Case 1:18-cv-12029-ADB Document 604 Filed 11/14/22 Page 1 of 219
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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 21, 2022
`ELI LILLY AND COMPANY,
` 8:59 a.m.
`
`
` Defendant.
`_______________________________
`
`TRANSCRIPT OF JURY TRIAL DAY 4
`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
`^
`Official Court Reporters
`John J. Moakley U.S. Courthouse
`1 Courthouse Way, Room 5204
`Boston, MA 02210
`joycedebra@gmail.com
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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 21, 2022
`ELI LILLY AND COMPANY,
` 8:59 a.m.
`
`
` Defendant.
`_______________________________
`
`TRANSCRIPT OF JURY TRIAL DAY 4
`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
`^
`Official Court Reporters
`John J. Moakley U.S. Courthouse
`1 Courthouse Way, Room 5204
`Boston, MA 02210
`joycedebra@gmail.com
`
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`Case 1:18-cv-12029-ADB Document 604 Filed 11/14/22 Page 2 of 219
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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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`Case 1:18-cv-12029-ADB Document 604 Filed 11/14/22 Page 5 of 219
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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 21, 2022.)
`THE COURT: So I'm just going through my pending
`motions list, and you guys have the other Teva case. And I'd
`ask that somebody let me know what they want me to do with the
`pending motion while the IPR is going on.
`MS. MARTIN: That's on me, Your Honor. I had to,
`throughout the e-mail to Teva, confer with them about -- our
`position is that the motion is mooted by the amended pleading,
`but I haven't conferred with them on that.
`MS. GRAMMEL: Your Honor, I'm in a position to confirm
`that we also agree that the motion is mooted because Lilly
`amended its counterclaims in a way that renders the motion --
`THE COURT: Music to my ears. Cross one off the list.
`Okay. So we have a few minutes. Not everybody's here. Is
`everyone here that we need?
`MR. KLINE: Yes, Your Honor.
`THE COURT: Anything for this morning?
`MS. GRAMMEL: Yes, Your Honor.
`THE COURT: It's going so well.
`MS. GRAMMEL: I apologize. Your Honor, there is a
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`09:00
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`dispute between the parties with respect to the availability of
`a Lilly witness, Mr. Pettibone. Teva had disclosed clips from
`his deposition to be played on Wednesday evening, I believe;
`and then in response, Lilly informed us they objected to Teva
`playing any of his clips because they will be calling him live
`during their case-in-chief.
`We responded requesting them to confirm his
`availability to testify on Monday or Tuesday, which is a time
`frame in which Teva is expecting to encompass the close of its
`evidence. Lilly responded that they will not make him
`available during that time, but that Teva will be required to
`hold open its case-in-chief until an undisclosed time, at which
`Lilly will choose to call him during their rebuttal case.
`Counsel indicated to us last night when we conferred
`on the issue that they were not able to tell us what that time
`frame was expected to be because they don't know. Teva's
`position is that Mr. Rotterman is unavailable under federal
`Rule of Civil Procedure 32(a)(4) --
`THE COURT: I thought it was Pettibone.
`MS. GRAMMEL: Oh, I apologize. It is Mr. Pettibone.
`Thank you, Your Honor.
`And because he -- there is no dispute he resides and
`currently is more than 100 miles away from the Court,
`Your Honor, and is expected to remain so, at least through the
`conclusion of Teva's case-in-chief.
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`So we would -- given that Lilly is not in a position
`to make him available for live testimony in Teva's
`case-in-chief, we would maintain that he is unavailable and
`that, under Rule 32, that we may play his deposition clips as
`an alternative.
`THE COURT: How long are the clips?
`MS. GRAMMEL: Your Honor, I can get you that answer
`very quickly: 13 minutes and ten seconds.
`THE COURT: Okay.
`MR. O'QUINN: Ms. Garcia Daneshvar will argue for us.
`MS. DANESHVAR: Your Honor, we disagree. We think
`that, under the rules, it is inappropriate for Teva to use his
`testimony by deposition. Mr. Pettibone is not a corporate
`witness, and he is not unavailable. He will be here at trial,
`available to testify live in the coming weeks.
`And we want to point out that, at that time, Teva will
`have the opportunity to examine him by procedures that the
`parties have agreed on this morning, with respect to beyond
`the -- beyond the scope of cross-examination. And I also want
`to note that it wasn't until just a few days ago that Teva
`inquired as to Mr. Pettibone's availability to testify live in
`their case. And he, unfortunately, right now, is just
`unavailable, but he will become available later in this trial.
`MS. GRAMMEL: May I respond very briefly, Your Honor?
`THE COURT: Sure.
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`MS. GRAMMEL: To the extent Your Honor is interested
`in receiving it, I do have a couple of cases on the standard
`for the time at which availability is assessed under Rule 34,
`and it is at the time that the deposition is to be played, not
`at any time during the duration of trial, including in another
`party's presentation of their case.
`THE COURT: Well, I'm not going to overly dig into the
`rule right now, although I can -- one of us can. You can. But
`as you know, my overall philosophy of trials -- that I want you
`guys to try your cases the way you want to try them.
`And if Teva wants to call this guy in their
`case-in-chief as part of their ordinarily presentation and he's
`not available, they can do it by deposition, as far as I'm
`concerned, unless we find case law that squarely tells me I
`can't do it like that. So we'll take a look at that this
`morning.
`
`MS. GRAMMEL: Thank you, Your Honor.
`THE COURT: So --
`MR. O'QUINN: Just one point of clarification,
`Your Honor -- if that were to be the case, I think the cross
`when he appears live would be narrowed to the scope of the
`direct.
`
`THE COURT: Yes.
`MR. O'QUINN: They don't get deposition and beyond
`
`cross.
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`THE COURT: I think that's right.
`MR. O"QUINN: Thank you, Your Honor.
`MS. GRAMMEL: I believe that's our understanding, as
`well, Your Honor.
`THE COURT: Okay.
`MS. GRAMMEL: And one other issue, Your Honor. --
`there is expected to be played in Teva's case today deposition
`clips from the deposition of a Ms. Laura Steele. Under the
`party's agreed-upon stipulation or -- excuse me -- trial
`procedure stipulation, the deadline for Teva to provide its
`objections to Lilly's counterdesignations is one day prior to
`the testimony being played at 7:00 p.m.
`We did identify our objections at that time last
`night. We indicated that we believed that this was untimely
`because the parties had originally believed her testimony would
`be played yesterday. The parties had engaged in a discussion
`around it at that time.
`Teva has taken a very hard look at these objections
`and really wants to only present the ones to Your Honor that
`actually matter. Without having had the benefit of any
`engagement from Lilly about these objections, we still cut our
`objections down by about half. There's a small group of them
`that, Your Honor, we feel are very important to Teva, and we
`would really appreciate the opportunity to be heard on the
`merits of those objections.
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`THE COURT: Where do I have them?
`MS. GRAMMEL: I will hand them up to you, Your Honor.
`I have prepared -- and I will hand to counsel for Lilly.
`May I approach?
`THE COURT: Yes. You don't have to stand up every
`time I enter the room, and you also do not have to ask to
`approach.
`
`MS. GRAMMEL: Thank you, Your Honor.
`MR. O'QUINN: Sydney Kestle will argue for Lilly,
`Your Honor.
`MS. GRAMMEL: So, Your Honor, what you have in front
`of you is a chart that we've prepared. It groups into
`categories that have similar objections that Teva has raised so
`that we can address them efficiently.
`I apologize; this is a lengthier document than I would
`hope to be in the position of handing you. This witness did
`provide impressively long answers at times, so it's mostly a
`function of the length of the counterdesignations, which are
`produced here in full.
`But we are prepared to discuss these in groups so that
`the Court could address them at one. We can present our
`explanation and the basis for our objection. We might respond.
`And then to the extent Your Honor agrees with this procedure,
`we can proceed row by row and address them in that manner.
`THE COURT: Have you guys engaged on these at all?
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`MS. GRAMMEL: No, Your Honor. I did ask Lilly five
`times by e-mail and once when we spoke last night at 10:00 p.m.
`to please engage with the substance on --
`THE COURT: That was not by e-mail.
`MR. O'QUINN: There's a bit more to the story,
`Your Honor.
`THE COURT: Let me ask you -- so when is this witness
`supposed to -- when are these going to be played?
`MS. GRAMMEL: Your Honor, I can grab that --
`MS. KESTLE: Your Honor, if I may --
`MS. GRAMMEL: Yes, Your Honor, this is the third
`witness, so we have the conclusion of Dr. Ravetch's testimony.
`The deposition of --
`THE COURT: Before or after lunch?
`MS. GRAMMEL: I believe it's likely to be after lunch.
`This is going to be two hours in the morning, we think about an
`hour and a half, ballpark, for Dr. Ravetch's conclusion of his
`direct and cross.
`MR. O'QUINN: Yeah, that would be my expectation,
`Your Honor.
`THE COURT: After lunch. Okay.
`MS. KESTLE: If I may, they originally were planning
`to play Ms. Steel's deposition testimony yesterday, on
`Thursday. The parties exchanged designations, counters,
`objections. We all met and conferred on that. We resolved any
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`and all outstanding objections. We prepared a final clip that
`the parties were expecting and ready to play yesterday.
`There were absolutely no objections by Teva that were
`raised yesterday before Your Honor, and at the last minute last
`night, they raised an entire universe of new objections that we
`had not seen before, and we think that those objections have
`been waived.
`MS. GRAMMEL: Your Honor, that is mostly correct. The
`parties did engage in all of the procedures set out in the
`trial procedure stipulation, which were deadlines according to
`the expectation to be played yesterday. Had we played
`yesterday, Teva had every expectation of playing the
`agreed-upon video.
`Teva was able to provide further reflection to the
`counterdesignations, and because the date for the deposition to
`be played slipped to today, the leading deadlines also slipped
`to yesterday, and Teva timely disclosed objections under that
`schedule. Lilly has likewise been proceeding under this
`understanding that the deadlines are keyed off of the expected
`date of the event in court, not the date of the original
`disclosure when -- the day prior to the disclosure of Teva's
`objections last night, on Wednesday.
`In fact, Lilly sent us an e-mail indicating they would
`not be engaging in the deadline for Dr. Blake's testimony that
`day, because her testimony had slipped a day; and they would,
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`therefore, be taking it up the following day.
`THE COURT: Okay. I need to read these. And as you
`know, I have another proceeding here in six minutes. So
`there's no way I'm going to get these read and be able to hear
`this. So if this could be held off until after lunch, I can
`read them during the less gripping portions of this morning,
`and we can have a conversation about if --
`MS. KESTLE: Your Honor, if I may provide a
`supplemental chart that we have with the original --
`THE COURT: Yup.
`So I know -- I understand your views that I don't need
`to read them, but I'd like to read them before we have this
`conversation.
`MS. GRAMMEL: And, Your Honor, if it would be helpful,
`I also can provide a full clip report of the entire universe of
`each of the parties designations so that you can refer to the
`testimony in context, if it would be helpful.
`THE COURT: Sure, if you have it.
`MS. GRAMMEL: I do have it, Your Honor.
`MS. KESTLE: We have one, as well.
`MS. GRAMMEL: You know what? Mine might have notes on
`it. So if you have a clean one, I would actually greatly
`appreciate it, if you wouldn't mind providing it to the Court.
`MS. KESTLE: This was the agreed-upon clip for
`yesterday.
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`THE COURT: And so if I -- if I did, like -- one of
`the mechanics of this, if I did not allow the objection -- or
`if I allow the objection, how would you get the video ready
`for --
`
`MS. GRAMMEL: Your Honor, Teva's hot-seat technician,
`our court technologist, is prepared to make those adjustments.
`We have discussed the universe and have a game plan.
`THE COURT: Okay.
`MR. O'QUINN: We would just ask that we be able to
`review the final clip.
`THE COURT: Yes, and we'll -- and just in terms of the
`jury, I like to sort of be able to give them a little state of
`the state before I send them off on Friday. Do you feel like
`we're on schedule, ahead of schedule, behind schedule? What
`are we doing?
`MS. GRAMMEL: I'm going to defer to Mr. Kline on that,
`Your Honor.
`MR. KLINE: Last night I used the expression "We're
`two days in and three days behind." But I don't think we are,
`Your Honor. We're a little behind where we thought we would
`be, but not more than half a day or so. So I think we're
`generally on track.
`THE COURT: Okay. What do we -- what are we
`attributing the behindness to?
`MR. KLINE: Everything takes a little longer than you
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`think.
`
`THE COURT: Is there anything I'm doing that you feel
`is delaying it in any way?
`MR. KLINE: No, Your Honor. It's on us.
`THE COURT: Okay. Because if there is, I'd like to
`fix it. I feel like we're --
`MR. KLINE: I mean the collective "us." Some of the
`crosses -- I mean, Dr. Abdiche's cross was longer than her
`direct, certainly that previewed that, but I don't think I had
`planned on -- expected that. So things like that. It takes a
`lot longer.
`THE COURT: Okay. I'm trying to start right on time,
`hold the breaks, so -- but if we're slipping and there is
`anything I am doing and I can correct it, I would like to
`correct it.
`MR. KLINE: Sure thing. Thank you, Your Honor.
`MS. GRAMMEL: Thank you, Your Honor.
`THE COURT: Do you have copies of the cases on record?
`MS. GRAMMEL: I certainly do, Your Honor. I have
`highlighted copies. I will provide a copy to counsel for
`Lilly, as well.
`THE COURT: Great.
`(Court in recess at 9:12 a.m.
`and reconvened at 10:06 a.m.)
`(The jury enters the courtroom.)
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`THE COURT: You're going to think I have a different
`excuse every morning. But this morning it was --
`THE DEPUTY CLERK: I already told them.
`THE COURT: Karen's computer crashed. Lynne, our
`hotshot IT person, came up and is now standing guard back there
`just in case it happens again.
`So resume.
`MS. BLAIS: Okay. Thank you, Your Honor.
`THE COURT: And you're still under oath, as I'm sure
`you understand.
`THE WITNESS: Yes. Thank you.
`MS. BLAIS: So yesterday when I read the agreed upon
`exhibits, I missed one. So I'd like to add PTX-1040 to the
`exhibits I'll be using with Dr. Ravetch, and I understand
`there's no objection.
`MR. RAICH: No objection.
`THE COURT: Okay. So that's admitted.
`(Exhibit PTX 1040 received into evidence.)
`JEFFREY RAVETCH, PhD, having been previously duly
`sworn by the Clerk, was further examined and testified as
`follows:
`
`CONTINUED DIRECT EXAMINATION
`
`BY MS. BLAIS:
`Q.
`Good morning, Dr. Ravetch. How are you?
`A.
`Good morning.
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`Case 1:18-cv-12029-ADB Document 604 Filed 11/14/22 Page 17 of 219
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`Okay. And let's turn back to where we left off, which is
`Q.
`with your tutorial.
`MS. BLAIS: And so if we could go to slide 208,
`
`please.
`
`Okay. Is it working?
`TRIAL TECHNICIAN: Sorry.
`BY MS. BLAIS:
`Q.
`Okay. So we'll start with your tutorial. Did you create
`slides to help present a tutorial to the jury today?
`A.
`Yes, I did.
`Q.
`Okay. Let's go, please, to slide 209. What are you
`showing here?
`A.
`So this is a collection of the patents that are being
`discussed today, the '045 patent, the '907 patent, and the '908
`patent, and these are the front pages of each of those patents.
`Q.
`Okay. I'd like to draw your attention to the titles of
`the three Zeller patents, and I believe they're on slide 210.
`Just in very general terms, what do these patents cover?
`A.
`Well, all of these patents cover methods of treatment.
`The '045 title is, "Methods of Using Anti-CGRP Antagonist
`Antibodies." The '907 and '908 are methods for treating
`headache using antagonist antibodies directed against CGRP.
`Q.
`Okay. Now, you've prepared slides describing some of the
`technical words that are mentioned in these titles; is that
`right?
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`Case 1:18-cv-12029-ADB Document 604 Filed 11/14/22 Page 18 of 219
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`4-18
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`Yes, I did.
`A.
`Okay. Let's highlight those words, and then we can go
`Q.
`into your tutorial. So what have you highlighted on this
`slide?
`A.
`Well, the terms that I've highlighted are the terms that
`were construed or defined by the Court for the purposes of the
`infringement analysis, so methods of using -- one term -- CGRP,
`antagonist, and antibody.
`Q.
`Okay. Great. And you mentioned the Court has construed
`these terms. Did you apply the Court's definitions when
`analyzing infringement in this case?
`A.
`Yes, I did.
`Q.
`So let's start with the term "method" and turn to your
`next slide. What are you showing here?
`A.
`So this is the abstract or the summary of the invention
`from the '045 patent, and it instructs the reader that the
`invention features "methods for preventing or treating
`CGRP-associated disorders, such as vasomotor symptoms,
`including headaches," and it lists various types of headaches,
`"by administering an anti-CGRP antagonist antibody." And it
`goes on to describe one of those antibodies, G1, in the patent.
`Q.
`Okay. So let's turn to your next slide and would you
`please describe for the jury what an antibody is.
`A.
`Yeah. So you've been hearing about antibiotics throughout
`the case. I gave a short discussion earlier in my testimony.
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`Case 1:18-cv-12029-ADB Document 604 Filed 11/14/22 Page 19 of 219
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`4-19
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`As I said, antibodies are a type of protein, and they are
`proteins that are produced by the immune system. They are made
`up of chains of amino acids. And amino acids are the chemical
`building blocks of proteins. They are approximately 20 amino
`acids normally found in our bodies, and they are linked
`together in a head-to-tail fashion to determine a protein.
`When you link amino acids together in this way, the
`various chemical differences between the amino acids will
`determine what type of folding occurs, or the shape of the
`final protein. In the case of antibodies, that shape
`determines its function, and one of its functions is to
`recognize and bind to target substances that we call antigens.
`Anything an antibody will bind to is called an antigen.
`Q.
`On the right hand of your slide, you've got a rotating
`image. What is that?
`A.
`So this is a three dimensional depiction of what an
`antibody actually looks like. As I mentioned before,
`antibodies are invisible. They're found in our bodies.
`However, we don't see them. For scientists to be able to
`visualize, techniques have to be developed that will allow the
`three dimensional structure to be determined. And in the case
`of the antibody, the three dimensional structure has this very
`distinctive Y-like shape. There's two arms of the Y, and
`there's the stem of the Y. What you are looking at now are the
`actual atoms that make up this structure, those little bumps
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`Case 1:18-cv-12029-ADB Document 604 Filed 11/14/22 Page 20 of 219
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`4-20
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`represent different atomic structures, and the overall shape is
`what determines the antibody's function.
`Q.
`Now, is there another way that scientists often depict
`antibodies?
`A.
`Yes, as pretty as this picture is, we don't use this in
`our day-to-day work. Instead, we use a little graphic, a
`Y-like graphic. And it's meant to represent the same Y
`structure for the full length or intact antibody. This Y
`structure is composed of four different chains, two of them are
`shaded in green, and two are shaded in blue. The length is --
`determines the name of the chain. So not surprisingly, the
`green chain is called the light chain, and the blue chain is
`called the heavy chain, because they have different weights,
`molecular weights. Now, what's interesting about the antibody
`is at the tips of the Y, you see these little protruding
`finger-like structures. Those are actually loops of amino
`acids that actually make contact with the antigen. And that
`determines how the antibody will interact with the antigen and
`bind to the antigen, and that's the first step in how
`antibodies are going to carry out their biological function.
`Q.
`Now, you talked here about amino acids. Have you prepared
`a slide to illustrate this concept?
`A.
`Yes, I have.
`Q.
`Okay. Let's turn to the next slide, please. What are you
`showing here?
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`Case 1:18-cv-12029-ADB Document 604 Filed 11/14/22 Page 21 of 219
`
`4-21
`
`As I said, amino acids are chemicals. They're the
`A.
`building blocks that are found in our body and, in a protein,
`they are linked together in a head to tail fashion. They are
`20 of them and we use a single letter code to denote each of
`the different amino acids. So A stands for alanine, I for
`isoleucine, C for cysteine, and so forth. So scientists have
`this convention, this shorthand, that they use to communicate
`to each other what a protein structure will be based on the
`chains of amino acids.
`All right. We refer to these linear chains as the
`sequence. Right? We also call it the primary structure. It's
`the beginning of the process by which antibodies ultimately
`find their final shape, which is their structure, and thereby
`their function.
`Q.
`On your slide, you've depicted the amino acid sequence
`here at the top in a straight line. Is that how amino acids
`appear in nature?
`A.
`No, as I said, the different chemical compositions of the
`amino acids will dictate how they'll interact with each other
`in a three dimensional space, and what happens is they fold.
`They fold into these shapes. I've shown just a schematic of a
`type of shape with loops and bends. And proteins, like you saw
`for the antibody, have these very distinctive recognizable
`shapes when the amino acid sequence is dictating their ultimate
`structure.
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`Case 1:18-cv-12029-ADB Document 604 Filed 11/14/22 Page 22 of 219
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`4-22
`
`And do you have an image that shows how folded amino acid
`Q.
`chains look in the context of an antibody?
`A.
`Absolutely. So the next illustration now looks at that
`same antibody structure you saw before, with all the bumps on
`it, but now we're only looking at the peptide chains, the amino
`acid chains that make up the protein structure. And in blue,
`you see the heavy chain, in green, you see the light chain.
`And you can see how these chains are not in a straight line,
`but they're folded and bending on each other, determining
`particular structures that dictate the ultimate shape of the
`molecule.
`Q.
`Now, you mentioned previously that antibodies bind to
`antigens. Have you prepared a slide to summarize that concept?
`A.
`Yes, I have.
`Q.
`Okay. So could you explain what you're showing here?
`A.
`So as I said, the tips of the Y are where the antigen
`binding sites are located on antibodies. In this case, I'm
`showing CGRP as the antigen. And one thing you'll notice right
`away, because we try to draw it to scale, is that the antibody
`is about 30 times larger than CGRP. CGRP is a very small
`protein. We call it a peptide. It's only 37 amino acids long.
`Antibodies are much larger proteins, and they have hundreds of
`amino acids in each of the various chains. So the relative
`sizes will matter. And I think you heard about that from both
`Dr. Zeller and Dr. Abdiche yesterday, that the size of the
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`Case 1:18-cv-12029-ADB Document 604 Filed 11/14/22 Page 23 of 219
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`4-23
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`antigen relative to the antibody is one of the determinates for
`how the antibody will function when it recognizes that antigen.
`Q.
`Now, how does the antibody bind to its antigen?
`A.
`It binds through these particular amino acid sequences
`that are found on the tips of the Y, and we have a name for
`that whole region, we call it the "antigen binding site." But
`each of those little fingers, if you will, are loops of amino
`acids that are found in a portion of the antibody, which is
`called a "variable domain." So the names start to get a bit
`complicated. So antibodies have a region that's variable and a
`region that's relatively constant. And in the variable domain,
`there are sub regions that are hyper variable. All of this
`came from initial studies done 50, 60 years ago, when
`scientists first started to sequence antibodies and determined
`that there were regions that differed between antibodies and
`regions that were relatively conserved. Those variable domains
`turned out to be the regions where the antigen binding sites
`are and those fingers are meant to represent the particular
`hyper-variable regions or as you heard yesterday, the CDR
`loops.
`Q.
`Now, you mentioned that you were also going to talk about
`CGRP. Have you prepared a slide to illustrate that tutorial?
`A.
`Yes, I have.
`Q.
`Okay. And so could you please describe to the jury, what
`is CGRP?
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`Case 1:18-cv-12029-ADB Document 604 Filed 11/14/22 Page 24 of 219
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`4-24
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`So CGRP is the shorthand for calcitonin gene-related
`A.
`peptide. As I said, peptides are short or small amino acid
`sequences. In the case of CGRP, it's 37 amino acids. So that
`small peptide is a neuropeptide, which means released from
`neurons, and it sends biological signals in the body to do a
`variety of functions, including transmit pain and determining
`the blood vessel dilation, or width. All right. In the case
`of headaches, CGRP binds to its receptor, which is another much
`larger protein found on the surface of the muscle cells that
`are lining the blood vessels. And as CGRP binds to its
`receptor, it sends a signal to those cells, because the
`receptor sits both outside the cell, goes through the membrane
`of the cell, into the inside of the cell, and then sends a
`signal to the cell to expand. And when it expands, more blood
`will flow through those blood vessels. And as you've heard
`yesterday, when blood flows into blood vessels, that
`vasodilation is associated with headache pain.
`Q.
`Now, there's an image on the right slide of your slide.
`Where did this image come from?
`A.
`So this image came from the Lilly website, provided to
`physicians and to patients, to describe the product Emgality.
`Q.
`And what's the red structure in the image from Lilly's
`website?
`A.
`So the red structure is the depiction of what CGRP might
`look like. It's a much smaller protein, as we've said. It has
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`Case 1:18-cv-12029-ADB Document 604 Filed 11/14/22 Page 25 of 219
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`4-25
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`this V-like shape. And we're showing CGRP making contact with
`a purple blobby structure, which is the outside portion of the
`CGRP receptor. Remember, the receptor sits outside the cell to
`communicate signals from the outside into the cell, And that's
`the
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