Vol. 4-641
`
`UNITED STATES DISTRICT COURT
`SOUTHERN DISTRICT OF INDIANA
`INDIANAPOLIS DIVISION
`
`
`
`ELI LILLY AND COMPANY, )
`
` Cause No. )
`)
` Plaintiff, 1:10-CV-01376-TWP-DKL
`)
` Indianapolis, Indiana
` vs.
` August 22, 2013
`)
`)
`
` 9:04 a.m.
`TEVA PARENTERAL MEDICINES, )
`INC., APP PHARMACEUTICALS, )
`LLC, PLIVA HRVATSKA D.O.O., )
`TEVA PHARMACEUTICALS USA, )
`INC., BARR LABORATORIES, INC.,)
`
` )
`)
` Defendants.
`)
`
`
`
`V O L U M E IV
`
`Before the Honorable
`TANYA WALTON PRATT
`
`OFFICIAL REPORTER'S TRANSCRIPT OF
`BENCH TRIAL
`
`
`
`
`
`
`
`David W. Moxley, RMR, CRR, CMRS
`United States District Court
`46 East Ohio Street, Room 340
`Indianapolis, Indiana 46204
`
`Court Reporter:
`
`
`
`PROCEEDINGS TAKEN BY MACHINE SHORTHAND
`TRANSCRIPT CREATED BY COMPUTER-AIDED TRANSCRIPTION
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`UNITED STATES DISTRICT COURT
`SOUTHERN DISTRICT OF INDIANA
`INDIANAPOLIS DIVISION
`
`
`
`ELI LILLY AND COMPANY, )
`
` Cause No. )
`)
` Plaintiff, 1:10-CV-01376-TWP-DKL
`)
` Indianapolis, Indiana
` vs.
` August 22, 2013
`)
`)
`
` 9:04 a.m.
`TEVA PARENTERAL MEDICINES, )
`INC., APP PHARMACEUTICALS, )
`LLC, PLIVA HRVATSKA D.O.O., )
`TEVA PHARMACEUTICALS USA, )
`INC., BARR LABORATORIES, INC.,)
`
` )
`)
` Defendants.
`)
`
`
`
`V O L U M E IV
`
`Before the Honorable
`TANYA WALTON PRATT
`
`OFFICIAL REPORTER'S TRANSCRIPT OF
`BENCH TRIAL
`
`
`
`
`
`
`
`David W. Moxley, RMR, CRR, CMRS
`United States District Court
`46 East Ohio Street, Room 340
`Indianapolis, Indiana 46204
`
`Court Reporter:
`
`
`
`PROCEEDINGS TAKEN BY MACHINE SHORTHAND
`TRANSCRIPT CREATED BY COMPUTER-AIDED TRANSCRIPTION
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`APPEARANCES
`
`For Plaintiff:
`
`
`
`
`
`
`
`
`
`
`
`For Defendants:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Vol. 4-642
`
`Adam L. Perlman, Esq.
`David M. Krinsky, Esq.
`Dov P. Grossman, Esq.
`Bruce R. Genderson, Esq.
`Megan A. Hughes, Esq.
`Andrew V. Trask, Esq.
`Williams & Connolly, LLP
`725 Twelfth Street, N.W.
`Washington, DC 20005
`
`Jan M. Carroll, Esq.
`Barnes & Thornburg, LLP
`11 South Meridian Street
`Indianapolis, IN 46204-3535
`
`James P. Leeds, Esq.
`Eli Lilly and Company
`Lilly Corporate Center
`Indianapolis, IN 46285
`
`Daryl L. Wiesen, Esq.
`Goodwin Procter, LLP
`53 State Street
`Boston, MA 02109
`
`Michael B. Cottler, Esq.
`Emily L. Rapalino, Esq.
`Elaine Herrmann Blais, Esq.
`Natasha E. Daughtrey, Esq.
`Brian J. Prew, Esq.
`Goodwin Procter, LLP
`620 Eighth Avenue
`New York, NY 10018
`
`Kandi Kilkelly Hidde, Esq.
`E. Ashley Paynter, Esq.
`Bingham McHale LLP
`2700 Market Tower
`10 West Market Street
`Indianapolis, IN 46204-4900
`
`Ali I. Ahmed, Esq.
`APP Pharmaceuticals, LLC
`Three Corporate Drive
`Lake Zurich, IL 60047
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`Vol. 4-643
`
`I N D E X
`
`DEFENDANT'S WITNESSES
`
` PAGE
`
`THOMAS SCHULZ
`
`Direct Examination by Ms. Blais ...............644
`
`
` .............
`684
`Cross-examination by Mr. Grossman
` .............
`Redirect Examination by Ms. Blais
`701
`
`Recross-examination by Mr. Grossman ..........701
`
`
`PLAINTIFF'S WITNESSES PAGE
`
`DR. CLET NIYIKIZA
`
`
`
`
`
`
`
`Direct Examination by Mr. Genderson ...........711
`
`I N D E X O F E X H I B I T S
`
`TRIAL EXHIBITS
`
`1152 ..........................................703
`
`
` ..........................................
`1398
`703
`
` PAGE
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`Vol. 4-711
`
` 1
`
` 2
`
` 3
`
`(The witness is sworn.)
`
`THE COURT: You may have a seat.
`
`And I'm going to go ahead and make a brief ruling on
`
` 4
`
`the Rule 52 motion. In a bench trial, the Court may decline
`
` 5
`
`to render a judgment until the close of the evidence, and
`
` 6
`
`that's what the Court is going to do in this matter.
`
` 7
`
`With respect to the best-mode defense, since that
`
` 8
`
`defense was withdrawn, the Court does not believe it needs to
`
` 9
`
`render a judgment on that one. We all are of the
`
`10
`
`understanding that it's no longer to be litigated.
`
`11
`
`Okay. Mr. Genderson, I assume you're going to
`
`12
`
`examine the next witness.
`
`13
`
`14
`
`15
`
`16
`
`MR. GENDERSON: I am, Your Honor.
`
`THE COURT: Okay.
`
`MR. GENDERSON: Thank you.
`
`Your Honor, Eli Lilly calls as its first witness,
`
`17
`
`Dr. Clet Niyikiza.
`
`18
`
`19
`
`20
`
`THE COURT: Okay.
`
`DR. CLET NIYIKIZA, PLAINTIFF'S WITNESS, SWORN
`
`DIRECT EXAMINATION
`
`21
`
`BY MR. GENDERSON:
`
`22
`
`Q. Dr. Niyikiza, could you please introduce yourself to Judge
`
`23
`
`Pratt?
`
`24
`
`25
`
`THE WITNESS: Good morning, Judge Pratt.
`
`THE COURT: Good morning, Doctor.
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-712
`
` 1
`
`A. My name is Clet Niyikiza. And it's spelled C-L-E-T for
`
` 2
`
`the first name, and the last name is N-I-Y-I-K-I-Z-A.
`
` 3
`
`And I'm the executive vice president of development
`
` 4
`
`for Merrimack Pharmaceuticals based in Cambridge,
`
` 5
`
`Massachusetts, and I live just outside Philadelphia.
`
` 6
`
`THE COURT: Okay.
`
` 7
`
`BY MR. GENDERSON:
`
` 8
`
`Q. Dr. Niyikiza, do you hold a Ph.D.?
`
` 9
`
`A. Yes.
`
`10
`
`Q. In what subject?
`
`11
`
`A. I hold a Ph.D. in mathematics and in statistics.
`
`12
`
`Q. Are you the inventor of the '209 patent that's been
`
`13
`
`talked about in this case?
`
`14
`
`A. Yes, I am.
`
`15
`
`Q. Where were you employed at the time that you -- of your
`
`16
`
`work that led to that patent?
`
`17
`
`A. I was employed by Eli Lilly and Company here in
`
`18
`
`Indianapolis.
`
`19
`
`Q. Have you ever testified in a courtroom before?
`
`20
`
`A. No.
`
`21
`
`Q. Have you ever testified in deposition other than in this
`
`22
`
`case?
`
`23
`
`A. No.
`
`24
`
`Q. Have you ever been inside this courthouse before?
`
`25
`
`A. Yes, I have. Some years back when I was being sworn in as
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-713
`
` 1
`
`a United States citizen, with my family.
`
` 2
`
`Q. Dr. Niyikiza, could you briefly describe how you conceived
`
` 3
`
`of the invention that resulted in the '209 patent?
`
` 4
`
`A. Yes. This was back in early 1997, and I was on the team
`
` 5
`
`that was developing a drug then called pemetrexed, or Alimta.
`
` 6
`
`And the program was in full swing. We had completed the Phase
`
` 7
`
`1s and we were in Phase 2s, and we started basically
`
` 8
`
`looking at the overall safety of the drug, which is part of
`
` 9
`
`what you do. And there were no particularly severe toxicity
`
`10
`
`or toxicities that were any different than what you see with
`
`11
`
`commonly marketed chemotherapies.
`
`12
`
`However, there was a puzzling situation, certainly in
`
`13
`
`my mind, and that was, you would have patients come to the
`
`14
`
`doctor in these clinical trials; the tests on all clinical
`
`15
`
`parameters would be fine, ready to go. Some patients would be
`
`16
`
`given the treatment, and for multiple cycles of treatment,
`
`17
`
`they would be fine. Others would be given treatment, and
`
`18
`
`quickly they would develop toxicities. Certainly, that
`
`19
`
`started worrying us.
`
`20
`
`In my mind and in the mind of pretty much everybody
`
`21
`
`who was involved, but certainly in mine, there was no way to
`
`22
`
`really have a rational reason why these patients who looked
`
`23
`
`otherwise normal for the trial were developing these problems,
`
`24
`
`but even more worrisome was that we couldn't tell or predict
`
`25
`
`who was going to develop these problems.
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-714
`
` 1
`
`So, at that time I basically thought it was important
`
` 2
`
`to conduct a more-advanced analysis of what we had,
`
` 3
`
`multivariate analysis. Because we didn't know anything about
`
` 4
`
`what could be possibly causing these problems in patients, we
`
` 5
`
`decided to collect more than 60 variables on the patients,
`
` 6
`
`ranging from the disease characteristics, the laboratories,
`
` 7
`
`and some of the markers related to the folate metabolism that
`
` 8
`
`biochemists were looking at. And then I conducted a --
`
` 9
`
`THE COURT: Doctor, I believe the defense has an
`
`10
`
`objection.
`
`11
`
`MR. WIESEN: Your Honor, I don't want to -- mean to
`
`12
`
`interrupt Dr. Niyikiza, and I let this go on, but the
`
`13
`
`narrative nature of the testimony makes it impossible to
`
`14
`
`enforce the rules of evidence, to contemplate hearsay, to
`
`15
`
`figure out whether we've drifted from back to expert
`
`16
`
`testimony.
`
`17
`
`18
`
`MR. GENDERSON: Your Honor --
`
`THE COURT: I don't believe he's gone from back to
`
`19
`
`expert, but would you -- it is narrative, so would you --
`
`20
`
`MR. GENDERSON: I can break it down into shorter
`
`21
`
`questions.
`
`22
`
`BY MR. GENDERSON:
`
`23
`
`Q. Dr. Niyikiza, I just want to do this by way of background,
`
`24
`
`so let's try to -- we'll try to be brief now.
`
`25
`
`But you said you conducted a multivariate analysis.
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-715
`
` 1
`
`How many factors did you consider?
`
` 2
`
`A. We considered -- I considered about 60 to 70 factors.
`
` 3
`
`Q. And when you finished that analysis, what conclusions, if
`
` 4
`
`any, were you able to draw from the data?
`
` 5
`
`A. When I completed the analysis, I observed that there were
`
` 6
`
`two critical markers in the patient's blood called
`
` 7
`
`homocysteine and methylmalonic acid that were linked to the
`
` 8
`
`toxicities that we were seeing.
`
` 9
`
`Q. And was there a correlation between the toxicities and
`
`10
`
`either of those markers?
`
`11
`
`A. Yes, there was. There was a correlation between elevated
`
`12
`
`homocysteine levels -- that's one of the markers that was
`
`13
`
`involved -- but there was also a colinearity that I observed
`
`14
`
`between another one called methylmalonic acid that was
`
`15
`
`colinear with the homocysteine marker. And the homocysteine
`
`16
`
`marker was strongly predicting the toxicity. The MMA was
`
`17
`
`colinear with homocysteine.
`
`18
`
`Q. And, Doctor, as a result of the observations from that
`
`19
`
`study, did you conceive of any proposal for treating patients
`
`20
`
`to try to alleviate the toxicities that were being seen?
`
`21
`
`A. Yes, I did. And actually, there was something that was
`
`22
`
`unusually puzzling in that observation, because even though
`
`23
`
`elevated homocysteine was strongly predicting the toxicity,
`
`24
`
`these were not markers that were outside the normal range.
`
`25
`
`So, that meant basically that in my mind, that these patients
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-716
`
` 1
`
`did not have what we call deficiencies in these markers
`
` 2
`
`because it was all subclinical based on what I was seeing.
`
` 3
`
`So, my idea was, since doctors can't tell, since these
`
` 4
`
`markers are now suggesting that these patients are having
`
` 5
`
`problems within normal range, I conceived of the idea that
`
` 6
`
`maybe cancer is taking away these folate pools; and the
`
` 7
`
`patient, although looking normal, their system may be
`
` 8
`
`compromised in a subclinical way with cancer. And what I
`
` 9
`
`needed to do was not to give large amounts of folic acid and
`
`10
`
`B12. In this particular case, only B12 -- I mean folic acid
`
`11
`
`was being given, and I thought it would be important to give
`
`12
`
`very low amounts that you normally would give to people in
`
`13
`
`order to restore normal folic pools, so that you can actually
`
`14
`
`correct and regrow patients back to the same baseline levels.
`
`15
`
`And it was also important to give B12, and the reason
`
`16
`
`was that even though I didn't establish the correlation
`
`17
`
`between the methylmalonic acid, which is an indication of B12
`
`18
`
`deficiency, I still had a strong colinearity that I kept in
`
`19
`
`check, because that meant that it had a role. I just didn't
`
`20
`
`have yet enough to prove.
`
`21
`
`Q. And you mentioned, Doctor, that in prior trials, there was
`
`22
`
`larger amounts of folic acid given. What quantities of folic
`
`23
`
`acid had Lilly given in prior trials in which they had
`
`24
`
`pretreated patients with folic acid?
`
`25
`
`A. Yes. Lilly was conducting clinical development of a drug
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-717
`
` 1
`
`called lometrexol and another one called LY309887, and often
`
` 2
`
`we refer to it as '887. And in those trials, they were giving
`
` 3
`
`five milligram of folic acid. In this particular case for
`
` 4
`
`'887, they were given those five milligram two days before
`
` 5
`
`therapy, the day of treatment, and two days after. And in
`
` 6
`
`lometrexol, they would give five milligram, seven days before
`
` 7
`
`treatment and then follow that regimen I just described.
`
` 8
`
`So, when I looked at what we were doing there as a
`
` 9
`
`company in the situation I was facing, I concluded that we
`
`10
`
`were probably not giving it -- correcting the problem the
`
`11
`
`right way.
`
`12
`
`Q. We're going to go into this in more detail, Doctor, but I
`
`13
`
`want to ask a little bit about your background first. Do you
`
`14
`
`have any experience -- strike that.
`
`15
`
`At the time you were doing this and when you were
`
`16
`
`working for Lilly in the late 1990s, did you have any
`
`17
`
`background in oncology?
`
`18
`
`A. No.
`
`19
`
`Q. Did you have any background in nutrition or vitamins?
`
`20
`
`A. No.
`
`21
`
`Q. Could you briefly describe for the Court your educational
`
`22
`
`background?
`
`23
`
`A. Yes, I certainly can. I was -- I did my undergraduate
`
`24
`
`studies at the International Institute of Statistics and
`
`25
`
`Applied Economics that is in Rwanda in eastern Africa. And
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-718
`
` 1
`
`then I came to the --
`
` 2
`
`Q. Excuse me, Doctor, one second.
`
` 3
`
`Where did you grow up?
`
` 4
`
`A. I grew up in Rwanda and came to this country in 1983.
`
` 5
`
`Q. And where did you do your advanced studies?
`
` 6
`
`A. Yes. I did my master's degree in mathematics and
`
` 7
`
`statistics at the Department of Mathematics of Indiana
`
` 8
`
`University in Bloomington, and I did also my Ph.D. in
`
` 9
`
`mathematics and statistics from the same university here in
`
`10
`
`Indiana.
`
`11
`
`Q. What were the circumstances of your coming to the United
`
`12
`
`States?
`
`13
`
`A. I was actually worried about the safety of my family and
`
`14
`
`myself. I was essentially running ahead of the genocide that
`
`15
`
`took place some 12 years later, and took some members of my
`
`16
`
`family.
`
`17
`
`Q. Did you -- were you married at the time?
`
`18
`
`A. Yes, I was. And I had actually left my young wife and
`
`19
`
`child there when I came here.
`
`20
`
`Q. What did you do when you first came to the United States?
`
`21
`
`A. Oh, it was a difficult situation, because I didn't speak
`
`22
`
`English. That was not my native language or a language that I
`
`23
`
`had learned. I was speaking French and some -- obviously
`
`24
`
`Kinyarwanda and some other languages. But I was given $50 by
`
`25
`
`the U.S. Embassy and a scholarship for a few months to come to
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-719
`
` 1
`
`Georgetown University.
`
` 2
`
`So, when I got there, I knew that, given the risk that
`
` 3
`
`I was running with my family, this was going to be my new
`
` 4
`
`home, but I didn't know what to do. I didn't speak good
`
` 5
`
`English, and so I couldn't really study, for example, law or
`
` 6
`
`study business. But, I noticed that there were a number of
`
` 7
`
`graduate students in the course at Georgetown -- in the
`
` 8
`
`course, yes, where they didn't speak really English but they
`
` 9
`
`were Ph.D. students. So, one morning I ran a quick survey
`
`10
`
`asking them what they were studying, and I noticed that almost
`
`11
`
`all of them were studying science and mathematics and still
`
`12
`
`didn't speak good English. So I thought that was my break
`
`13
`
`into the new home that I was trying to forge here. So, I
`
`14
`
`decided to study mathematics, because it didn't require me to
`
`15
`
`speak fluent English. I could recognize numbers regardless of
`
`16
`
`which language they are written in, so I was fine. So, I
`
`17
`
`applied for different programs in universities.
`
`18
`
`Q. And how did you pick Indiana?
`
`19
`
`A. Indiana University was very kind in multiple ways, because
`
`20
`
`I applied in about five schools, but they were the first one
`
`21
`
`to get back to me. And obviously, not having a family, not
`
`22
`
`having many options, I jumped on it. But, they were also the
`
`23
`
`ones who gave me a graduate teaching assistantship, which
`
`24
`
`meant I could go to school and have the university pay for my
`
`25
`
`education, so it was a good deal.
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-720
`
` 1
`
`But, also, they are very well-known for advanced
`
` 2
`
`mathematical programs, especially in the area of turbulence
`
` 3
`
`theory, mathematical statistics that are usually used in a
`
` 4
`
`number of fronts.
`
` 5
`
`Q. Did your family join you at some point?
`
` 6
`
`A. Yes. I managed to work in restaurants in Bloomington in
`
` 7
`
`addition to the teaching assistantship, but I was also helped
`
` 8
`
`by an old couple in Bloomington that got to know me and my
`
` 9
`
`story, and they helped me guarantee some funds with the
`
`10
`
`immigration. So my wife and the kids joined me in 1986. I
`
`11
`
`was still a graduate student.
`
`12
`
`Q. After you obtained your Ph.D., Doctor, where did you go?
`
`13
`
`A. I joined a company in Palo Alto called Centex, Centex
`
`14
`
`Research. It has since been acquired by Roche, so it doesn't
`
`15
`
`exist anymore, but it's the Genentech of today, the same
`
`16
`
`buildings that we had. And later I was asked to do work in
`
`17
`
`discovery and development.
`
`18
`
`Q. Is that in the drug field, Doctor?
`
`19
`
`A. Pharmaceutical company.
`
`20
`
`Q. And you got your Ph.D. in what year?
`
`21
`
`A. I got my Ph.D. in 1991.
`
`22
`
`Q. And you joined Centex in that year?
`
`23
`
`A. Yes, because I had a family to take care of; and the first
`
`24
`
`job I had a chance to find, I took it.
`
`25
`
`Q. When did you leave Centex?
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-721
`
` 1
`
`A. I left Centex in February of 1993.
`
` 2
`
`Q. Where did you go?
`
` 3
`
`A. I joined Eli Lilly and Company here in Indianapolis.
`
` 4
`
`Q. What attracted you to Lilly?
`
` 5
`
`A. There was a number of factors. I think Lilly has
`
` 6
`
`really -- had made at that time, and still I think does, made
`
` 7
`
`tremendous effort to hire Ph.D. mathematicians and
`
` 8
`
`statisticians and using them to help discovery researchers
`
` 9
`
`figure out the complexity of systems, biology and the like,
`
`10
`
`and to be able to guide on interpreting the results there with
`
`11
`
`the discovery scientists.
`
`12
`
`But there was also another thing that attracted me
`
`13
`
`there, and that was Lilly had made effort to invest in two big
`
`14
`
`Cray supercomputers at that time; and those were, for a
`
`15
`
`mathematician like me, a delight because it gave me a chance
`
`16
`
`to really crack numbers in a very efficient way. I believe
`
`17
`
`it's the only company in the industry that had it outside of
`
`18
`
`the Department of Defense. So, I felt that that gave me
`
`19
`
`really an opportunity for someone like me who had studied
`
`20
`
`mathematics and statistics to be able to impact on future
`
`21
`
`medicines that may help people.
`
`22
`
`Q. What were your first responsibilities, Doctor, when you
`
`23
`
`started at Lilly in 1993?
`
`24
`
`A. They assigned me first to a drug called gemcitabine, which
`
`25
`
`I was working on in discovery, in fact, also in development;
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-722
`
` 1
`
`but also, they assigned me to work on what they called
`
` 2
`
`antifolate action group, so the group of antifolates that
`
` 3
`
`pemetrexed was part of.
`
` 4
`
`Q. Is gemcitabine a cancer drug as well?
`
` 5
`
`A. Yes, it is.
`
` 6
`
`Q. Is it on the market today?
`
` 7
`
`A. It is on the market today.
`
` 8
`
`Q. What's it called?
`
` 9
`
`A. It's called Gemzar.
`
`10
`
`Q. What does it treat?
`
`11
`
`A. When we started, the team that I was on, we directed it
`
`12
`
`towards pancreatic cancer. We got it approved for lung
`
`13
`
`cancer. We got it approved for bladder cancer. It's approved
`
`14
`
`in, I believe, breast cancer, also. So, I was on that
`
`15
`
`program, also, for about 12 years.
`
`16
`
`Q. Doctor, we've heard testimony about three different
`
`17
`
`compounds that Lilly was developing in the antifolate program.
`
`18
`
`A. Right.
`
`19
`
`Q. The first one was lometrexol. Did you work on lometrexol
`
`20
`
`at all?
`
`21
`
`A. No. Actually, when I joined Eli Lilly, lometrexol was
`
`22
`
`being taken off-line.
`
`23
`
`Q. What was your understanding at the time as to why it was
`
`24
`
`being taken off-line?
`
`25
`
`MR. WIESEN: Objection, Your Honor. I think this is
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-723
`
` 1
`
`plainly going to be hearsay.
`
` 2
`
`MR. GENDERSON: Your Honor, it goes to his state of
`
` 3
`
`mind, because it's relevant to what he did later and why he
`
` 4
`
`did it.
`
` 5
`
`THE COURT: I'll overrule it. It's interesting. I
`
` 6
`
`would like to hear it.
`
` 7
`
`A. So, lometrexol, which was an antifolate targeting an
`
` 8
`
`enzyme called GARFT -- I never try to pronounce it. It's such
`
` 9
`
`a long name. But the lometrexol was taken off-line for
`
`10
`
`essentially two reasons: One, it was very toxic; and the
`
`11
`
`company had tried to correct that with 5-milligram folic acid
`
`12
`
`supplementation in the regimen I described earlier, and it
`
`13
`
`didn't work. It was still toxic; but also, the efficacy
`
`14
`
`seemed to be completely jeopardized.
`
`15
`
`So they decided that it was toxic, and it didn't have
`
`16
`
`enough efficacy; and the company just decided to stop it.
`
`17
`
`BY MR. GENDERSON:
`
`18
`
`Q. The next compound that's been discussed and you mentioned
`
`19
`
`is the '887 compound?
`
`20
`
`A. Right.
`
`21
`
`Q. Did you actually work on the development of that compound?
`
`22
`
`A. Yes, I actually did. When I got there, it was starting
`
`23
`
`Phase 1; but also, this is one that was using the same
`
`24
`
`regimen of 5 milligrams of folic acid.
`
`25
`
`Q. What was your understanding of why that regimen of
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-724
`
` 1
`
`5 milligrams of folic acid were being used?
`
` 2
`
`A. The understanding was that it was going to help reduce the
`
` 3
`
`toxicities from the drug.
`
` 4
`
`Q. And you said you also worked on pemetrexed, is that right?
`
` 5
`
`A. Yes, I did.
`
` 6
`
`Q. We're going to go back and talk about this period. I
`
` 7
`
`still want to do a little more about your background.
`
` 8
`
`At some point after the year 2000, did you take
`
` 9
`
`another position at Lilly?
`
`10
`
`A. Yes, I did. At that time, the human genome was just
`
`11
`
`sequenced, and the library was becoming available; and there
`
`12
`
`was a sense that the understanding of the human genome was
`
`13
`
`going to really impact how we move our strategies of
`
`14
`
`discovering new drugs against cancer.
`
`15
`
`So I was asked by Lilly to be the first head of the
`
`16
`
`pharmacogenomics group. And at that time, they promoted me to
`
`17
`
`Lilly research fellow, which is one of the highest titles that
`
`18
`
`you could get on the technical track; and they asked me to
`
`19
`
`spearhead this pioneering department.
`
`20
`
`Q. And how long did you -- that occurred in 2001, is that
`
`21
`
`right?
`
`22
`
`A. 2001, yeah.
`
`23
`
`Q. How long did you stay at Lilly?
`
`24
`
`A. I left Lilly in 2005.
`
`25
`
`Q. And did you have that same position from 2001 to 2005?
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-725
`
` 1
`
`A. That's right. I did.
`
` 2
`
`Q. Why did you leave Lilly?
`
` 3
`
`A. Well, actually, I was offered an opportunity to continue
`
` 4
`
`to do research in cancer, but this time by GlaxoSmithKline in
`
` 5
`
`Philadelphia, where I was appointed global vice president of
`
` 6
`
`medicine development strategy for the oncology program within
`
` 7
`
`the company.
`
` 8
`
`Q. And did you move to Philadelphia at that point?
`
` 9
`
`A. Yes. I moved to Philadelphia.
`
`10
`
`Q. And that was in 2005?
`
`11
`
`A. 2005.
`
`12
`
`Q. When did you leave Glaxo?
`
`13
`
`A. I left GlaxoSmithKline in early 2009.
`
`14
`
`Q. Why did you leave?
`
`15
`
`A. Actually, it's a combination of a number of things, mostly
`
`16
`
`personal. I had lost my wife to cancer, my wife of 25 years;
`
`17
`
`and she had left me with a 14-year-old son. And I felt like I
`
`18
`
`needed to take the time and really take care of him. Sorry.
`
`19
`
`Q. At some point, Doctor, did you take another position?
`
`20
`
`A. Yes. I thought I was going to just stay there and help
`
`21
`
`him go through the process, but I was asked by the board of
`
`22
`
`directors of Merrimack Pharmaceuticals in Cambridge to go and
`
`23
`
`spearhead a development. So I was offered a position of
`
`24
`
`executive vice president of development, which is what I hold
`
`25
`
`today.
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-726
`
` 1
`
`Q. Did they allow you to stay in Philadelphia?
`
` 2
`
`A. Yes, they did. That was one of the things that they were
`
` 3
`
`very nice about. They basically said that I could commute,
`
` 4
`
`and they made it possible to do so.
`
` 5
`
`Q. What is -- just very briefly, what is Merrimack's
`
` 6
`
`business, and what do you do for Merrimack?
`
` 7
`
`A. We focus on the research and development of medicines
`
` 8
`
`against cancer, but we also work on cardiovascular disease.
`
` 9
`
`Q. Doctor, while you were at Eli Lilly, did you do any
`
`10
`
`teaching?
`
`11
`
`A. Yes, I did. And I went back to Bloomington in a sense to
`
`12
`
`give back, because they had helped me some decades back going
`
`13
`
`through school. So I was teaching mathematics to
`
`14
`
`undergraduate students, both during the year, but also they
`
`15
`
`had special programs in the summer for kids coming out of high
`
`16
`
`school that needed some adjustments in the mathematical field,
`
`17
`
`so I did that.
`
`18
`
`But, I also taught graduate students, and particularly
`
`19
`
`focusing on graduate students who were not necessarily
`
`20
`
`mathematicians but wanted to learn how to use advanced
`
`21
`
`mathematical techniques to do research. So they were mostly
`
`22
`
`Ph.D.s from other fields of science and medicine, but also
`
`23
`
`actually Ph.D. graduate students in mathematics.
`
`24
`
`Q. Are you involved today in any community organizations,
`
`25
`
`Doctor?
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-727
`
` 1
`
`A. Yes, I am. I have been serving on the C-Change, and
`
` 2
`
`C-Change is a national organization that was created by
`
` 3
`
`President George Bush, Sr.; and it has folks, executives in
`
` 4
`
`industries, high-ranking officials in government -- I think
`
` 5
`
`Senator Feinstein is co-chairing that -- but also people in
`
` 6
`
`academia. And the effort is to spearhead a support of
`
` 7
`
`advancing cancer research, cancer treatment and advocating for
`
` 8
`
`availability of treatment for people.
`
` 9
`
`So, I have been serving that for nearly probably five
`
`10
`
`years. I remember when I signed up. It's been a while.
`
`11
`
`But, I also -- I also went back to my homeland, in a
`
`12
`
`sense, because I became a founding member of the Presidential
`
`13
`
`Advisory Council for President Kagame of Rwanda since 2007;
`
`14
`
`and there I serve on that council, but I also am senior
`
`15
`
`science advisor for him in matters of health care, but I also
`
`16
`
`help him in developing strategies for global investments. So,
`
`17
`
`I do that.
`
`18
`
`Q. Are you paid for your work with the government of Rwanda,
`
`19
`
`Doctor?
`
`20
`
`A. No, no. It's -- it's all giving back.
`
`21
`
`Q. And, Doctor, let's turn back now to the work you were
`
`22
`
`doing in the mid-1990s at Eli Lilly; and there's been
`
`23
`
`discussion in this case about a patent that Dr. Grindey issued
`
`24
`
`that Dr. Grindey called the '974 patent. Were you aware of
`
`25
`
`that patent while you were working at Lilly?
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-728
`
` 1
`
`A. No. Actually, I became aware of it recently when they
`
` 2
`
`were discussing it. I didn't know about it when I was there.
`
` 3
`
`Q. Did you base your work on anything having to do with that
`
` 4
`
`patent, to your knowledge?
`
` 5
`
`A. No.
`
` 6
`
`Q. And the '887 compound that you mentioned was in Phase 1
`
` 7
`
`studies; did that compound get to Phase 2 studies?
`
` 8
`
`A. I don't believe so because it was having a lot of toxicity
`
` 9
`
`problems despite the supplementation with large amounts of
`
`10
`
`folic acid that it ended up not moving forward. It was just
`
`11
`
`too toxic and the efficacy seemed to be not there.
`
`12
`
`Q. I'm sorry, the efficacy --
`
`13
`
`A. The efficacy was not there.
`
`14
`
`Q. And that compound was also discontinued?
`
`15
`
`A. Yes, I believe so.
`
`16
`
`Q. Do you know when it was discontinued?
`
`17
`
`A. I don't recall exactly the time, but I know --
`
`18
`
`MR. WIESEN: I'm going to object to this on the
`
`19
`
`ground of relevance, Your Honor. If he can't establish that
`
`20
`
`it was something that was publicly known -- I realize we're
`
`21
`
`going to get some background on pemetrexed, but going off onto
`
`22
`
`other compounds --
`
`23
`
`MR. GENDERSON: Your Honor, that's my last question
`
`24
`
`on that.
`
`25
`
`THE COURT: Okay. His answer was he doesn't recall
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-729
`
` 1
`
`exactly the time.
`
` 2
`
`MR. GENDERSON: I'm moving on to another subject,
`
` 3
`
`Your Honor.
`
` 4
`
`THE COURT: Okay. You may.
`
` 5
`
`BY MR. GENDERSON:
`
` 6
`
`Q. Now, Doctor, when you were introducing your invention
`
` 7
`
`concept and you used the term "multivariate analysis," can you
`
` 8
`
`explain how you performed the multivariate analysis in
`
` 9
`
`connection with the work you were doing on pemetrexed?
`
`10
`
`A. Yes. Your Honor, maybe explaining it in mathematical
`
`11
`
`terms, it's a complex process; but I can probably use an
`
`12
`
`example that I always use to explain what this concept is all
`
`13
`
`about.
`
`14
`
`So, essentially, it is a concept where an event is
`
`15
`
`happening you observe. It may be due to multiple reasons, but
`
`16
`
`you don't know which one, or you can't pull together the
`
`17
`
`picture of what could be really happening.
`
`18
`
`So, if you take, for example, a patient that comes to
`
`19
`
`the doctor and they say, "I'm coughing," okay, the doctor will
`
`20
`
`say we have a patient who is coughing; but it doesn't mean
`
`21
`
`that there is anything else. They may have been drinking
`
`22
`
`water the wrong way most of the evening.
`
`23
`
`But if they are coughing, the doctor will say, "Okay.
`
`24
`
`Is your cough dry or are you pooling some sputum?" And the
`
`25
`
`patient would say, "Yes." Then the doctor has to go to the
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-730
`
` 1
`
`next variable and say, "Wait a minute, is it salty?" So we
`
` 2
`
`have now three variables that he's tracking. And the patient
`
` 3
`
`may say, "Yes."
`
` 4
`
`And if the doctor then say, "Do you have blood in your
`
` 5
`
`cough," and they say, "Yes" or "No," the "yes" may mean we
`
` 6
`
`have a severe case of pneumonia. Or "no," it may mean it's
`
` 7
`
`relatively okay. A quick antibiotic will fix it.
`
` 8
`
`So, multivariate analysis is a mathematical approach
`
` 9
`
`that takes multiple variables to try to explain a phenomenon
`
`10
`
`that otherwise you couldn't see with the naked eye, so to
`
`11
`
`speak.
`
`12
`
`So in this case, the doctor makes the diagnosis based
`
`13
`
`actually on multiple variables related to the condition of the
`
`14
`
`patient as they present. So, that's how I understood it.
`
`15
`
`Now, in the case of pemetrexed, the multivariate
`
`16
`
`analysis was extremely relevant because a patient presented.
`
`17
`
`They measured several variables. They looked at them from a
`
`18
`
`clinical perspective. There was no problem. Some patients
`
`19
`
`get in trouble, others don't.
`
`20
`
`So the fundamental application of multivariate
`
`21
`
`analysis was to say, I'm going to take everything we know
`
`22
`
`about these patients, tease them out, have them shake hands,
`
`23
`
`mathematically, so to speak, and hopefully I will isolate a
`
`24
`
`particular reason why some are going down and others are not.
`
`25
`
`And that's in that context that I used multivariate analysis.
`
`Lilly Ex. 2116
`Sandoz v. Lilly IPR2016-00318
`
`
`
`NIYIKIZA - DIRECT/GENDERSON
`
`Vol. 4-731
`
` 1
`
`Otherwise, it's many years of Ph.D. work that I can't go
`
` 2
`
`through.
`
` 3
`
`Q. And, Doctor, when you're doing that with pemetrexed and
`
` 4
`
`the number of variables you were using, is it possible to
`
` 5
`
`tease out which is causing -- what may be causing the problem
`
` 6
`
`without using a high-powered computer?
`
` 7
`
`A. It would be very difficult.
`
` 8
`
`Q. You mentioned earlier that you found that there was a
`
` 9
`
`correlation between homocysteine levels that were subclinical
`
`10
`
`but elevated and toxicity you were finding. Can you explain
`
`11
`
`what you mean by the word "correlation"?
`
`12
`
`A. The word "correlation" is used in statistics to indicate
`
`13
`
`that if you have two variables, two things that are happening,
`
`14
`
`the correlation means when you act on this variable, this one
`
`15
`
`also act. So, sometimes they act going in the same direction,
`
`16
`
`and it's a positive correlation; it's also a positive
`
`17
`
`correlation when they act going down together.
`
`18
`
`But when you have one that shift in opposite direction
`
`19
`
`to the other, we call them a negative correlation, but we
`
`20
`
`still say they are correlated variables. So that's what I
`
`21
`
`meant. So, in this particular case, the data, the first pass
`
`22
`
`of the data was establishing a dynamic relation between
`
`23
`
`homocysteine going up and the incidence of the toxic
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
