A.
`activity score, originally published by Dr. Sutherland and
`later modified. The difference from that one here and the
`clinical activity index shown in Table 1 here is published
`by Rachmilewitz. It contains seven different subscores.
`The DAI, for example, only four subscores and one of the
`subscores where it comprises an endoscopic subscore. An
`endoscopic subscore is not contained here in this clinical
`activity index.
`Let's turn to, would you turn to PTX-97 in your
`Q.
`binder. Are you with me?
`Yes.
`A.
`What is this?
`Q.
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`Dr. Falk Ex. 2024
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 3
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`551
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`Greinwald - direct
`This is a clinical study, a pharmacographic study of
`A.
`the GI transit and release of Sm-labeled mesalamine granules
`on one hand, Salofalk granules, versus Sm-labeled mesalamine
`tablets had in male healthy volunteers on the other hand.
`The male healthy volunteers, the document says it's a final
`version of November 29, 1999.
`And this is SAG 16 that you referred to earlier?
`Q.
`That is the study code, SAG 16.
`A.
`What is a scintigraphic analysis?
`Q.
`So you use a specific rate you are labeling to allow,
`A.
`actually, the detection, or the location of a specific
`formulation within the GI tract. You can make it visible.
`Do you radiolabel the drug?
`Q.
`No, you don't label the API. But you put your label
`A.
`within the formulation.
`So you have to manufacture it that way?
`Q.
`That's correct. You have to manufacture it in a
`A.
`specific way. And you have to control, also, the release
`behavior is not changed afterwards, compared to the
`original.
`Did you have a role in this study?
`Q.
`Pardon?
`A.
`Did you have a role in this study?
`Q.
`Yes. I was project director of the study in this
`A.
`function. I actually overlooked the writing of this
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`Dr. Falk Ex. 2024
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 4
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`Greinwald - direct
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`552
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`protocol.
`And what were the study objectives?
`Q.
`The study objectives were -- which page? Oh, yes. At
`A.
`page 7. The study objective was actually to demonstrate by,
`by pharmacoscintigraphy, that Salofalk pellets released the
`active ingredient 5-ASA in the same anatomical region like
`Salofalk tablets in healthy volunteers.
`And was there a secondary objective?
`Q.
`Yes. We wanted to measure also the transit time
`A.
`within the stomach and the mouth and absorption of different
`target areas.
`Was this study conducted with or without food?
`Q.
`This was conducted without food. Why it was conducted
`A.
`without food, because we used Salofalk 500-milligram tablets
`as a comparator, and it was known that food intake would
`compromise the gastric emptying of this the big monolithic
`tablets at that time, and we wanted a fair comparison of,
`for example, gastric emptying, transit in the GI tract
`without any confounding influence by food.
`All right. Could you turn to page 9 of that study
`Q.
`report.
`Yes.
`A.
`The table at the bottom that has transit times; is
`Q.
`that right?
`Yes. I've got it.
`A.
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`Dr. Falk Ex. 2024
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 5
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`553
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`Greinwald - direct
`And what sort of transit behavior did you assess?
`Q.
`So we measured the time enteric post formulations were
`A.
`emptied from the stomach, so gastric emptying. Then we
`measured the time when the drugs were located in the small
`intestine. We measured the oral transit time, small
`intestine. Furthermore, we measured the disappearance from
`the small intestine. We also measured the time when the
`formulations have been in the EUC, the colon, and we
`measured the colon.
`All right. And so what does disappearance from the
`Q.
`small intestine mean?
`So this means that the pellets, for example, left the
`A.
`small intestine after 3.7 hours, whereas the tablets under
`the fasting conditions left it after 3.8 hours. So under
`fasting conditions, the behavior of both tablets and
`granules in this respect were more or less identical.
`All right. If you turn to page 37 to 38, can you
`Q.
`describe for the Court how the relative percent absorption
`was assessed?
`Yes.
`A.
`Maybe if we can look at 38?
`Q.
`Yes.
`A.
`There's a document.
`Q.
`So it was calculated from the ratio of the extent of
`A.
`absorption in the target region and the overall extent of
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`GeneriCo v. Dr. Falk IPR2016-00297
`Page 6
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`Greinwald - direct
`absorption up to the time in which the last technical
`concentration 5-ASA was observed.
`Okay. And did you determine what the mean relative
`Q.
`absorption of 5-ASA in the ileocecal region and the
`ascending colon were?
`Yes. This is given on page 38 in Table 1 of this
`A.
`document, so this, that 52 percent of the totally absorbed
`5-ASA under the pellet formulations were absorbed when
`pellets were located in the ileocecal region. Body percent
`of 5-ASA of the totally absorbed 5-ASA on the tablets were
`absorbed when tablets were in the ileocecal region.
`What does that indicate in terms of release in the
`Q.
`ileocecal region in ascending colon?
`So in this case, there's a release, because if you
`A.
`measure a certain blood level, it can only be the blood and
`it had been released before.
`Okay. Now, is this the study that enabled you to put
`Q.
`the release, the 80 to 90 percent of release information
`into the SAG?
`Yes.
`A.
`Okay. And was this study ever published?
`Q.
`This study was published by Brunner and co-workers.
`A.
`Okay. Turn to PTX-80 in your binder, please.
`Q.
`80.
`A.
`Is this the publication to which you are referring?
`Q.
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`Dr. Falk Ex. 2024
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 7
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`555
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`A.
`Q.
`A.
`Q.
`A.
`Q.
`
`Greinwald - direct
`This is the publication, yes.
`And you were one of the named authors?
`Was one of the co-authors, correct.
`It was published in 2003?
`It was published in 2003. Correct.
`Thank you, Doctor.
`Could you turn to PTX-834 in your binder?
`834. Yes.
`A.
`And what is this?
`Q.
`This is --
`A.
`What is this document?
`Q.
`Yes. This is a clinical trial report of a study on
`A.
`which the SAG Code 19. Basically, the main purpose of this
`study was to determine the food effect between Salofalk
`granules, so one of the main purposes of this study was to
`see if there were any difference with given or without
`concomitantly with food.
`Okay. Thank you.
`Q.
`Can you turn to 97 and describe to the Court
`what the results were?
`97.
`A.
`Unless you remember it.
`Q.
`I remember that there was a marked food effect and
`A.
`this is described on the top of page 97. It says, a marked
`food-effect with respect to systemic availability as
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`GeneriCo v. Dr. Falk IPR2016-00297
`Page 8
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`Greinwald - direct
`Can you point out the key points of that poster?
`Q.
`First of all, let me ask a question. Were you involved in
`preparing this poster?
`I was involved in preparing the poster, correct.
`A.
`Can you point out the key points?
`Q.
`Yes.
`A.
`From this poster?
`Q.
`Yes.
`A.
`In your mind?
`Q.
`So we collaborated amongst the three-gram daily dose
`A.
`is the ultimate dose for treatment of active ulcerative
`colitis. Furthermore, we were able to demonstrate that
`moderate disease activity might profit from higher dosing.
`And furthermore, that relapses on low dose 5-ASA might
`profit from higher dosing.
`All right. Thank you.
`Q.
`Can you turn to PTX-554 in your binder?
`
`Yes.
`A.
`Do you recognize that, Doctor?
`Q.
`Yes. That's a publication on a clinical based study,
`A.
`the Salofalk granules, published by Marakhouski is the first
`author. And a study, divided dose regimens of mesalamine
`granules versus mesalamine tablets starting with a starting
`dose of 0.5 grams three times a day. And there was a chance
`if there was a non-proper response to increase dose up to
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`Greinwald - direct
`three grams a day, or was given a divided dose regimen,
`and it was a short-term study. It was for active ulcerative
`colitis.
`
`560
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`THE COURT: Doctor, mesalazine?
`THE WITNESS: It's identical in Europe. Usually
`coined mesalazine whereas in United States it's called
`mesalamine.
`BY MS. BOURKE:
`And what activity index was used to assess efficacy?
`Q.
`We used the clinical activity index again of
`A.
`mesalamine in this study.
`And what were the conclusions?
`Q.
`The conclusions were that mesalamine pellets were as
`A.
`effective as tablets in the treatment of mild to moderately
`active ulcerative colitis and we found out that the dose
`escalation of three grams per day given in divided doses,
`one gram, three a day, was a valid option for non-responders
`to a starting dose of 1.5 grams a day.
`And if you turn to page 6 of that document.
`Q.
`Yes.
`A.
`And in that first paragraph in the second column.
`Q.
`Right.
`A.
`Was there a recommending for the starting dose?
`Q.
`Yes. The authors concluded actually that considering
`A.
`the excellent tolerability and especially the minimized
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`systemic 5-ASA load associated with the granules, a dose of
`30 is given here, a typo, which was later corrected to the
`journal. A dose of three grams per day should be considered
`right from the start of the treatment.
`Okay. I think you also mentioned SAG 27. Could you
`Q.
`turn to PTX-844 in your binder.
`What is this document?
`This is the study report of the study SAG 27. The SAG
`A.
`27 study was a study comparing three different dose regimens
`for maintenance of ulcerative colitis to three different
`dose regimens of Salofalk granules. That was the standard
`dose of 0.5 grams 3 times daily. That was the standard, and
`we wanted to test whether 1.5 grams once a day was equally
`effective than the standard dose; and, secondly, we tested a
`third dose. It was a three-gram once daily, so a higher
`dose. So those are those findings.
`And what were the study dates?
`Q.
`Pardon?
`A.
`When was the study conducted?
`Q.
`Oh, the study was conducted between May 17th, 2005,
`A.
`and April 27, 2007.
`Okay. And what were the conclusions?
`Q.
`Oh, the conclusions -- let's see.
`A.
`I can direct you to page 103, if that helps.
`Q.
`Yes. Conclusions. The three treatment regimens were
`A.
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`Dr. Falk Ex. 2024
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 11
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`Greinwald - direct
`highly efficacious in maintaining clinical remission.
`However, treatment with three-gram mesalamine given once a
`day was fairly optimal dose.
`So was this study ever published?
`Q.
`This study was published. It was also in abstract
`A.
`form and also as a full paper.
`Was Falk's objective of obtaining a once daily dose
`Q.
`achieved?
`No. Actually, this was a fail, in the regulatory
`A.
`perspective, a failed study. We were disappointed with the
`results. We at that time were already, a submission ongoing
`based on our active ulcerative colitis study. Marketing
`pushed us to move forward without waiting for the study.
`And so in the dossier, actually tried to extrapolate from
`active to maintenance, so we submitted and during the
`process, actually one year later, actually, when it was
`still ongoing, this study emerged and caused a little crisis
`in the development team.
`So I called actually for a meeting with my
`regulatory affairs team. We decided actually to make this
`transparent to the reviewers, so we called actually the
`reviewer at that time. We made the outline of this, the
`core data here available to the reviewer. And the reviewer
`recommended to Dr. Falk Pharma at the time to reject, to
`reject this maintenance provision portion at the time and to
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`Dr. Falk Ex. 2024
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 12
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`move forward only with the OD portion for active.
`So we followed his recommendation. We
`checked it actually our claim for maintenance OD and moved
`only forward for active.
`So turn to PTX-438 in your binder, please. What is
`Q.
`this, Doctor?
`This is an abstract with the top-line results for the
`A.
`SAG 27 study. This abstract was presented at the Digestive
`Disease Week in California in the year 2008 between May 17
`and May 22.
`Does this abstract indicate that the SAG 27 study was
`Q.
`a failure?
`No, it does not indicate that it was a failure.
`A.
`Rather, it put forward the second primary objective of the
`study that was the dose finding component. So we concluded
`that the dosage of 3 grams mesalamine gives Salofalk
`granules once a day safe and shows it is the best efficacy
`of prevention of early relapse UC. That was put forward as
`a message. I have to remind you that this is a meeting
`where gastroenterologists and scientists come, this is
`directed to doctors, this abstract, and not to regulators.
`So the clinical message here was that three gram OD was the
`most favorable dose to maintain remission.
`If you look at the statement about midway down, it
`Q.
`says, "All three treatment recommendation were efficacious
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`Dr. Falk Ex. 2024
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 13
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`Greinwald - direct
`in maintaining clinical remission of ulcerative colitis over
`one year."
`
`564
`
`Do you see that?
`Yes, I see this. I think, from the hindsight, it is
`A.
`kind of an oversight. So we put just comparing numbers, but
`he had no statistical proof. Actually, the regulatory
`authorities decided that it's not a founded basis, actually,
`for giving us approval for OD treatment of 1.5.
`Did you make a second attempt?
`Q.
`Yes, we did. But we had to wait until further data
`A.
`emerged. And we knew of the Salix program on Apriso so for
`maintenance of remission, the MPUC3003 and 3004 studies.
`They compared 1.5 grams once a day with placebo and they
`demonstrated superiority. We were informed in time about
`top-line results. And under the publications of the
`agreement, Salix shared, actually, the top-line results as
`well as the clinical -- the finished reports with us. And
`when we had all this together, we formed a new dossier,
`based on SAG 27, but also based on MPUC3003 and MPUC3004,
`and submitted it again to the authorities and tried to get
`an OD claim then for maintenance, also.
`You said that Salix shared with you the results of
`Q.
`MCUC3003 and 3004. Did they share with you the unblinded
`data?
`A.
`
`Yes, they shared with us unblinded data.
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`Dr. Falk Ex. 2024
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 14
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`Do you remember about when that was?
`Q.
`No, I do not.
`A.
`If you -- would it have been closer to the time when
`Q.
`they received it?
`I think so, because they had an obligation to promptly
`A.
`inform us.
`So if you turn to PTX-184 in your binder, please.
`Q.
`What is this?
`This is the current summary of product characteristics
`A.
`for four different strengths of Salofalk granules.
`What does it reflect for dosing for acute?
`Q.
`It reflects now the OD dosing and it says that
`A.
`Salofalk granules are labeled for 1.5 gram OD to 3 gram OD
`mesalamine daily.
`What does it reflect for maintenance of remission
`Q.
`dosing?
`For maintenance of remission, the standard treatment
`A.
`is still 0.5 grams mesalamine given three times a day based
`on the submission I just mentioned, including the Salix
`study, we were able, actually, to be granted only, that an
`OD label is only applied to patients known to be at an
`increased risk for relapse or due to difficulties to adhere
`to the application of divided doses. Only in these cases, a
`3 gram OD is granted.
`Thank you, Doctor.
`Q.
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`Dr. Falk Ex. 2024
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 15
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`years with Granu-Stix. Correct?
`Correct.
`A.
`And you published a few studies on Granu-Stix?
`Q.
`All of them, yeah.
`A.
`Your name appears on many of them. Is that right?
`Q.
`Yes.
`A.
`Now, I want to talk with you about one of those
`Q.
`studies that you were asked about earlier. Turn to PTX-554.
`Yes.
`A.
`Now, this is the Marakhouski study. Correct?
`Q.
`This is correct.
`A.
`As you testified, this is a study about induction
`Q.
`remission. Correct?
`This is also correct.
`A.
`In this particular study, the drug is administered
`Q.
`three times per day. Correct?
`This is correct.
`A.
`And it was administered without food. Correct?
`Q.
`This is also correct, because we used Salofalk tablets
`A.
`as a comparator. And in the label of the comparator it was
`clear that Salofalk tablets had to be given without food.
`That was the reason for that.
`Just because the granules were also given without
`Q.
`food?
`A.
`
`This is correct.
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`Dr. Falk Ex. 2024
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 16
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