Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 1 of 394 PageID #: 5651
`376
`
`- VOLUME 2 -
`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
`NOVARTIS PHARMACEUTICALS
`CIVIL ACTION
`CORPORATION and NOVARTIS
`AG,
`Plaintiffs,
`
`Wilmington, Delaware
`Tuesday, August 30, 2016
`8:30 o'clock, a.m.
`- - -
`BEFORE: HONORABLE RICHARD G. ANDREWS, U.S.D.C.J.
`
`NO. 14-1043 (RGA)
`CIVIL ACTION
`
`NO. 14-1196 (RGA)
`CIVIL ACTION
`
`NO. 14-1289 (RGA)
`
`::::::::::::::::::::::::::::::::
`
`vs.
`BRECKENRIDGE
`PHARMACEUTICALS INC.,
`Defendant.
`------------------------
`NOVARTIS PHARMACEUTICALS
`CORPORATION and NOVARTIS
`AG,
`Plaintiffs,
`
`vs.
`ROXANE LABORATORIES,
`INC.,
`Defendant.
`------------------------
`NOVARTIS PHARMACEUTICALS
`CORPORATION and NOVARTIS
`AG,
`Plaintiffs,
`
`vs.
`PAR PHARMACEUTICAL,
`INC.,
`Defendant.
`
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`10
`11
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`376
`
`- VOLUME 2 -
`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
`NOVARTIS PHARMACEUTICALS
`CIVIL ACTION
`CORPORATION and NOVARTIS
`AG,
`Plaintiffs,
`
`Wilmington, Delaware
`Tuesday, August 30, 2016
`8:30 o'clock, a.m.
`- - -
`BEFORE: HONORABLE RICHARD G. ANDREWS, U.S.D.C.J.
`
`NO. 14-1043 (RGA)
`CIVIL ACTION
`
`NO. 14-1196 (RGA)
`CIVIL ACTION
`
`NO. 14-1289 (RGA)
`
`::::::::::::::::::::::::::::::::
`
`vs.
`BRECKENRIDGE
`PHARMACEUTICALS INC.,
`Defendant.
`------------------------
`NOVARTIS PHARMACEUTICALS
`CORPORATION and NOVARTIS
`AG,
`Plaintiffs,
`
`vs.
`ROXANE LABORATORIES,
`INC.,
`Defendant.
`------------------------
`NOVARTIS PHARMACEUTICALS
`CORPORATION and NOVARTIS
`AG,
`Plaintiffs,
`
`vs.
`PAR PHARMACEUTICAL,
`INC.,
`Defendant.
`
`1 2 3 4 5 6 7 8 9
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 2 of 394 PageID #: 5652
`377
`
`APPEARANCES:
`
`McCARTER & ENGLISH, LLP
`DANIEL M. SILVER, ESQ.
`BY:
`
`-and-
`
`FITZPATRICK, CELLA, HARPER & SCINTO
`BY: NICHOLAS N. KALLAS, ESQ.
`CHARLOTTE JACOBSEN, ESQ.,
`WILLIAM E. SOLANDER, ESQ.,
`CHRISTINA SCHWARZ, ESQ. and
`CHRISTOPHER E. LOH, ESQ.
`(New York, New York)
`
`Counsel for Plaintiffs
`Novartis Pharmaceuticals Corporation
`and Novartis Ag,
`
`RICHARDS, LAYTON & FINGER
`BY:
`KELLY E. FARNAN, ESQ.
`
`-and-
`
`MERCHANT & GOULD PC
`BY:
`B. JEFFERSON BOGGS, JR., ESQ. and
`MATTHEW L. FEDOWITZ, ESQ.
`(Alexandria, Virginia)
`Counsel for Defendant
`Breckenridge Pharmaceuticals, Inc.
`
`-and-
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 3 of 394 PageID #: 5653
`378
`
`APPEARANCES (Continued):
`
`MERCHANT & GOULD PC
`BY:
`CHRISTOPHER J. SORENSON, ESQ.,
`RACHEL C. HUGHEY, ESQ. and
`MARY BRAM, ESQ.
`(Minneapolis, Minnesota)
`
`Counsel for Defendant
`Breckenridge Pharmaceutical, Inc.
`
`POTTER, ANDERSON & CORROON LLP
`BY:
`DAVID E. MOORE, ESQ.
`
`-and-
`
`GOODWIN & PROCTER LLP
`KEITH A. ZULLOW, ESQ.,
`BY:
`MICHAEL B. COTTLER, ESQ.,
`RICHARD WARE, ESQ. and
`MARCIA GROSS, ESQ.
`(New York, New York)
`
`Counsel for Defendant
`Roxane Laboratories, Inc.
`
`RICHARDS, LAYTON & FINGER, P.A.
`BY:
`STEVEN J. FINEMAN, ESQ.
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 4 of 394 PageID #: 5654
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`
`APPEARANCES (Continued):
`
`LATHAM & WATKINS LLP
`BY:
`DANIEL G. BROWN, ESQ.
`(New York, New York)
`
`-and-
`
`LATHAM & WATKINS LLP
`BY:
`BRENDA L. DANEK, ESQ.
`(Chicago, Illinois)
`
`-and-
`
`LATHAM & WATKINS LLP
`BY:
`PARKER M. TRESEMER, ESQ.
`(Los Angeles, California)
`
`Counsel for Defendant
`Par Pharmaceutical, Inc.
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 5 of 394 PageID #: 5655
`Fung - direct
`380
`P R O C E E D I N G S
`
`(Proceedings commenced in the courtroom,
`beginning at 8:30 a.m.)
`
`Please be
`
`All right.
`
`THE COURT:
`Good morning.
`Dr. Fung is somewhere around here.
`THE WITNESS:
`Good morning, your
`
`seated.
`
`Honor.
`
`Good morning.
`THE COURT:
`Dr. FUNG, having been previously
`sworn resumed the witness stand.
`MR. LOH:
`Good morning, your
`
`Honor.
`
`Good morning.
`
`THE COURT:
`BY MR. LOH:
`Good morning, Dr. Fung.
`Q.
`Good morning.
`A.
`Yesterday we were talking about a
`Q.
`selection of a lead chemical compound for
`chemical modification.
`I would like to turn to a
`different topic this morning, and that's
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 6 of 394 PageID #: 5656
`Fung - direct
`381
`motivation to modify.
`And for this part of the
`examination, I would just like you to assume,
`and I know you don't agree, but I would like you
`to assume that a POSA would have selected
`Rapamycin as a lead compound.
`Are you with me?
`All right.
`A.
`If I could have PDX-2045.
`Q.
`What were you asked to consider on
`this second topic of the motivation to modify?
`This has to deal with whether
`A.
`there would have been a financial or market
`incentive to create a derivative that had the
`same characteristics, the same immunosuppressant
`quality as Rapamycin.
`What's your answer to this
`Q.
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`question?
`
`As a consultant to POSA,
`A.
`recommended this approach, or this rationale as
`a reason to do -- a "me-too" as we heard
`yesterday.
`
`My feeling about this is, as a
`practicing transplant physician, looking at
`issues that deal with problems that our patients
`
`
`
`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 7 of 394 PageID #: 5657
`Fung - direct
`382
`have, the motivation for me to recommend change,
`research approach to changing something, which
`really based on a need.
`And since we didn't
`really know what the needs were, what the
`limitations of Rapamycin were, I think making a
`change from a financial standpoint doesn't make
`any sense.
`As of October of 1992, would a
`Q.
`transplant physician have switched a transplant
`patient from one immunosuppressant drug to
`another immunosuppressant drug that had the same
`immunosuppressive activity?
`No.
`We tend to keep our patients
`A.
`on the same regimen that they've been on, and
`successfully have been on.
`And clearly this idea of the first
`to market, and then having a second drug that
`has the same characteristics coming on board, we
`would have adopted the first drug into a
`protocol.
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`It helps us understand, you know,
`how to monitor the patients; how to prescribe
`the drugs, how to educate the patients, what
`color pills they take, all that kind of stuff.
`
`
`
`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 8 of 394 PageID #: 5658
`Fung - direct
`383
`So it doesn't make sense at that point to have
`another drug that came in that didn't really
`offer any other benefits, to then adopt that
`into a new protocol.
`Now, let's leave the motivation to
`Q.
`modify question behind.
`If I could turn to the next topic
`that you were asked to address, which is
`reasonable expectation of success.
`Again, I know you don't agree.
`But for this part of the direct examination, I
`want you to assume that a POSA would have
`selected Rapamycin as a lead compound and also
`would have had motivation to make it Everolimus.
`Are you with me?
`Yes.
`A.
`First of all, what tests
`Okay.
`Q.
`would a POSA have considered in evaluating a
`compound's immunosuppressive activity?
`As we've heard yesterday as Dr.
`A.
`Randy Morris outlined, there are ways to do
`screening of immunosuppressive drugs.
`There are a number of tests that can be done in
`vitro, in a test tube model, and those that are
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 9 of 394 PageID #: 5659
`Fung - direct
`384
`done in animal models.
`We heard Dr. Partridge talk about
`Q.
`skin graft assays, do you remember that?
`Yes.
`A.
`What is a skin graft assay?
`Q.
`A skin graft assay, takes, in this
`A.
`case, skin from an unrelated mouse and
`transplants it usually on the back of the
`recipient.
`Immunosuppressive drugs are
`administered either orally as we heard
`yesterday, gavage, intramuscularly,
`intravenously, some way.
`Then the drug then
`circulates through the body and has an action on
`the immune system, and you measure the survival
`of the graft simply by looking at it whether it
`looks normal or not.
`If it doesn't, it's
`usually because of rejection.
`Then you measure
`time that it takes for the skin to be rejected.
`Usually, you have a control group,
`which is no treatment, and then you have a
`comparative group, which is, in this case,
`Rapamycin and its derivative.
`What unit of measurement does the
`Q.
`skin graft assay produce?
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 10 of 394 PageID #: 5660
`Fung - direct
`385
`It's usually measured in days,
`A.
`sometimes weeks.
`It depends on how powerful the
`immunosuppressive agent is.
`The survival time of the graft in
`Q.
`
`days?
`
`Yes.
`A.
`And is there a standard deviation
`Q.
`that is associated with that unit of
`measurement?
`Well, there should be, because
`A.
`what you do is, you can't just rely on one
`animal.
`You take a group of animals.
`You look
`at the time from the first animal rejection to
`the last animal rejection, and you get an
`average or mean.
`You get a standard deviation
`to identify how wide that spread is.
`And is it proper to ignore the
`Q.
`standard deviations when you're comparing skin
`graft assay data?
`No.
`A.
`What could happen if you ignore
`Q.
`the standard deviation?
`Well, because standard deviations
`A.
`then give you an idea of overlap.
`If they
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 11 of 394 PageID #: 5661
`Fung - direct
`386
`overlap then they're probably not statistically
`significant.
`It could lead you to make a wrong
`conclusion.
`Now, were you in the courtroom
`Q.
`when Dr. Partridge testified that POSA would
`seek guidance from the cyclosporine A derivative
`SDZ IMM 125 when contemplating modifying
`Rapamycin?
`A.
`Q.
`
`1 2 3 4 5 6 7 8 9
`
`Yes, I did.
`PDX-2047.
`Do you agree with Dr. Partridge
`that a POSA would have taken guidance from IMM
`125 when how determining how to modify
`Rapamycin?
`I don't see the rationale for that
`A.
`outside of the chemical glitch that we talked
`about yesterday.
`Because making a change to
`cyclosporine as we talked about yesterday,
`cyclosporine binds to a unique immunophilin
`cyclophilin, and this complex then binds to the
`effector protein, making the same change on
`Rapamycin, which is a compound which is quite
`different, binding FK binding protein itself was
`known.
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 12 of 394 PageID #: 5662
`Fung - direct
`387
`But we wouldn't know what the
`change on that Rapamycin would do, but clearly
`we wouldn't have an understanding or
`appreciation of what it would do to the effector
`protein binding.
`Cyclosporine A and Rapamycin have
`Q.
`different binding proteins?
`Yes.
`A.
`Different effector proteins?
`Q.
`Yes.
`A.
`And is the cyclophilin binding
`Q.
`protein for cyclosporine A similar in any way to
`the FKBP binding protein for Rapamycin?
`No.
`A.
`And is the calcineurin effector
`Q.
`protein for cyclosporine A similar in any way to
`the then unknown effector for Rapamycin?
`No.
`A.
`On PDX-2047, Dr. Fung
`MR. LOH:
`referred to JTX-65, Bauman II at pages 4 to 5.
`Plaintiff's move to introduce into
`evidence JTX-65.
`MR. BOGGS:
`
`No objection, your
`
`Honor.
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 13 of 394 PageID #: 5663
`Fung - direct
`388
`THE COURT:
`All right.
`Admitted without objection.
`
`(JTX-65 was admitted into
`
`evidence.)
`BY MR. LOH:
`Q.
`
`PDX-2048.
`So we know that the binding and
`effector proteins for cyclosporine A and
`Rapamycin are different.
`Are there any other
`differences between cyclosporine A and Rapamycin
`that would be apparent to a transplant physician
`or immunologist as of October 1992?
`Well, since Rapamycin hadn't
`A.
`gotten to clinical testing, it's really hard to
`compare apples to apple's comparison.
`We knew Cyclosporin's limitation,
`We knew its efficacy.
`We hadn't
`toxicity.
`determined that for Rapamycin, as we heard.
`So, just looking at the baboon
`data fairly -- the over lap -- I mean, the side
`effect profile doesn't overlap with cyclosporine
`in humans.
`But again, as I said, we don't know
`what Rapamycin's side effect profile was in
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 14 of 394 PageID #: 5664
`Fung - direct
`389
`
`humans.
`
`different.
`Q.
`yesterday.
`
`But just looking at this, they are
`
`And we discussed this a little bit
`
`Can you summarize what the
`differences are in the toxicity profiles of
`cyclosporine A and Rapamycin?
`Well, in humans we knew that it
`A.
`caused nephrotoxicity.
`And this is dose
`limiting, which is one of the major problems
`with long-term use.
`Some of these other ones
`are more mild, but still, clearly associated
`with cyclosporine.
`And Rapamycin as we talked about
`yesterday, its GI side effects and the sort of
`the systematic side effects.
`It does not
`include nephrotoxicity, that we knew of in
`animal models, again, hadn't been tested in
`humans at that time.
`Did cyclosporine A toxicities bear
`Q.
`any relation to Rapamycin toxicities?
`No.
`A.
`Were Rapamycin's toxicities in
`Q.
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 15 of 394 PageID #: 5665
`Fung - direct
`390
`humans known as of October 1992?
`No.
`A.
`And was the mechanism of
`Q.
`Rapamycin's toxicities known as of October 1992?
`No.
`A.
`And I believe we talked about this
`Q.
`a little bit before, but I just wanted to make
`certain that we've covered this.
`By October 1992, had it been
`determined that Rapamycin's effector protein was
`not calcineurin?
`Yes.
`A.
`On PDX-2048, Dr. Fung
`MR. LOH:
`referred to JTX-l4, Donatsch 1992 at page 39,
`and JTX-94, Collier 1991 at page 2247.
`Plaintiff's move to introduce into evidence
`JTX-14.
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`MR. BOGGS:
`THE COURT:
`
`No objection.
`Admitted without
`
`(JTX-14, JTX-94 were admitted into
`
`PDX-2049.
`
`objection.
`
`evidence.)
`BY:
`MR. LOH:
`Q.
`
`
`
`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 16 of 394 PageID #: 5666
`Fung - direct
`391
`Why do the differences in
`cyclosporine A and Rapamycin's reported
`toxicities matter when you're making a chemical
`modification to Rapamycin?
`Well, the purpose for making the
`A.
`modifications in this case of IMM 125 was to
`really reduce its toxicity.
`The early
`pre-clinical animal data suggested that it did.
`Subsequently we all knew that it didn't.
`But besides the fact, making that
`change to Rapamycin simply because it did have a
`number of toxicities that we knew at the time,
`making that change to try to reduce its toxicity
`because it hadn't been determined in humans was
`premature.
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`And clearly, I wouldn't have
`surmised or guessed that making a change to a
`structurally unrelated chemical would have the
`same effect.
`So as of October 1992, would a
`Q.
`modification made to cyclosporine A have taught
`or suggested anything to POSA about what effects
`that modification might have on Rapamycin and
`its properties?
`
`
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`Fung - direct
`392
`No, because we didn't know the
`A.
`properties of Rapamycin, and making a change to
`Rapamycin would have given us a drug which we
`would have had two unknowns.
`PDX-2050.
`Q.
`Now, I want to leave behind the
`selection of the lead compound, the motivation
`to modify, and the reasonable expectation of
`success, and turn to the last topic that you
`were asked to address, which is objective
`evidence of non-obviousness, okay?
`Yes.
`A.
`PDX-2051.
`Q.
`Let's discuss long-felt and unmet
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`need first.
`
`Was there a long-felt, but unmet
`need in the immunosuppressant field in October
`of 1992?
`
`The long-felt-need was clear
`Yes.
`A.
`through the history of organ transplantation.
`Clearly when cyclosporine came on board, we've
`heard its principle limitation was they
`nephrotoxicity.
`What happen to try to minimize
`
`
`
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`Fung - direct
`393
`nephrotoxicity you give less cyclosporine.
`Less
`cyclosporine gives you more rejection.
`When you
`try to suppress the rejection you get more
`toxicity.
`
`So that balance was what we call a
`dose limiting factor.
`The long-felt, but unmet
`need was to find a maintenance immunosuppressant
`drug in a liver transplant patients that had the
`efficacy of cyclosporine A, but has reduced
`nephrotoxicity.
`And so, this could be done by
`increasing the efficacy or decreasing the
`nephrotoxicity.
`PDX-2052.
`Q.
`When was the long-felt-need in the
`immunosuppressant field first recognized?
`This was identified as early as
`A.
`the first human trials of cyclosporine that Sir
`Roy Calne did in 1982.
`He noted that
`nephrotoxicity has been the most serious
`complication, and this can make management
`difficult.
`
`On PDX-2052, Dr. Fung
`MR. LOH:
`referred to JTX-10, Calne 1982 at page 335.
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`
`
`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 19 of 394 PageID #: 5669
`Fung - direct
`394
`Plaintiff's move to introduce into
`evidence JTX-10.
`THE COURT:
`
`Admitted without
`
`objection.
`
`(JTX-10 Admitted into evidence.)
`
`BY MR. LOH:
`Now, why was the need unmet in
`Q.
`October of 1992?
`Well, cyclosporine had been
`A.
`approved in 1983, and there were no other means
`of therapy approved through 1992.
`Did Everolimus meet the need?
`Q.
`Yes.
`A.
`PDX-2053.
`Q.
`Can you explain why Everolimus met
`
`that need?
`The trial that you see on the
`A.
`screen called H2304 was the largest liver
`transplant prospective randomized study ever
`conducted.
`
`I was the principle investigator.
`I created the protocol, designed the study with
`two of my European colleagues.
`And the study
`was sponsored by Novartis in 2006.
`
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 20 of 394 PageID #: 5670
`Fung - direct
`395
`We finalized the paperwork,
`submitted the paperwork to the European and
`American regulatory agencies and began
`enrollment of the trial of over 750 patients in
`2007.
`
`One year data that was reported by
`Paul De Simone from clearly showed that at the
`one year mark, 12 months after a patient had
`been followed, a minimum of 12 months, that
`patients that were given Everolimus and reduced
`dose of Tacrolimus exhibited superior renal
`function compared to the Tacrolimus control arm.
`This was a FDA mandated control
`
`arm.
`
`The drugs were used exactly as the
`FDA standard of care is.
`And this was at one
`year post-transplant.
`The difference in renal
`function was clinically relevant in standard
`risk patients without compromising efficacy,
`meaning that our rejection rates were not worse
`than Tacrolimus, and, in fact, they were better.
`We had less rejection.
`We had less severe
`rejection, and an acceptable safety profile.
`And the same cohort of patients
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 21 of 394 PageID #: 5671
`Fung - direct
`396
`Dr.
`were reported at year two, year three.
`Saliba also from France reporting that year the
`renal function in this group, in the Everolimus
`reduced Tacrolimus arm had achieved good
`function without penalty of in terms of
`efficacy.
`
`And Dr. Fischer from Germany at
`year three noted that the size and persistence
`of the renal benefit -- in other words, the
`difference in quality of kidney function favored
`Everolimus and reduced Tacrolimus.
`And the
`difference is striking.
`MR. LOH:
`On PDX-2053, Dr. Fung referred to
`JTX-41, De Simone at 2012 at page 3015, PTX-143,
`Saliba at 2013 at page 1741 and PTX-53, Fischer at
`2015 at page 1461.
`Plaintiffs move to introduce into evidence
`PTX-41, PTX-143 and PTX-53.
`MR. BOGGS:
`No objection
`Thank you.
`THE COURT:
`All right.
`Admitted without objection.
`
`(PTX-41, PTX-143 and PTX-53 were
`admitted into evidence.)
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 22 of 394 PageID #: 5672
`Fung - direct
`397
`
`BY MR. LOH:
`Now, did any of the publications
`Q.
`that we just saw on the last slide acknowledge
`the existence of a long-felt, but unmet need
`before Everolimus was ever invented?
`Yes, as I mentioned, unmet need,
`A.
`long-felt was present since the beginning.
`But
`clearly in our working hypothesis as the study
`was put together and as highlighted in the
`statement, the 2012 De Simone follow-up was
`identifying an immunosuppressive regimen that
`preserved renal function while maintaining
`efficacy represents an urgent unmet medical need
`after liver transplantation.
`MR. LOH:
`PDX-2054, Dr. Fung
`referred to PTX-41, De Simone 2012 at page 3015.
`BY MR. LOH:
`Now, did the H2304 study use the
`Q.
`standard dose of Everolimus as a control?
`Yes.
`Any study now that is
`A.
`comparative in liver transplantation must in
`terms of immunosuppression use the Tacrolimus
`steroid control arm, that is, the accepted FDA
`standard of care.
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 23 of 394 PageID #: 5673
`Fung - direct
`398
`There is also one for
`But for Tacrolimus is as was
`cyclosporine.
`conducted in the control group.
`And Tacrolimus was in the control
`Q.
`
`group?
`
`Yes.
`A.
`Did the H2304 study include
`Q.
`cyclosporine A?
`It did not.
`A.
`2055.
`Q.
`Now, since the H2304 study did not
`involve cyclosporine, how do you know that the
`combination of Everolimus and low dose
`Tacrolimus is as effective as cyclosporine A and
`causes less nephrotoxicity?
`Well there is lots of data
`A.
`comparing cyclosporine with Tacrolimus in liver
`transplantation.
`And basically the studies have
`suggested or shown that Tacrolimus is at least
`as effective as cyclosporine in most studies
`that showed that it is better.
`Gary
`Levy from the University of Toronto published
`this paper showing that the efficacy of
`cyclosporine and Tacrolimus in liver transplants
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 24 of 394 PageID #: 5674
`Fung - direct
`399
`patients is equivalent at 12 months and their
`renal function is similar showing the H2304 date
`where the Everolimus to Tacrolimus group has
`equal or better efficacy and better renal
`function.
`Now using our algebraic A plus B is
`greater than C, the C greater than A.
`That kind of formulation shows
`that Everolimus and Tacrolimus is better -- at
`least equal -- better than cyclosporine.
`Okay.
`And just to be clear, is
`Q.
`the combination of everolimus and low dose
`tacrolimus better than standard dose tacrolimus
`in terms of its clinical outcomes?
`Yes.
`A.
`On PDX-2055, Dr. Fung
`MR. LOH:
`refers to PTX-94, Levy 2006 at page 1464.
`Plaintiffs move to introduce into evidence
`PTX-94.
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`MR. BOGGS:
`
`No objection, your
`
`Honor.
`
`THE COURT:
`without objection.
`(PTX-94 was admitted into evidence.)
`
`All right.
`
`Admitted
`
`BY MR. LOH:
`
`
`
`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 25 of 394 PageID #: 5675
`Fung - direct
`400
`Dr. Fung, what is a de novo liver
`Q.
`transplant patient?
`It simply means that it's a
`A.
`patient who received a recent transplant.
`novo, from the beginning.
`PDX-2056.
`Do you prescribe
`Q.
`everolimus in combination with low dose
`tacrolimus to your de novo liver transplant
`patients?
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`De
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`As the -- everolimus
`Yes, we do.
`A.
`was approved by the FDA in 2013, became
`available on our formulary in 2014.
`We adopted
`our protocols for de novo liver transplant
`patients that are adults to get everolimus and
`tacrolimus.
`We also transplant pediatric
`patients and other patients that don't fit the
`everolimus/tacrolimus definition, indication,
`but 50 percent of our new patients receive
`everolimus and tacrolimus and the other
`25 percent receive mycophenolate mofetil and
`tacrolimus or the FDA standard of tacrolimus and
`corticosteroid.
`So 50 percent of your de
`Okay.
`Q.
`novo liver transplant patients receive
`
`
`
`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 26 of 394 PageID #: 5676
`Fung - direct
`401
`everolimus and low dose tacrolimus?
`Yes.
`A.
`And then 25 percent receive
`Q.
`mycophenolate mofetil and tacrolimus?
`Yes.
`A.
`Another 25 percent receive
`Q.
`tacrolimus and steroids?
`Yes.
`A.
`Why do you prescribe everolimus
`Q.
`plus low dose tacrolimus more often than you
`prescribe the combination of MMF and tacrolimus
`to your de novo liver transplant patients?
`Well, simply because of the
`A.
`benefits that were highlighted in the H2304
`study regarding kidney function and some other
`benefits that have subsequently been
`demonstrated.
`Why don't you prescribe everolimus
`Q.
`in combination with low dose tacrolimus to all
`of your de novo liver transplant patients?
`Well, the indications for patients
`A.
`in this were de novo and adult and so some of
`our retransplant patients, patients that are
`pediatric patients, these also were patients
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 27 of 394 PageID #: 5677
`Fung - direct
`402
`that had gotten a whole liver and about
`20 percent of our patients get partial livers.
`They get a living donor or we take a liver, cut
`it in half and give it to two recipients.
`Those
`patients do not fit the indication population
`for everolimus and tacrolimus.
`So are you prescribing everolimus
`Q.
`plus tacrolimus to all the patients you have
`and can receive it based on this FDA approved
`label?
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`As many as we can.
`Yes.
`A.
`Do you understand that Dr. Tullius
`Q.
`has provided the opinion that MMF in combination
`with tacrolimus met the long-felt need that you
`identified?
`Yes, I am.
`A.
`Do you agree that MMF
`PDX-2057.
`Q.
`in combination with tacrolimus met the long-felt
`need in October 1982 for a maintenance regimen
`for liver transplant patients as effective as
`cyclosporine A but with reduced nephrotoxicity?
`No.
`As I think we talked about
`A.
`in the introduction, when we looked at the
`timeline of drug development, neither MMF nor
`
`
`
`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 28 of 394 PageID #: 5678
`Fung - direct
`403
`tacrolimus were approved by the FDA in
`October 1992, and surely the combination of MMF
`and tacrolimus had not been tested together
`until both drugs were approved in 1994, and
`there was therefore no data relating to the
`neurotoxicity benefit, if there was, with MMF
`and tacrolimus as of 1992.
`PDX-2058.
`Do you understand that
`Q.
`Dr. Tullius has provided the opinion that Ochiai
`1991 reports that the combination of MMF and
`tacrolimus reduces renal vasculitis associated
`with tacrolimus alone in dogs?
`Yes, I am.
`A.
`Do you agree with his opinion?
`Q.
`No.
`I think Stephan Tullius just
`A.
`misread this paper.
`The vasculitis that was
`reported in the Ochiai paper was actually
`vasculitis that was seen in the heart.
`So the coronary arteries of the
`patient, of these dogs, even though they were
`given a kidney transplant, then went -- on
`autopsy the hearts showed the vasculitis, not
`the kidney.
`Heart vasculitis is not synonymous
`with kidney toxicity.
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 29 of 394 PageID #: 5679
`Fung - direct
`404
`So this data from Ochiai 1991 does
`Q.
`not represent reduced nephrotoxicity?
`No.
`A.
`On PDX-2058, Dr. Fung
`MR. LOH:
`referred to DTX-82, Ochiai 1991 at page 2719.
`BY MR. LOH:
`PDX-2059.
`Q.
`of others, PDX-2060.
`Did the FDA approve any liver
`transplant maintenance treatments after
`cyclosporine A and before October 1992?
`No.
`A.
`Did you hear Dr. Partridge testify
`Q.
`that there was a lot of interest in rapamycin
`derivatives as of 1992?
`Yes.
`A.
`Has any one rapamycin derivative
`Q.
`other than everolimus ever obtained FDA approval
`or been tested clinically for the treatment of
`transplant patients?
`No.
`A.
`When were rapamycin's
`PDX-2061.
`Q.
`immunosuppressive properties first discovered?
`Well, they were actually described
`A.
`
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`
`
`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 30 of 394 PageID #: 5680
`Fung - direct
`405
`in 1977 by Martel.
`This was in a rat model of
`an autoimmune disease, basically mimicking a
`mouse model, rat model of multiple sclerosis.
`Here, rapamycin given to those
`animals inhibited the immune response and
`prevented development of, you know, this
`autoimmune disorder and it was described in
`1997.
`
`So this was the first
`Okay.
`Q.
`report in the literature of rapamycin's
`immunosuppressant properties?
`Yes.
`A.
`And how long a period elapsed
`Q.
`between this first disclosure of rapamycin's
`immunosuppressive properties and the invention
`of everolimus?
`Fifteen years.
`A.
`MR. LOH:
`On PDX-2061, Dr. Fung
`refers to PTX-98.
`Martel 1997.
`Sorry.
`1997 --
`1977, at page 48.
`Plaintiffs move to introduce into
`evidence PTX-98.
`And I'm sorry.
`I misspoke.
`The reference that we were talking about is
`Martel 1977.
`
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 31 of 394 PageID #: 5681
`Fung - direct
`406
`THE WITNESS:
`Yes.
`MR. BOGGS:
`No objection, your
`
`Honor.
`
`THE COURT:
`without objection.
`(PTX-98 was admitted into evidence.)
`
`All right.
`
`Admitted
`
`BY MR. LOH:
`Let's turn now to the
`PDX-2062.
`Q.
`unexpected properties of everolimus.
`And before
`we go on, can you explain what the half-life of
`a drug is?
`So half-life is calculated when
`A.
`you have a certain level of a drug in the blood
`and you measure the time for that level to drop
`by 50 percent, so that simply called it T1 half
`or half-life.
`What are the half-lives
`PDX-2063.
`Q.
`of everolimus and rapamycin?
`Everolimus' half-life is 30 hours
`A.
`and rapamycin's half-life is 62 hours.
`Is this a substantial difference?
`Q.
`Yes.
`A.
`PDX-2063, Dr. Fung
`MR. LOH:
`refers to JTX-56, the Zortress package insert at
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 32 of 394 PageID #: 5682
`Fung - direct
`407
`
`page NPC2227703.
`And PTX-671, the Rapamune package
`insert at page BRK-EVR-59732.
`Plaintiffs move into evidence
`JTX-56 and PTX-671.
`MR. BOGGS:
`THE COURT:
`without objection.
`(JTX-56 and PTX-671 were admitted into
`
`No objection.
`All right.
`Admitted
`
`evidence.)
`BY MR. LOH:
`Now, if we go back in time to
`Q.
`October 9th, 1992, and we take the '772 patent
`out of the POSA's hands, would the POSA have
`known anything about everolimus or its
`properties at that time?
`No.
`A.
`And so would that POSA have
`Q.
`reasonably expected that the half-life of
`everolimus would be 50 percent shorter than the
`half-life of rapamycin?
`No.
`A.
`Is a shorter half-life
`PDX-2064.
`Q.
`of everolimus clinically beneficial?
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 33 of 394 PageID #: 5683
`Fung - direct
`408
`Yes.
`A.
`Can you explain how?
`Q.
`Everolimus' half-life is, as you
`A.
`said, demonstrated half as long as rapamycin's,
`and so the dosing schedule for everolimus is
`twice-a-day administration whereas rapamycin is
`given once a day.
`So what that means is that you're
`giving twice a day a smaller amount twice a day
`whereas you're giving a larger amount once a day
`when you are using rapamycin.
`And the shorter
`elimination of everolimus results in less
`accumulation, so the peak levels of the drug
`also are less, and when you stop the drug, the
`elimination allows the everolimus to be cleared
`faster, and so if you have a side effect, a
`toxicity that you need to deal with, it goes
`away faster when you are using everolimus.
`MR. LOH:
`On PDX-2064, Dr. Fung
`referred to PTX-79, Kahan 1999 at page 1106.
`Plaintiffs move to introduce into
`evidence PTX-79.
`MR. BOGGS:
`THE COURT:
`
`No objection.
`All right.
`Admitted
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`Case 1:14-cv-01043-RGA Document 166 Filed 10/17/16 Page 34 of 394 PageID #: 5684
`Fung - direct
`409
`without objection.
`(PTX-79 was admitted into
`
`evidence.)
`BY MR. LOH:
`Can you provide us some examples
`Q.
`of side effects that would be quickly more
`resolved with everolimus?
`Well, two of the major side
`A.
`effects of everolimus and rapamycin are the
`effect on thrombocytopenia, and particularly the
`platelets, which are responsible for clotting.
`Those suppressed platelet counts is one of the
`side effects, the other one being mouth
`ulcerations, and this can be quite painful and
`actually limit the amount of drug that patients
`can take.
`
`And so both of those have been
`reported to, in terms of resolution, to be
`faster when everolimus is discontinued than when
`rapamycin is discontinued.
`PDX-2065.
`Do the everolimus and
`Q.
`rapamycin product labels contain instructions
`concerning the administration of these drugs
`with cyclosporine A?
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`
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