Case 1:18-cv-12029-ADB Document 625 Filed 12/08/22 Page 1 of 188
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`UNITED STATES DISTRICT COURT
`DISTRICT OF MASSACHUSETTS
`
`_______________________________
`TEVA PHARMACEUTICALS
`INTERNATIONAL GMBH and
`TEVA PHARMACEUTICALS USA, INC.,
`
` Plaintiffs, Civil Action
` No. 18-12029-ADB
`
`V.
` October 31, 2022
`ELI LILLY AND COMPANY,
` 8:30 a.m.
`
`
` Defendant.
`_______________________________
`
`TRANSCRIPT OF JURY TRIAL DAY 10
`BEFORE THE HONORABLE ALLISON D. BURROUGHS
`UNITED STATES DISTRICT COURT
`JOHN J. MOAKLEY U.S. COURTHOUSE
`1 COURTHOUSE WAY
`BOSTON, MA 02210
`
`
`
`DEBRA M. JOYCE, RMR, CRR, FCRR
`KRISTIN KELLEY, RPR, CRR
`Official Court Reporters
`John J. Moakley U.S. Courthouse
`1 Courthouse Way, Room 5204
`Boston, MA 02210
`joycedebra@gmail.com
`
`
`
`10-1
`
`UNITED STATES DISTRICT COURT
`DISTRICT OF MASSACHUSETTS
`
`_______________________________
`TEVA PHARMACEUTICALS
`INTERNATIONAL GMBH and
`TEVA PHARMACEUTICALS USA, INC.,
`
` Plaintiffs, Civil Action
` No. 18-12029-ADB
`
`V.
` October 31, 2022
`ELI LILLY AND COMPANY,
` 8:30 a.m.
`
`
` Defendant.
`_______________________________
`
`TRANSCRIPT OF JURY TRIAL DAY 10
`BEFORE THE HONORABLE ALLISON D. BURROUGHS
`UNITED STATES DISTRICT COURT
`JOHN J. MOAKLEY U.S. COURTHOUSE
`1 COURTHOUSE WAY
`BOSTON, MA 02210
`
`
`
`DEBRA M. JOYCE, RMR, CRR, FCRR
`KRISTIN KELLEY, RPR, CRR
`Official Court Reporters
`John J. Moakley U.S. Courthouse
`1 Courthouse Way, Room 5204
`Boston, MA 02210
`joycedebra@gmail.com
`
`
`
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`APPEARANCES:
`FOR THE PLAINTIFFS:
`DOUGLAS J. KLINE, ESQ.
`ELAINE HERRMANN BLAIS, ESQ.
`ROBERT FREDERICKSON, III, ESQ.
`ERIC T. ROMEO, ESQ
`MOLLY GRAMMEL, ESQ.
`JOSHUA S. WEINGER, ESQ.
`KEVIN P. MARTIN, ESQ.
`TARA ROSE THIGPEN, ESQ.
`Goodwin Procter, LLP
`100 Northern Avenue
`Boston, MA 02210
`617-570-1000
`dkline@goodwinlaw.com
`eblais@goodwinlaw.com
`rfrederickson@goodwinprocter.com
`eromeo@goodwinprocter.com
`mrhodes@goodwinprocter.com
`kmartin@goodwinprocter.com
`jweinger@goodwinprocter.com
`tthigpen@goodwinlaw.com
`NATASHA E. DAUGHTREY, ESQ.
`SEAN M. ANDERSON, ESQ.
`Goodwin Procter LLP
`601 S. Figueroa Street
`Los Angeles, CA 90017-5704
`213-426-2500
`NDaughtrey@goodwinlaw.com
`AUDIE SOUCY, ESQ.
`GRACE PEACE TRUONG, ESQ.
`GABRIEL BRUNO FERRANTE, ESQ.
`Goodwin Procter LLP
`New York Times Bldg
`620 8th Ave
`New York, NY 10018
`212-813-8100
`MADELINE DiLASCIA, ESQ.
`Goodwin Procter, LLP
`1900 N St NW
`Washington, DC 20036
`202-346-4000
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`FOR THE DEFENDANT:
`CHARLES E. LIPSEY, ESQ.
`RYAN P. O'QUINN, ESQ.
`Finnegan,Henderson,Farabow,Garrett & Dunner, LLP.
`1875 Explorer Street
`Reston, VA 20190
`571-203-2700
`charles.lipsey@finnegan.com
`oquinnr@finnegan.com
`EMILY R. GABRANSKI, ESQ.
`MARTA GARCIA DANESHVAR, ESQ.
`OULU (LULU) WANG, ESQ.
`Finnegan, Henderson, Farabow, Garrett & Dunner, LLP
`Two Seaport Lane, 6th Floor
`Boston, MA 02210-2001
`202-408-4331
`emily.gabranski@finnegan.com
`marta.garcia@finnegan.com
`lulu.wang@finnegan.com
`PIER D. DeROO, ESQ.
`DANIELLE A. DUSZCZYSZYN, ESQ.
`J. MICHAEL JAKES, ESQ.
`SYDNEY R. KESTLE, ESQ.
`YOOJIN LEE, ESQ., PhD.
`MATTHEW J. LUNEACK, ESQ.
`WILLIAM B. RAICH, ESQ.
`DENISE MAIN, ESQ.
`Finnegan, Henderson, Farabow, Garrett & Dunner, LLP
`901 New York Avenue Northwest
`Washington, DC 20814
`202-408-4418
`pier.deroo@finnegan.com
`danielle.duszczyszyn@finnegan.com
`mike.jakes@finnegan.com
`matthew.luneack@finnegan.com
`william.raich@finnegan.com
`denise.main@finnegan.com
`ANDREA L. MARTIN, ESQ.
`Burns & Levinson LLP
`125 Summer Street
`Boston, MA 02110
`617-345-3000
`amartin@burnslev.com
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`ALSO PRESENT:
`FROM TEVA PHARMACEUTICALS:
`Jo Hilliard, Esq.
`Lori Wolf, Esq.
`Colman Ragan, Esq.
`FROM ELI LILLY:
`Christalyn Rhodes, PhD
`Gerry Keleher, Esq.
`Pat Hastings
`Mira Mulvaney, Esq.
`Amanda Walter
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`P R O C E E D I N G S
`(The following proceedings were held in open
`court before the Honorable Allison D. Burroughs, United States
`District Judge, United States District Court, District of
`Massachusetts, at the John J. Moakley United States Courthouse,
`1 Courthouse Way, Boston, Massachusetts, on October 31, 2022.)
`THE COURT: You're both standing up so I take you have
`something on your mind.
`MR. KLINE: Some easy things.
`THE COURT: Famous last words.
`MR. KLINE: I think the first one is easy, your Honor.
`We have an agreed list of acronyms. So I can -- we've
`got them tabbed for the jurors. So do you want to just leave
`it here and we can hand it out?
`THE COURT: Karen can hand them out, that would be
`
`great.
`
`MR. KLINE: I'll just leave those here, your Honor.
`THE COURT: Yes.
`MR. KLINE: You know, we still have pending this
`timing issue. Mr. Lipsey and I had some back-and-forth
`yesterday, but I don't think we reached a resolution. I'll
`leave this here, your Honor. This is -- we've been handing out
`this running document. So that's what that is.
`I think where the parties have been -- it's our view
`we should be prepared to close on Monday the 7th. Mr. Lipsey
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`obviously can speak for himself, but he suggested maybe closing
`on Wednesday the 9th. I thought that was too late. Offered
`maybe we could compromise to Tuesday the 8th.
`(Discussion off the record.)
`MR. KLINE: So I just want to identify that for the
`Court, your Honor, because obviously it's important for all of
`us to know what our schedule is.
`And then, with regard to objections and such, I think
`the -- mindful that the jury -- we're supposed to begin that in
`ten minutes, I think your second live witness is Dr. or
`Ms. Ramseyer, and there are some objections to her exhibits.
`Then there are some deposition designations. There are more
`objections to Dr. McDonnell's slides and such; that could
`probably wait until the break, but we should probably try to
`decide the Ramseyer objections before we start because we
`expect she would come on before the break.
`MR. LIPSEY: Your Honor, some of the timing issue is
`that we're experiencing some difficulties. We got a mountain
`of objections last night, to almost every line of the
`deposition testimony of their own witnesses, almost every
`demonstrative exhibits, and some of these are depositions that
`we were planning on reading in this morning. Some of it is
`they are trying to relitigate the motion in limine that your
`Honor made about post-trial matters bearing on enablement.
`They're trying to relitigate your decision -- your denial of
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`their motion on judicial estoppel, and we need some guidance
`and some assistance on how to productively work through these
`things, or we're never going to get our case in.
`THE COURT: The way you characterized it, they
`shouldn't be doing those things, but I'm sure there's another
`side to that.
`MR. KLINE: There certainly is, your Honor. What I
`would say is none of that -- they constantly -- from our
`perspective, they make disclosures, they make designations,
`they make -- they disclose demonstratives, they're very
`objectionable. We have a process. I would say this group of
`people spends all night long resolving many of those issues,
`and by the time we show up in court each morning, more often
`than not, most of those issues have been resolved.
`There is a way to streamline that, which is not to do
`things that are objectionable; that's our position. We even
`offered to move up some of the scheduling on these half days,
`and they said they didn't want to do that.
`Be that as it may, your Honor, that doesn't bear on
`timing on the court day because these processes would reduce
`the amount of evidence that is coming in that, in our view, is
`objectionable and would shorten the time --
`THE COURT: Are we arguing about the timing now --
`because I'm going to put that off -- or we arguing about the
`designations for today --
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`MR. LIPSEY: We have a lot of disputes that bear on
`the evidence that was supposed go in this morning.
`THE COURT: So let's take the six minutes to start
`resolving those and see how far we can get.
`MR. KLINE: I would do Ms. Ramseyer first because I
`think she's likely to come up before the break.
`MR. RAICH: I think that's an appropriate place to
`start. There are some issues that just cut across many of
`these things, for example, their blanket objection to the use
`of post-filing evidence relating to Section 112, which is just
`applying to many, many different witnesses. We think that's
`already been litigated. We're prepared to stand here and argue
`it again, but that is a common issue across many of the
`objections, I mean, the blizzard of objections that we received
`last night. So that is one issue.
`THE COURT: Let's take the blanket objections, the
`big-ticket issues and save them until 1:00. We have some extra
`time today because they're leaving at 1:00. Let's just do what
`we need to do to get through this morning.
`MR. KLINE: That would be Ms. Ramseyer, I think.
`MS. GABRANSKI: Your Honor, there are three
`exhibits --
`MS. THIGPEN: Your Honor, they're Teva's objections.
`I would appreciate if we could, perhaps, go first to preview
`the issue.
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`THE COURT: They're their exhibits. I thought they
`were going to explain to me what they are, but if you want to
`go first you can. But start talking because we now only have
`four minutes.
`MS. THIGPEN: Sure. I only have two pages of 18 point
`font, I think I can do this pretty quickly.
`Can we approach with the transcript portions.
`Good morning, your Honor, Tara Thigpen on behalf of
`
`Teva.
`
`Teva objects, as Ms. Gabranski said, to three of the
`exhibits that Lilly intends to admit through Dr. Ramseyer's
`testimony. The objections for all three of these exhibits
`relate to the same issue: That Dr. Ramseyer disclaimed
`knowledge of the topics contained in these documents in her
`deposition.
`Your Honor, Lilly designated Dr. Ramseyer as a
`30(b)(6) representative for three journal topics: Those
`portions of the BLA that Lilly agreed to produce, the
`supplements and amendments to those portions, and the
`supplemental BLA application for episodic cluster headache.
`And these three exhibits can be broken down, generally, into
`two buckets that I am going to address very briefly for you.
`The first bucket is TX 5092, which I believe you have
`in front of you, that's Lilly's initial IND submission for
`galcanezumab. When asked about this initial IND submission,
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`Dr. Ramseyer testified that not only was she not involved, she
`had not been involved in any initial submissions, but that she
`couldn't even opine who was involved in that initial
`submission.
`The second bucket covers Exhibits 5093 and 5094, which
`are generally correspondences to the FDA about the change in
`galcanezumab IND from Lilly to Artaeus and Artaeus back to
`Lilly. When asked in her deposition if she was aware that
`Lilly had licensed galcanezumab to an entity called Artaeus,
`Dr. Ramseyer responded that she was not aware. And this is
`precisely the situation that this Court has addressed in the
`context of 30(b)(6) generally and others have addressed
`directly.
`30(b)(6) required that Dr. Ramseyer have viewed
`materials known or reasonable available to her. And the
`requirement is twofold behind that rationale, it's so that we
`could have a meaningful deposition and to prevent sandbagging
`of an opponent by conducting a halfhearted inquiry before the
`deposition but a thorough and vigorous one before trial.
`Teva was not able to meaningfully question
`Dr. Ramseyer at her deposition, and it would be extremely
`prejudicial to allow them to come in through her testimony now.
`Thank you.
`MS. GABRANSKI: Your Honor, these are official
`documents. They're letters to FDA, they're kept in a central
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`repository. We're not intending to have Dr. Ramseyer opine
`broadly about these. She's largely just an authenticating
`witness when it comes to these documents. To the extent --
`last night on the meet and confer, Teva took the position that
`Dr. Ramseyer would have to have personal knowledge or had to
`have been involved in the drafting or creation of these
`documents in order for her -- for them to be admissible, which
`is not something that we're aware of in the case law.
`We asked for any authority on the call last night, and
`they provided authority to you, but apparently didn't provide
`it to us.
`The records are -- Dr. Ramseyer in her testimony will
`testify that the records are maintained in the central
`regulatory affairs repository, that she had access to these,
`that when she took the role in 2017 that she would have
`reviewed these documents, but she's not providing substantive
`testimony about, like, the contents of these documents. She's
`primarily just admitting them and will leave the content to
`what's on the face of the documents.
`THE COURT: Well, is it really -- is there a
`dispute -- forget about through this witness, is there a
`dispute that these documents are admissible?
`MS. THIGPEN: I don't believe so, your Honor.
`THE COURT: So why don't we just admit them.
`MS. GABRANSKI: That would -- Lilly would like that,
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`thank you.
`THE COURT: Then we won't ask this witness about them
`at all. Okay?
`MS. GABRANSKI: With respect to 5092, we had a
`question about what would be included typically in an IND
`submission. Can we ask that question either with reference to
`this exhibit or more broadly?
`MS. THIGPEN: Your Honor, I think for Dr. Ramseyer to
`opine on topics that we weren't able to question her on at her
`deposition would be entirely inappropriate.
`THE COURT: I mean, you're telling me that she
`testified she didn't know anything about this IND, and -- but
`you don't want her even to testify as to what an IND is?
`MS. THIGPEN: Well, we had asked her if she was
`involved in any other initial IND submissions and she said she
`was not, so the line of questioning stopped there.
`THE COURT: She might still know what they are.
`MS. THIGPEN: She might, your Honor.
`THE COURT: So I think that question is okay, but not
`in reference to this document.
`MS. GABRANSKI: Thank you, your Honor.
`MS. THIGPEN: Thank you, your Honor.
`MR. RAICH: Your Honor, there are also videos to be
`played this morning, and I think that there are pending
`objections related to this.
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`Again, this issue about the use of post-filing
`evidence is, I think, relevant to many of the objections. My
`colleague, Ms. Lee, is prepared to discuss them in more detail.
`THE COURT: Are you going to play that before or after
`the break?
`MR. RAICH: I guess it depends on exactly when the
`break occurs --
`THE COURT: 11:00.
`MR. RAICH: 11:00?
`MR. LIPSEY: There's one deposition that only involves
`two documents which I think we could clean up in two minutes.
`THE COURT: Okay.
`MR. LIPSEY: And that's Dr. Bonhauf and Dr. Rosenthal,
`there were two documents that were objected to.
`And one of them is Plaintiffs' Trial Exhibit 1991,
`it's a letter where -- it's addressed to him and Dr. Zeller,
`and it's the people making the antibodies for them that say we
`should immunize with the full length CGRP, and this shows where
`the programs of Lilly and Rinat diverged.
`He's an addressee on it.
`The other is a -- another one of the Rinat slide
`decks, Trial Exhibit 3394, relating to this CSD experiment.
`Dr. Rosenthal's fingerprints are all over the CSD
`experiment based on evidence already in the record. And this
`is the genesis of concern by the group that they need to test
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`the BIBN molecule to see whether it works there, and that is
`carried through into other documents that Dr. Rosenthal
`reviewed, and he ultimately instructed his people not to do
`that experiment. So we think it's clearly something within the
`scope of his knowledge. He testified he was the leader of the
`band, it's plainly a business record. It is on a topic that he
`was intimately familiar with and we think it should be
`received.
`THE COURT: Was he going to say he's seen this slide
`deck before?
`MR. LIPSEY: I asked him whether it was in the form of
`a Rinat slide deck, and he said yes.
`MS. DAUGHTREY: Your Honor, in reference to Exhibit
`3394, the slide deck you're referring to, I'll just hand up
`some -- the relevant deposition testimony on this.
`So on this exhibit, it begins on the bottom of page
`150 of his testimony at line 20. He's shown the document and
`is asked: "Is this in the form of a Rinat presentation,
`correct?"
`And he says: "Yes."
`If you would turn to a page 15530, under the heading
`"Cortical Spreading Depression," he just reads -- the question
`is reading in what the title says, and Dr. Rosenthal says:
`"That's what it says on the presentation. I don't know who
`made it."
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`And then he's made representations about the fact that
`this was actually a document from Mr. Poulsen, and that's the
`end of the questioning.
`He was not asked questions: Do you recognize this?
`What was it? Were you familiar with it?
`He says he doesn't know who wrote this relevant
`sentence that they're going to try and have read into the
`record.
`
`Essentially counsel asked him sentences from this
`document and said, "Do you see that?" And he said, "Yes, it's
`there, but I don't know who wrote it."
`So I don't think they've laid the proper foundation
`based on the testimony or having that document come in to
`evidence based on Dr. Rosenthal's testimony.
`The other document, Exhibit 1991, Dr. Rosenthal was
`
`asked --
`
`THE COURT: Are they all here?
`THE CLERK: Yes.
`MS. DAUGHTREY: -- "Do you see that it's addressed to
`you and Dr. Zeller?" And he just says, "Yes."
`Then when he's asked substantive questions about that
`Zymed document, well, the only substantive question he's asked,
`he doesn't -- he can't really testify substantively about the
`document. It's literally just counsel reading in snippets from
`the Zymed document and saying, "Do you see that?" and he says,
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`"Yes."
`
`THE COURT: The one that's addressed to him I think
`comes in and they can ask him about.
`The slide deck, I mean, there's not -- if he were here
`live, we could try to lay a foundation, but there isn't a
`foundation for it at the moment.
`I think that you could ask him, if that statement
`appeared in a slide deck, does he agree or disagree with it,
`right?
`
`Oh, he's not here.
`MS. DAUGHTREY: He's not here. This is the only thing
`that we have, your Honor.
`THE COURT: So --
`MR. LIPSEY: I mean, by way of foundation, your Honor,
`he original -- the documents in evidence show he originally
`said, Do this dermal vasodilation and then do CSD. His
`lieutenant said, Oh, no, the CSD is more important.
`He then says, Do CSD and then do vasodilation.
`So the experiment is done, it fails, the report of the
`failure is sent to Dr. Rosenthal.
`Dr. Rosenthal then receives -- later on, he's
`participating in a presentation to the RRC where they say, Oh,
`boy, if BIBN and our antibody don't work in the same place,
`we're going to have to terminate everything, we suggest doing
`this experiment comparing them in CSD.
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`Case 1:18-cv-12029-ADB Document 625 Filed 12/08/22 Page 17 of 188
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`10-17
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`Rosenthal responds, in documented evidence, Don't do
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`it.
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`So he clearly is intimately involved from start to
`finish with the CSD assay, and that's what this is about. It's
`unquestionably a business record of Rinat on that topic, and we
`think it should come into evidence.
`MS. DAUGHTREY: Your Honor, also, the other person
`that's on this document is Joerg Zeller, who was here, and they
`could have asked him about this document. He's the one that
`would have actually been involved in these experiments.
`THE COURT: Are you still talking about the slide deck
`or are you back to the other exhibit?
`MS. DAUGHTREY: I'm back to the other exhibit.
`THE COURT: The other exhibit is addressed to him,
`it's going to come in.
`But the slide deck --
`MS. DAUGHTREY: So, your Honor, just to make sure I
`understand. So even if he -- if it is addressed to him --
`THE COURT: Guys, now the jury is outside the door,
`this has gone on longer than two minutes. We'll take it up at
`the break.
`Come on in, Karen.
`THE CLERK: All rise for the jury.
`(Jury entered the courtroom.)
`THE CLERK: Court is in session. Please be seated.
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`Case 1:18-cv-12029-ADB Document 625 Filed 12/08/22 Page 18 of 188
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`10-18
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`THE COURT: Happy Halloween.
`I like the orange back there in the second row, two of
`
`JUROR: Thank you.
`THE COURT: I guess the black in the front row counts,
`
`you.
`
`too.
`
`All right. When you're ready, you can resume.
`RYAN DARLING, Ph.D., having been previously duly sworn
`by the Clerk, was further examined and testified as follows:
`CONTINUED DIRECT EXAMINATION
`
`BY MR. RAICH:
`Q.
`Good morning, Dr. Darling, welcome back.
`A.
`Good morning.
`Q.
`On Friday afternoon we were discussing Figure 1 in Exhibit
`3082.
`
`MR. RAICH: Sam, can you bring that back up.
`And, Dr. Darling, just to bring things up to speed a
`Q.
`little bit, you were discussing generally the challenges
`experienced in making galcanezumab as reflected in this Figure
`1 in your report, and you were discussing an antibody in
`particular called CE11-37.
`Do you recall that?
`Yes.
`A.
`And could you just briefly remind the jury what some of
`Q.
`the issues were that you experienced with CE11-37.
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`Case 1:18-cv-12029-ADB Document 625 Filed 12/08/22 Page 19 of 188
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`10-19
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`Yes. CE11-37 was a variant that we had improved the
`A.
`affinity at 37 degrees. We talked about the importance of that
`with being active at body temperature. But we then uncovered a
`whole series of other problems with the solubility of CE11-37.
`So that was, I think, approximately where we had wrapped up.
`Q.
`And did you prepare a document summarizing these
`solubility challenges that you observed with CE11-37?
`A.
`Yes, I described how we approached the problem we faced
`with CE11-37 as well as the ideas we had to resolve those
`issues.
`
`MR. RAICH: Sam, could you pull up PTX 1406 and in
`particular slide 27.
`Q.
`Dr. Darling, is this your summary slide?
`A.
`Yes, it is. I prepared this.
`Q.
`What does the top half of slide 27 of PTX 1406 show?
`A.
`Yeah, there's a lot of information on here, so let's step
`through this. If I can focus you to the upper table, there's
`two antibodies there called CE7 and CE11-37, so the 11-37 is
`the antibody we've been discussing that had high affinity.
`If you look to the far right under "Affinity" where it
`says 18 picomolar, or pM, that's the high affinity that we
`desired to have in our antibody.
`If you look at the CDR of each two sequence of 11-37,
`it differs by only two amino acids -- and each of those letters
`represents an amino acid -- compared to the antibody shown in
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`Case 1:18-cv-12029-ADB Document 625 Filed 12/08/22 Page 20 of 188
`
`10-20
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`the line above it, which is CE7.
`So those two amino acids are responsible for the
`higher affinity that we achieved, that I showed you on the
`right column, the 18 picomolar versus 200 picomolar, but they
`also resulted in the poor solubility. If you look at the
`column labeled "Solubility" in Citrate pH 6, you can see 11-37
`has a low number of 1.2 versus greater than a hundred for the
`CE7 antibody.
`So that is the solubility problem I was describing to
`
`you.
`
`Out of these two antibodies in particular, there's a
`total of 659 amino acids in the light chain and heavy chain,
`and out of those 659 amino acids, there's only two differences,
`and those are the two residues I've shown you here. And so you
`can see from this how just subtle changes in the antibody can
`have a dramatic impact on the behavior of that antibody.
`Q.
`Why was solubility important?
`A.
`Solubility is an important factor because you need to be
`able to concentrate enough antibody into solution so that
`eventually when we move into the clinic you could prepare it,
`administer to patients, and test it for whatever indication we
`would be pursuing.
`Q.
`And what's shown in the bottom half of PTX 1406?
`A.
`The bottom half describes how we overcame the problems
`with CE11-37.
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`Case 1:18-cv-12029-ADB Document 625 Filed 12/08/22 Page 21 of 188
`
`10-21
`
`I'll focus you to the lower left. And these images
`here we sometimes call blueberries and tomato images for
`obvious reasons.
`This is a computer-generated image of the binding
`domain of CE11-37 shown there. The thing you should know is
`that the blue colors represent positive amino acids and the red
`colors represent negative amino acids. And so they're opposite
`charges.
`The right side of this figure shows a large red node
`projecting from the surface. So there's a lot of negative
`charge on one side of the molecule. And we thought that could
`be contributing to the poor solubility.
`Q.
`And so what did you do about the poor solubility of
`CE11-37?
`A.
`So that hypothesis of the imbalance of the surface charge,
`we sought put to better balance that. If you look at the image
`right below CE11-37, that molecule that's labeled "J7," you can
`now see that the red and blue is more evenly distributed across
`the molecule, so the positive and negative charge is more
`balanced. And you can see there's three arrows pointing to
`that molecule, and those are three of the changes we made that
`reversed charges. So, for example, if it had a negative charge
`in the CE11-37, we could change that to a positive charge to
`better distribute that positive and negative charge across the
`surface.
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`Case 1:18-cv-12029-ADB Document 625 Filed 12/08/22 Page 22 of 188
`
`10-22
`
`And then, the results of that change, if you look in
`the lower right portion of this slide, you can see the
`solubility in Citrate pH 6 for J7 is now greater than 205
`milligrams per milliliter and we started at 1.2.
`So, again, a few changes in the right positions
`dramatically improved the behavior of J7; and, importantly, we
`maintained a high affinity of 31 picomolar versus the
`18 picomolar in the far right column there.
`Just to be clear, what we're referring to as J7 here
`in this figure is the galcanezumab antibody.
`Q.
`Thank you, Dr. Darling.
`Could we turn back to Exhibit 3082.
`And your flow chart ends with LA468-J7. Is there
`another name for LA468-J7?
`A.
`Yes, that is galcanezumab that we took forward into
`development and that was ultimately approved.
`Q.
`Your flow chart is a linear diagram from top to bottom.
`Does this reflect a straightforward discovery process for
`galcanezumab?
`A.
`No, this is better described as a high-level summary of a
`lot of work that occurred over a long period of time.
`Each box here represents sort of an example of a
`representative molecule as we went through the major steps of
`trying to discover galcanezumab.
`And we have talked about a few of these here, like,
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`Case 1:18-cv-12029-ADB Document 625 Filed 12/08/22 Page 23 of 188
`
`10-23
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`for example, CE11-37. There would have been other variants as
`well that we made at that step. So this just highlights some
`key molecules along that journey.
`Q.
`How long did it take to make galcanezumab?
`A.
`The immunizations, which are represented here at the top
`of this, were approximately in 2005. We declared galcanezumab
`the single molecule we selected to move into the clinic in
`December of 2009. So it was approximately five years' worth of
`work to get from the top box to the bottom box in this figure
`that you see.
`Q.
`How many people were involved?
`A.
`There would have been dozens of scientists involved with
`varying backgrounds and levels of expertise to make all of this
`happen.
`Q.
`Any estimate as to the cost involved?
`A.
`I don't know the cost for this particular project, but I
`did manage projects like this for several years in a job that I
`had following this, and I'd say it's average --
`MR. KLINE: Objection, your Honor, lack of foundation.
`Beginning of the answer.
`THE COURT: Sustained.
`BY MR. RAICH:
`Q.
`We'll move on.
`Dr. Darling, let's turn to Trial Exhibit 3079. I want
`to discuss galcanezumab itself.
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`Case 1:18-cv-12029-ADB Document 625 Filed 12/08/22 Page 24 of 188
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`10-24
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`MR. RAICH: Sam, could you project 3079.
`And, Dr. Darling, what is this document?
`Q.
`This is a report that describes the binding kinetics and
`A.
`affinity of galcanezumab to rat and human CGRP.
`Q.
`And in the title, what does the name LY2951742 refer to?
`A.
`That refers to the candidate molecule we had selected to
`go into the clinic, and it's galcanezumab.
`Q.
`And what does the "LY" prefix mean?
`A.
`So at Lilly, prior to picking a molecule to move into the
`clinic, that number would still be 2951742, but the letters
`before it would be LSN, which stands for Lilly's serial number,
`it's just a unique identifier for that molecule.
`When the company declares a candidate to move into
`development and clinical testing, that LSN changes to LY. So
`here it's referred to LY because we had selected that molecule.
`Q.
`And what does it mean to be selected as a clinical
`candidate?
`A.
`That means that the governing body that makes these
`decisions at Lilly has decided that, you know, the team has
`generated a sufficient data package and a compelling case for
`the company to continue to invest more money to move it out of
`our laboratories in discovery and into clinical trials.
`Q.
`In the title of TX 3079, what are binding kinetics?
`A.
`Yeah, if you think about an antibody binding to a peptide
`in solution, binding kinetics are how fast and how slow that's
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`Case 1:18-cv-12029-ADB Document 625 Filed 12/08/22 Page 25 of 188
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`10-25
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`happening.
`So there's two different binding kinetics. One is
`what we call on-rate and one is what we call off-rate.
`If you think about how fast or slow the antibody binds
`to the peptide and holds onto it, that's called on-rate.
`Off-rate is after it's already bound to the peptide, how long
`does it hold onto it before it falls back apart.
`So when antibodies are binding to their target,
`they're sort of an on and off of that binding. And so the
`kinetics determine how fast and slow that process is occurring.
`Q.
`If we turn to page 6, and there's a heading, "Surface
`Plasmon Resonance Assay (Biacore)." Can you explain what that
`is.
`This here is basically a detailed description of how you
`A.
`would conduct an experi
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