Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 1 of 124 PageID #: 7182
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`Vol. 5-861
`
`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 23, 2013 )
`
`
` 9:06 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 V
`
`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
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0001
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 2 of 124 PageID #: 7183
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`Vol. 5-862
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`APPEARANCES
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`For Plaintiff:
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`For Defendants:
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`Adam L. Perlman, Esq.
`David M. Krinsky, 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.
`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
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0002
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 3 of 124 PageID #: 7184
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`Vol. 5-863
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`PLAINTIFF'S WITNESSES
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` PAGE
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`I N D E X
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`CLET NIYIKIZA
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`Cross-examination by Mr. Wiesen ...............866
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`Redirect examination by Mr. Genderson .........959
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`HILARY CALVERT
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`(By video deposition)..........................982
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`I N D E X O F E X H I B I T S
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` PAGE
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`TRIAL EXHIBITS
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`2158 ..........................................865
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`22 ............................................866
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`60 ............................................866
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`64 ............................................866
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`74 ............................................866
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`80 ............................................866
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`312 ...........................................866
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`313 ...........................................866
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`314 ...........................................866
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`326 ...........................................866
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`327 ...........................................866
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`393 ...........................................866
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`394 ...........................................866
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`913 ...........................................866
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`1463 ..........................................866
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`Revised 2158 ..................................866
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`2100 ..........................................866
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`2102 ..........................................866
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`2110 ..........................................866
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`2120 ..........................................866
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`2123 ..........................................866
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`2058 ..........................................866
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`2257 ..........................................866
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`2262 ..........................................866
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`3011 ..........................................866
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`386 ...........................................980
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`391 ...........................................980
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`333 ...........................................980
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`392 ...........................................980
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`1385 ..........................................980
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`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0003
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 4 of 124 PageID #: 7185
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`Vol. 5-864
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`(In open court.)
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`THE COURT: If you would remain standing and raise
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`your right hand, I will swear you in for the day.
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`(The witness is sworn.)
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`THE COURT: You may have a seat. And we are back on
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`the record. This is Eli Lilly versus Teva Parenteral.
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`And, Mr. Genderson, I see you're ready.
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`MR. GENDERSON: Just some housekeeping, Your Honor,
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`from yesterday.
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`THE COURT: You may.
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`MR. GENDERSON: We had agreed that Exhibit 2158,
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`which was that long PowerPoint, we would only have in the
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`exhibit the slides that we actually used. There were the
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`three slides. So, we've done that. I've given a copy to
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`counsel, and if you would like a copy of them.
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`MR. WIESEN: And, Your Honor, we discussed yesterday
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`whether it would be demonstrative or whether it would be
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`actually an exhibit just because I'm not sure we set the
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`business record foundation, but either way, you're going to
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`have it, so I'm not sure it makes a big deal to us. If you
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`want to just take it into the record, that's fine.
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`THE COURT: Okay. Let's take it into the record.
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`MR. WIESEN: And I will say, just for the record,
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`that the third slide was the one that Mr. Genderson
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`represented was from the ASCO abstract in 2002, and he did
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0004
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 5 of 124 PageID #: 7186
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`Vol. 5-865
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`show that to me this morning, so it is included.
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`THE COURT: Okay. All right. Exhibit 2158 is
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`admitted into the record without objection.
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` (Trial Exhibit 2158 was
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` received in evidence.)
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`MR. GENDERSON: And, Your Honor, then just for the
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`record, I have a list of exhibits to move in from the
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`examination, and I've shared the list with counsel, and these
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`are all -- there's no objection to any of these.
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`THE COURT: You may.
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`MR. GENDERSON: Exhibits 22, 60, 64, 74, 80, 312,
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`313, 314, 326, 327, 393, 394, 913, 1463, the revised 2058
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`(sic) that we just discussed, 2100, 2102, 2110, 2120, 2123 --
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`I'm sorry, I apologize. 2058 is -- was not the one we
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`discussed. That one is -- is not objected. It's 2158, not
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`2058, is the one that was shortened, I apologize.
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`THE COURT: Okay. So the revised 21 --
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`MR. GENDERSON: -- 58. And 2058 is -- we move in,
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`as well. And then 2257, 2263 (sic), and 3011.
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`THE COURT: Do you agree?
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`MR. WIESEN: We do. We checked it ahead of time,
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`because it's a long list.
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`THE COURT: It is a long list. Okay, and those
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`exhibits that have just been read into the record are admitted
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`25
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`without objection.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0005
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 6 of 124 PageID #: 7187
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`NIYIKIZA - CROSS/WIESEN
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`Vol. 5-866
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`MR. GENDERSON: Thank you, Your Honor.
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` (Trial Exhibits 22, 60, 64, 74, 80,
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` 312, 313, 314, 326, 327, 393,
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` 394, 913, 1463, Revised 2158,
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` 2100, 2102, 2110, 2120, 2123,
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` 2058, 2257, and 3011 were
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` received in evidence.)
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`MR. GENDERSON: Did I say 2262 or 63?
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`THE COURT: You said 2263.
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`MR. GENDERSON: I apologize, Your Honor.
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`Mr. Krinsky caught that for me. I meant to say 2262.
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`THE COURT: 2262. So there is no 2263, correct?
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`MR. GENDERSON: Correct. I apologize.
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`THE COURT: That correction is noted.
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` (Trial Exhibit 2262 was
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`witness.
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` received in evidence.)
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`MR. GENDERSON: Thank you, Your Honor.
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`THE COURT: Counsel, you may cross-examine the
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`MR. WIESEN: Thank you, Your Honor.
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`CROSS EXAMINATION
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`22
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`BY MR. WIESEN:
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`23
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`Q. Good morning, Dr. Niyikiza.
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`24
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`A. Good morning.
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`Q. Dr. Niyikiza, I want to go back to some of the testimony
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0006
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 7 of 124 PageID #: 7188
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`NIYIKIZA - CROSS/WIESEN
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`Vol. 5-867
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`you provided yesterday during the December 1999 period. Do
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`you remember talking about that?
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`A. Yes.
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`Q. And you discussed with Mr. Genderson the sort of hectic
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`and rushed nature of getting out the letter to the FDA on
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`December 22nd, 1999, right?
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`A. Yes.
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`Q. I think, and you can check it in your binder if you want,
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`but it was Trial Exhibit 2262, right? We've got it up on the
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`screen, as well.
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`A. Okay.
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`Q. This was that December 22nd letter, right?
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`A. Yes.
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`Q. If we turn to the second page, the long paragraph in the
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`middle, "Lilly consulted a number of oncology experts." Do
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`you remember that?
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`A. Yeah.
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`Q. And you went through this in a little detail with
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`Mr. Genderson and talked about the specific statement, "These
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`experts felt that supplementation with low levels of folic
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`acid would not adversely affect efficacy with pemetrexed,"
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`right?
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`A. Yes.
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`Q. You explained that this letter was actually signed, if we
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`look at the next page, by G.G. Enas, not who was a
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0007
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 8 of 124 PageID #: 7189
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`NIYIKIZA - CROSS/WIESEN
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`Vol. 5-868
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`statistician, I think you said, right?
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`A. That's what the record says.
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`Q. Well, you knew Mr. Enas, right?
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`A. Yes, I know him.
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`Q. Did he work in the regulatory group, as well?
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`A. Yes, he was in the regulatory group.
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`Q. So he worked for Mr. Brophy?
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`A. I believe so.
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`Q. Do you know if he regularly signed letters to the FDA?
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`A. I don't know. I was not in that department, so I didn't
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`know the rules there.
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`Q. Okay. And you think Mr. Enas wasn't on the call with the
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`experts, right?
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`A. No. It's not that I don't think. I believe he was not
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`there.
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`Q. But you're not sure he wasn't on the call?
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`A. Well, unless he was silent on the call.
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`Q. He didn't identify himself as on the call?
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`A. Not that I know of.
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`Q. Was there anybody from regulatory on the call with the
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`experts?
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`A. I believe John Worzalla was on the call, who was the
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`regulatory person for the pemetrexed program.
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`Q. But John Worzalla didn't sign the letter? Now I think you
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`testified that, although this was December 22nd, you didn't
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0008
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 9 of 124 PageID #: 7190
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`NIYIKIZA - CROSS/WIESEN
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`Vol. 5-869
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` 1
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`get a chance to read this letter until after you got back from
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`Canada; is that right?
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`A. Yes. After the new year, actually.
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`Q. So sometime in early January, you read this letter?
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`A. No. The letter was already sent out, and as part of the
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`preparation for the FDA meeting, we received all the documents
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`that pertained to that preparation, and this comes as what is
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`part of that file. So, I saw it.
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`Q. So, do you remember when you saw this letter?
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`A. Oh, it would be probably sometime around February when we
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`were preparing for the meeting.
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`Q. I see. And at the time you reviewed this letter, did you
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`note that there was a mistake back on page 2 in the statement
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`that the experts agreed that the low levels of folic acid
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`would not adversely affect efficacy?
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`A. That's not what -- I didn't see the need to review it at
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`that time. I was just following to the next step of preparing
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`to discuss with the agency. I did not review the letter for
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`its accuracy, because I didn't write it. And usually when
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`they write, they don't really ask me to review the whole
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`thing. They asked me to review documents related to the
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`analysis that I would have performed.
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`Q. Okay. So in February when you got a copy of this letter,
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`January or February, whenever it was, did you review the whole
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`letter or not?
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0009
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 10 of 124 PageID #: 7191
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`NIYIKIZA - CROSS/WIESEN
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`Vol. 5-870
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`A. I read the documents, but I reviewed things pertaining to
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`what I have contributed to as the author, and this was not one
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`of them.
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`Q. So you read the letter, but you didn't review it?
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`A. I didn't review it because that was not the purpose of
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`getting that document.
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`Q. Okay. Well, when you read it, did you notice that this
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`was a mistake?
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`A. I did not notice at that time, but it was pointed out
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`because that was part of the discussion eventually we had with
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`the agency later on.
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`Q. It was pointed out to the agency that this was a mistake?
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`A. During the discussion with the FDA, it was pointed out
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`that there was still concern for efficacy that we also had and
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`had no evidence for until we corrected the data.
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`Q. And that was during the March 2000 meeting with the FDA?
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`A. That would be March 1st, the meeting we had.
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`Q. Okay. If you look at Exhibit 2100, that was, I think, the
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`next exhibit you went to with Mr. Genderson, right? This was
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`the letter from -- the fax from the FDA, January 6th?
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`A. Yes.
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`Q. Did you get a copy of this on or about January 6, 2000?
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`A. I did see the copy when we were asked to start preparing
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`for the meeting with the FDA, yes.
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`Q. So, it was sometime after January 6th?
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0010
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 11 of 124 PageID #: 7192
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`NIYIKIZA - CROSS/WIESEN
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`Vol. 5-871
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`A. Yes.
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`Q. Late January, early February, any idea when?
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`A. I really don't recall, yeah.
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`Q. And this one is actually addressed, if we look at the two,
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`to John Worzalla, right?
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`A. Yes. But that would be customary because when the FDA
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`addresses the sponsor, they send the letter to the
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`representative of the company within the regulatory for that
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`program, and it was John Worzalla who was in that role.
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`Q. And he had switched jobs from having been in the
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`preclinical group at Eli Lilly later to being in the
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`regulatory group, right?
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`A. I know he was in discovery. I know he was at this time
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`in the regulatory. Whether he had another job in between, I
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`don't know. But he was the regulatory person for the program
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`during this time.
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`Q. Now, the job of the FDA here is to require companies to
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`prove the safety and efficacy of a drug before they approve
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`it, right?
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`A. I don't know if it's to prove, because the requirement is
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`to show that the risk -- the risk is outweighed by the
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`benefit. I don't think that word "proved" is ever used
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`because it's a balance between what kind of safety you have
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`versus the benefit for the patient in terms of efficacy. So,
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`I really never had the agency or heard them use the word
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0011
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 12 of 124 PageID #: 7193
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`NIYIKIZA - CROSS/WIESEN
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`Vol. 5-872
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`"proof." They require to show the benefit that outweighed the
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`risk, because every medicine has a risk.
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`Q. When the FDA looks at a product or a file for review,
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`they're considering whether to approve the drug based on that
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`risk/benefit analysis, right?
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`A. I don't work with the FDA. I never worked with the FDA,
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`but that is what I understood the agency does. But whether
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`that is what they do, that's a decision of the agency, and I
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`don't know how they make that decision, except that as a
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`matter of standards, you have to demonstrate that there is a
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`benefit that is outweighing the risk for a drug to be
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`approved.
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`Q. Well, put it this way: At least for the FDA, just
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`demonstrating some therapeutic benefit for a drug is not
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`enough to get approval, right?
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`A. You're asking me a question I can't answer because I don't
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`work for the FDA. I don't know the rules they use to decide.
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`I know what the guidance says, which provides evidence that
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`there is a benefit that is outweighing the risk, but I don't
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`have any way of assessing how they actually measure that
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`benefit versus risk. That's an FDA rule that I couldn't speak
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`to, because I don't know.
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`Q. The FDA looks at both sides of the balance, the benefit
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`and the risk, when they decide whether or not to approve a
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`25
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`drug, don't they?
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0012
`
`

`

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`A. That's what the guideline says, yeah.
`
` 2
`
`Q. Thank you, Dr. Niyikiza. Now, after this letter, I think
`
` 3
`
`you were saying that there was going to be a meeting in March,
`
` 4
`
`and a briefing book was sent in February, right? That was --
`
` 5
`
`we looked -- you looked at the cover letter yesterday? That
`
` 6
`
`was Trial Exhibit 913; is that right?
`
` 7
`
`A. Yes.
`
` 8
`
`Q. And this exhibit is actually just two pages. It's just
`
` 9
`
`the cover letter for that briefing book, right?
`
`10
`
`A. Right.
`
`11
`
`Q. The briefing book itself is Trial Exhibit 76 if you want
`
`12
`
`it. It was also in your binder.
`
`13
`
`A. Yeah, I can see it here.
`
`14
`
`Q. My question, Dr. Niyikiza, is simply, you know that Lilly
`
`15
`
`didn't provide any correction to that statement from the
`
`16
`
`December 22nd, 1999, letter in the briefing book that they
`
`17
`
`provided in February of 2000, right?
`
`18
`
`A. I don't know if they needed to make a correction or not.
`
`19
`
`All I know is that I did not agree with that statement. But I
`
`20
`
`don't speak for the company; they may have seen that that's
`
`21
`
`still okay to make that statement. I just happen to disagree
`
`22
`
`because my data was showing that -- and from what I knew from
`
`23
`
`the discussion on the call was that this was not what the
`
`24
`
`experts told us. But as to whether Lilly would decide to make
`
`25
`
`the correction or not, that's not really my call.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0013
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 14 of 124 PageID #: 7195
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`NIYIKIZA - CROSS/WIESEN
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`Vol. 5-874
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`Q. Now, to get that March 1st, 2000, meeting --
`
` 2
`
`A. Yes.
`
` 3
`
`Q. -- Lilly had to make a specific request, right?
`
` 4
`
`A. Yes. You have to. At least you have to describe what you
`
` 5
`
`would like to discuss with them so that the agency has the
`
` 6
`
`right experts in the room on the issues you want discussed.
`
` 7
`
`Q. And Lilly made a specific request to the FDA, right?
`
` 8
`
`A. What request now?
`
` 9
`
`Q. To have a meeting concerning the subject of vitamin
`
`10
`
`supplementation?
`
`11
`
`A. Yes. In fact, the previous exhibit that counsel just
`
`12
`
`showed me specifies the three points that Lilly wanted to
`
`13
`
`discuss, and that would be the case.
`
`14
`
`Q. Let me show you what's been marked as Trial Exhibit 333.
`
`15
`
`A. Thank you.
`
`16
`
`Q. I'm showing you Exhibit -- Trial Exhibit 333. It's a
`
`17
`
`letter from Lilly to the FDA dated January 25th, 2000, and
`
`18
`
`it's specifically entitled a "Type A Meeting Request," right?
`
`19
`
`A. Yes.
`
`20
`
`Q. This is actually the formal request for the meeting that
`
`21
`
`ends up happening on March 1st, correct?
`
`22
`
`A. Yes. I would expect that to be the case. But, this
`
`23
`
`request was certainly made without my knowledge or
`
`24
`
`consultation, so this is the process. So, it would be
`
`25
`
`something that the regulatory people know how to do.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0014
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 15 of 124 PageID #: 7196
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`NIYIKIZA - CROSS/WIESEN
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`Vol. 5-875
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` 1
`
`Q. And when you got the materials to prepare for the
`
` 2
`
`March 1st meeting, this is another document you would have
`
` 3
`
`gotten in the regulatory file; is that right?
`
` 4
`
`A. Typically, not for a letter to request a meeting, but I
`
` 5
`
`certainly would have probably saw that in the material. But,
`
` 6
`
`it didn't represent something that required my expertise,
`
` 7
`
`because these are procedural documents from the regulatory
`
` 8
`
`people.
`
` 9
`
`Q. And if we look on the very first page of this -- the Bates
`
`10
`
`No. is ELAP13452 -- it actually in the first paragraph
`
`11
`
`references that December 22nd, 1999, letter, correct?
`
`12
`
`A. Yes.
`
`13
`
`Q. If we turn to -- the first few pages are just the forms
`
`14
`
`that go in front of this for an FDA filing to make sure the
`
`15
`
`agency kills as many trees as possible, I guess, right? And
`
`16
`
`then the formal meeting request starts on 13458?
`
`17
`
`A. Yes.
`
`18
`
`Q. And I want to turn to the next page, 13459.
`
`19
`
`A. Yes.
`
`20
`
`Q. And in your experience, Lilly would be careful with a
`
`21
`
`formal meeting request that was going from the head of the
`
`22
`
`regulatory group to the FDA, right?
`
`23
`
`A. That's certainly always the intent. You have to be -- to
`
`24
`
`provide the information you have to the best of your ability.
`
`25
`
`Q. Right.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0015
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 16 of 124 PageID #: 7197
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`NIYIKIZA - CROSS/WIESEN
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`Vol. 5-876
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`A. That's what I would expect.
`
` 2
`
`Q. And when you reviewed things for Lilly that were going to
`
` 3
`
`the agency, you were certainly careful to make sure that
`
` 4
`
`everything was as accurate as possible, right?
`
` 5
`
`A. For those that I was asked to review with my expertise,
`
` 6
`
`yes. But, the document contains material that come from
`
` 7
`
`completely different experts, and I certainly am not an expert
`
` 8
`
`in every aspect of it. So that would not be expected to be me
`
` 9
`
`reviewing them. Some of the aspects related to mathematical,
`
`10
`
`statistics, analysis, and interpretation of what those numbers
`
`11
`
`are saying; yes, they would consult me.
`
`12
`
`Q. And in this request for a meeting, if we look at the
`
`13
`
`second page of the specific meeting request, ELAP13459, the
`
`14
`
`second full paragraph --
`
`15
`
`A. Yes.
`
`16
`
`Q. -- Lilly repeats the point that the expert consultants all
`
`17
`
`agreed that adding the folic acid shouldn't impact efficacy,
`
`18
`
`right?
`
`19
`
`A. They do.
`
`20
`
`Q. They write, "External consultants, including an expert in
`
`21
`
`folate metabolism, were in agreement that this amount of folic
`
`22
`
`acid should be effective in reducing homocysteine levels, but
`
`23
`
`these low levels should not be detrimental to efficacy,"
`
`24
`
`right?
`
`25
`
`A. That's what the documents say. Again, I'm in disagreement
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0016
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 17 of 124 PageID #: 7198
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`NIYIKIZA - CROSS/WIESEN
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`Vol. 5-877
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` 1
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`here, as I did yesterday. This seems to me something that was
`
` 2
`
`a cut and paste from the various documents. But, certainly
`
` 3
`
`what I understood and what I actually was tasked to do is to
`
` 4
`
`make sure that we follow up and don't have adverse impact on
`
` 5
`
`the efficacy.
`
` 6
`
`So, this is a document prepared by the regulatory
`
` 7
`
`people, and they may have pasted things here and there, but I
`
` 8
`
`certainly still had the concern, although the risk was very
`
` 9
`
`low, and the experts also had the concern, but they reached a
`
`10
`
`point that the risk of losing patients outweighed the risk of
`
`11
`
`losing efficacy and that it was important to take the chance.
`
`12
`
`But, to my best recollection, they always had that concern,
`
`13
`
`and I was instructed to follow up.
`
`14
`
`Q. When you said that this was a cut and paste, do you mean
`
`15
`
`it was actually taken from the prior letter and sort of just
`
`16
`
`put right back in this next letter?
`
`17
`
`A. That's my guess of what I think is happening, because this
`
`18
`
`statement is similar to what was done before. I certainly was
`
`19
`
`not in agreement that that was indeed what took place in the
`
`20
`
`discussion with the experts.
`
`21
`
`Q. There's an additional statement in here that was -- that's
`
`22
`
`on the same subject but different than the prior one, right,
`
`23
`
`if we go about four lines further down, the sentence that
`
`24
`
`begins "since," if we could highlight that?
`
`25
`
`Right? In this letter, they also add a
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0017
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 18 of 124 PageID #: 7199
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`NIYIKIZA - CROSS/WIESEN
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`Vol. 5-878
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` 1
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`second point, which says, "Since the amount of folic acid that
`
` 2
`
`will be administered is low, patients who have normal levels
`
` 3
`
`of homocysteine should not be affected by the addition of this
`
` 4
`
`low level of folic acid. 400 micrograms folic acid is the
`
` 5
`
`usual amount found in multivitamins in the U.S."
`
` 6
`
`Do you see that?
`
` 7
`
`A. Yes.
`
` 8
`
`Q. That wasn't in the December 22nd letter, right?
`
` 9
`
`A. It looks like it was expanded, but again, Counsel, the
`
`10
`
`issue, at least from where I stand here, is not that I get to
`
`11
`
`decide on what Lilly writes in communications with the agency
`
`12
`
`and certainly don't make the decision on finally what
`
`13
`
`ultimately end up there. That's the decision above my pay
`
`14
`
`grade, for sure. So, there was heads of clinical
`
`15
`
`investigations, discovery researchers who made those
`
`16
`
`decisions.
`
`17
`
`What I do know is that the data I had suggested that
`
`18
`
`we needed to intervene in the manner that I had proposed for
`
`19
`
`nearly three years at that time, which was done already. What
`
`20
`
`I also do know is that the expert had tilted to now the worry
`
`21
`
`that we just lost patients from the trial and we needed to do
`
`22
`
`something, that the safety of Alimta was no longer as it was
`
`23
`
`before and that this is a big risk. But, they also expressed
`
`24
`
`that we still need to follow up to see if we have not affected
`
`25
`
`efficacy. And actually, when you track back further, you will
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0018
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 19 of 124 PageID #: 7200
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`NIYIKIZA - CROSS/WIESEN
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`Vol. 5-879
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` 1
`
`see that that was what I was doing all along, to try to see if
`
` 2
`
`that was indeed the case, that we had affected the efficacy.
`
` 3
`
`Q. Now, you, yourself, had no concerns that adding the
`
` 4
`
`vitamin B12 and folic acid would affect efficacy, right?
`
` 5
`
`A. Personally, I had always been of the position that because
`
` 6
`
`these markers, as they were appearing to influence the safety,
`
` 7
`
`were typically within the normal range. Although you had some
`
` 8
`
`markers that were high for some patients who experienced
`
` 9
`
`toxicity, the intervention that I was proposing in my
`
`10
`
`invention, that really would be no more than just folate
`
`11
`
`dietary supplementation that you see in regular food, should
`
`12
`
`not affect the efficacy. And in my mind all along, the
`
`13
`
`argument was that if you have intervention that restore good,
`
`14
`
`normal nutritional status of the cancer patient and you still
`
`15
`
`have a problem with the efficacy, knowing that patients will
`
`16
`
`eat normally, hopefully, as we go, and if a drug is affected
`
`17
`
`by that kind of intervention, you don't have a drug anyway.
`
`18
`
`So, all along I had believed that this kind of intervention
`
`19
`
`was the right way to go, but I was just a lone wolf for three
`
`20
`
`years or so.
`
`21
`
`Q. But you, yourself, just to make sure it's clear, were
`
`22
`
`never concerned that adding the low levels of folic acid and
`
`23
`
`B12 as you just described would have a negative effect on the
`
`24
`
`efficacy of pemetrexed, right?
`
`25
`
`A. I was never concerned. Maybe it's the naiveté that I was
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0019
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 20 of 124 PageID #: 7201
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`NIYIKIZA - CROSS/WIESEN
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`Vol. 5-880
`
` 1
`
`a mathematician in a field that is not really where I was
`
` 2
`
`trained, but it did beat the logic of common sense that if you
`
` 3
`
`give a patient with -- intervention in dietary folate supply
`
` 4
`
`and B12, you have a problem with the drug, then I think the
`
` 5
`
`issue is the drug, because patients, normally well cared for
`
` 6
`
`and who are hopefully functioning well despite the cancer,
`
` 7
`
`should have that kind of level in their diet anyway.
`
` 8
`
`So, my argument was -- maybe from a mathematician's
`
` 9
`
`perspective, but my argument was if you intervene in a manner
`
`10
`
`that I had identified, you should be just protecting patients
`
`11
`
`through what normally is the way patients receive this daily
`
`12
`
`folate support. So, I was not concerned. But, everybody
`
`13
`
`around me was, and that was puzzling all along.
`
`14
`
`Q. And your view was that basically the amount of folic acid
`
`15
`
`and vitamin B12 you were proposing was the amount somebody
`
`16
`
`would get if they were healthy and ate a normal, standard
`
`17
`
`diet, so if that was going to make the drug ineffective, then
`
`18
`
`Lilly was going to have a problem anyway, right?
`
`19
`
`A. Yeah, but with an added difference, a fundamental
`
`20
`
`difference. The fundamental difference is that the trouble on
`
`21
`
`the nutritional status of the patient was there; it was just
`
`22
`
`subclinical. So, the clinicians wouldn't pick it up. That
`
`23
`
`was the whole puzzle all along. And even when you had these
`
`24
`
`folates being depleted, it was not to the point where the
`
`25
`
`patient is folate deficient. So, to me, and I think to those
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0020
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 21 of 124 PageID #: 7202
`
`NIYIKIZA - CROSS/WIESEN
`
`Vol. 5-881
`
` 1
`
`who were involved in that whole saga of trying to rescue the
`
` 2
`
`patients and the drug, the pinch link was the observation that
`
` 3
`
`these markers were implicated. Otherwise, it would have been
`
` 4
`
`very difficult to be able to tell which patient is coming and
`
` 5
`
`having problem, which was essentially the problem all along.
`
` 6
`
`So, it's important to keep in mind the fact that we
`
` 7
`
`were able to correct the information and the fact that I was
`
` 8
`
`able to pin down the role of these markers is the one that led
`
` 9
`
`me to the observation, contrary to the mainstream thinking at
`
`10
`
`that time of the experts, that the way to go about this is to
`
`11
`
`just act so that you restore the normal folate pools.
`
`12
`
`Q. Dr. Niyikiza, let's go back to Trial Exhibit 333 for a
`
`13
`
`minute.
`
`14
`
`A. Yes.
`
`15
`
`Q. This was the type A meeting request, right?
`
`16
`
`A. Right, uh-huh.
`
`17
`
`Q. And I want to actually look for a minute at the form.
`
`18
`
`MR. WIESEN: So let's look at the fourth page,
`
`19
`
`13455. If we could pull out the signature block at the bottom
`
`20
`
`and then the text underneath it, so the whole bottom third.
`
`21
`
`BY MR. WIESEN:
`
`22
`
`Q. This document was signed by Greg Brophy, Ph.D., director,
`
`23
`
`U.S. Regulatory Affairs, right?
`
`24
`
`A. Yes.
`
`25
`
`Q. Submitted by Eli Lilly, right?
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1135-0021
`
`

`

`Case 1:10-cv-01376-TWP-DKL Document 325 Filed 09/27/13 Page 22 of 124 PageID #: 7203
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`NIYIKIZA - CROSS/WIESEN
`
`Vol. 5-882
`
` 1
`
`A. Yes.
`
` 2
`
`Q. It's dated January 25th, 2000, correct?
`
` 3
`
`A. Correct.
`
` 4
`
`Q. And there's a specific warning under there, "Warning: A
`
` 5
`
`willfully false statement is a criminal offense," and it cites
`
` 6
`
`the U.S. Code, right?
`
` 7
`
`A. Yes. I can read that, yes.
`
` 8
`
`Q. Let's talk for a minute, Dr. Niyikiza, about what your
`
` 9
`
`training and experience is. I think you said yesterday you're
`
`10
`
`a statistician, right?
`
`11
`
`A. I'm a mathematician with focus in mathematical statistics.
`
`12
`
`Q. Thank you.
`
`13
`
`A. More precisely, actually