Transcript of Andrew F. Calman, M.D., Ph.D.
`
`Tuesday, April 5, 2022
`
`Regeneron Pharmaceuticals, Inc. v. Novartis Pharma AG
`
`www.trustpoint.one
`www.aldersonreporting.com
`800.FOR.DEPO (800.367.3376)
`Scheduling@Trustpoint.One
`
`Reference Number: 114766
`
`Regeneron Exhibit 1208.001
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Tuesday, April 5, 2022
`
`Regeneron Pharmaceuticals, Inc. v. Novartis Pharma AG
`
`www.trustpoint.one
`www.aldersonreporting.com
`800.FOR.DEPO (800.367.3376)
`Scheduling@Trustpoint.One
`
`Reference Number: 114766
`
`Regeneron Exhibit 1208.001
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
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` UNITED STATES PATENT AND TRADEMARK OFFICE
`
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
` - - - - - - - - - - - - - - - - -x
`
` REGENERON PHARMACEUTICALS, :
`
` INC., : Case No.
`
` Petitioner, : IPR2021-00816
`
` v. :
`
` NOVARTIS PHARMA AG, et al., : Patent No.
`
` Patent Owners. : 9,220,631
`
` - - - - - - - - - - - - - - - - -x
`
`
`
` Tuesday, April 5, 2022
`
` Deposition of ANDREW F. CALMAN, M.D., PH.D.,
`
` a witness herein, called for examination by counsel
`
` for the Petitioner in the above-entitled matter,
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` pursuant to notice, the witness being duly sworn by
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` JOAN V. CAIN, a Notary Public in and for the
`
` Commonwealth of Virginia, taken remotely via Zoom at
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` 12:49 p.m. Eastern Daylight Time, Tuesday,
`
` April 5, 2022, and the proceedings being taken down
`
` by Stenotype by JOAN V. CAIN, Court Reporter, and
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` transcribed under her direction.
`
`www.trustpoint.one
`www.aldersonreporting.com
`
`800.FOR.DEPO
`(800.367.3376)
`Regeneron Exhibit 1208.002
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 2
`
` A P P E A R A N C E S
`
` On Behalf of Petitioner:
`
` CHRISTOPHER PEPE, ESQ.
`
` MATTHEW D. SIEGER, ESQ.
`
` Weil Gotshal & Manges LLP
`
` 2001 M Street, Northwest
`
` Washington, D.C. 20036
`
` Telephone: (202) 682-7000
`
` E-mail: christopher.pepe@weil.com
`
` matthew.sieger@weil.com
`
` -AND-
`
` ANDREW PETER GESIOR, ESQ.
`
` Weil Gotshal & Manges LLP
`
` 767 Fifth Avenue
`
` New York, New York 10153-0119
`
` Telephone: (212) 310-8000
`
` E-mail: andrew.gesior@weil.com
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`www.trustpoint.one
`www.aldersonreporting.com
`
`800.FOR.DEPO
`(800.367.3376)
`Regeneron Exhibit 1208.003
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 3
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` A P P E A R A N C E S C O N T I N U E D
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` On Behalf of Patent Owners:
`
` JOHN BENNETT, ESQ.
`
` Allen & Overy, LLP
`
` One Beacon Street
`
` Boston, Massachusetts 02108
`
` Telephone: (857) 353-4500
`
` E-mail: john.bennett@allenovery.com
`
` ALSO PRESENT:
`
` Petra Scamborova, Esq.
`
` Regeneron Pharmaceuticals, Inc.
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`www.trustpoint.one
`www.aldersonreporting.com
`
`800.FOR.DEPO
`(800.367.3376)
`Regeneron Exhibit 1208.004
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 4
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` C O N T E N T S
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` WITNESS EXAMINATION BY COUNSEL FOR
`
` Andrew F. Calman, M.D., Ph.D. Petitioner
`
` By Mr. Pepe 5
`
`PREVIOUSLY MARKED EXHIBITS REFERENCED
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`EXHIBIT NO. 2204 Declaration of Andrew F. 6
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` Calman, M.D., Ph.D., in
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` Support of Patent Owner
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` Response, 1/18/22
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`www.trustpoint.one
`www.aldersonreporting.com
`
`800.FOR.DEPO
`(800.367.3376)
`Regeneron Exhibit 1208.005
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 5
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` P R O C E E D I N G S
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` - - -
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` 12:49 p.m.
`
` April 5, 2022
`
` - - -
`
` ANDREW F. CALMAN, M.D., PH.D.,
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` having been duly sworn under penalties of perjury by
`
` the Notary Public, was examined and did testify as
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` follows:
`
` THE COURT REPORTER: Thank you.
`
` Please begin.
`
` EXAMINATION BY COUNSEL FOR PETITIONER
`
` BY MR. PEPE:
`
` Q All right. Good morning, Dr. Calman.
`
` A Good morning.
`
` Q Now, you understand that you're here today
`
` for a deposition for a declaration that you
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` submitted in IPR2021-00816 concerning U.S. Patent
`
` No. 9,220,631?
`
` A I do. And if I could ask you to turn your
`
` volume up slightly, please.
`
` Q Okay. Are you having trouble hearing me?
`
`www.trustpoint.one
`www.aldersonreporting.com
`
`800.FOR.DEPO
`(800.367.3376)
`Regeneron Exhibit 1208.006
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 6
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` A Minimally.
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` Q Okay.
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` MR. BENNETT: We're going to turn up the
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` speakers a little bit. So we'll see if that's a
`
` little better.
`
` BY MR. PEPE:
`
` Q All right. So you should have a box of
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` exhibits with you. Do you have that near you?
`
` A Yes.
`
` Q Okay. So you can go ahead and take out the
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` exhibit labeled Exhibit 2204.
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` A Okay.
`
` Q All right. And can you -- do you have that
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` in front of you now?
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` A Yes.
`
` Q All right. Do you recognize that as a
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` declaration that you submitted in this proceeding?
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` A Yes.
`
` Q Okay. Do you want to just flip through and
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` make sure all the pages are there?
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` A It appears to be complete.
`
` Q All right. So I'm just going to start off
`
`www.trustpoint.one
`www.aldersonreporting.com
`
`800.FOR.DEPO
`(800.367.3376)
`Regeneron Exhibit 1208.007
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 7
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` by going through how things are going to work today.
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` The most important part, we have a court
`
` reporter on the video with us who's going to be
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` writing down everything we say. So it's important
`
` that we don't speak over each other. So if I'm
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` asking a question, please let me finish before you
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` answer, and when you're answering, I'll do my best
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` to let you finish before I ask my next question.
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` Does that sound good?
`
` A Yes.
`
` Q Okay. And I'll take a break about once
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` every hour. If you need to take a break for some
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` other reason before we get to an hour, just let me
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` know. I'll just ask that if there's a pending
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` question you answer it before we go on break.
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` Does that sound good?
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` A Yes.
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` Q All right. And if you don't understand a
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` question I ask you, please let me know, and I will
`
` do my best to rephrase the question and ask a better
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` one.
`
` Does that make sense?
`
`www.trustpoint.one
`www.aldersonreporting.com
`
`800.FOR.DEPO
`(800.367.3376)
`Regeneron Exhibit 1208.008
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 8
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` A Okay.
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` Q All right. Now, Dr. Calman, you submitted
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` a declaration in this IPR, but you also served as an
`
` expert on behalf of Novartis in an ITC proceeding
`
` involving Novartis and Regeneron.
`
` Do you recall that?
`
` A Yes, I do.
`
` Q Okay. Do you recall when you first
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` began -- well, let me ask a preliminary question.
`
` Is your consulting agreement for this
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` matter with the law firm or with Novartis
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` specifically?
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` A Well, the letter of engagement came from
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` the law firm of -- currently of Allen & Overy, but
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` Novartis was mentioned as the client.
`
` Q Okay. Prior to that, did you have a
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` consulting arrangement with a law firm named Goodwin
`
` Procter?
`
` A Yes, similarly. We had a similar letter of
`
` agreement.
`
` Q Okay. Do you recall when you first entered
`
` into a consulting agreement with Goodwin Procter?
`
`www.trustpoint.one
`www.aldersonreporting.com
`
`800.FOR.DEPO
`(800.367.3376)
`Regeneron Exhibit 1208.009
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 9
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` A I don't recall. I think it was
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` approximately 2020.
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` Q Okay. Do you have a sense of how much time
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` you've billed both Goodwin Procter and Allen & Overy
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` for your work since you were first retained?
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` A First retained for this matter or first
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` retained at all?
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` Q First retained at all.
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` A It would be a guess rather than an
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` estimate.
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` Q Okay. What's your best guess?
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` A My guess is it's somewhere between 80 and
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` 120,000, but that's just a guess.
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` Q Okay. Now, with respect to this particular
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` proceeding, do you recall when you first started
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` working on your declaration?
`
` A So I -- there was, as you know, an IPR that
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` preceded this one that was not instituted because of
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` the pending ITC matter, as I understand it. And I
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` did do some work with counsel on that. And that
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` was -- that was, you know, about a year ago, I
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` think. So some of that work, you know, was used in
`
`www.trustpoint.one
`www.aldersonreporting.com
`
`800.FOR.DEPO
`(800.367.3376)
`Regeneron Exhibit 1208.010
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 10
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` this matter also.
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` Q Okay. Now, if you take a look at your
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` declaration that you have in front of you,
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` Exhibit 2204, on the last page it indicates that you
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` signed your declaration on January 18th, 2022.
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` A Yes.
`
` Q Do you see that? Do you know how much
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` earlier than January 18th, 2022 you started working
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` on this particular declaration?
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` A I would estimate four to six weeks before,
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` with the caveat that there were some components that
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` we had worked on in the earlier iteration of the
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` IPR.
`
` Q Okay. Do you have a sense of how much time
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` you spent on this particular declaration, with the
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` understanding that you had leveraged some previous
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` work?
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` A You know, it's, again, just an estimate. I
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` would say probably 30 to 40 hours.
`
` Q Now, with respect to the deposition today,
`
` how much time did you spend preparing?
`
` A I would estimate somewhere between 15 and
`
`www.trustpoint.one
`www.aldersonreporting.com
`
`800.FOR.DEPO
`(800.367.3376)
`Regeneron Exhibit 1208.011
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 11
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` 25 hours.
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` Q Okay. And did you have any meetings with
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` any of the attorneys from Allen & Overy in
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` preparation for today?
`
` A Yes.
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` Q Okay. And when did those meetings take
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` place?
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` A So I met in person yesterday with
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` Mr. Bennett, and then there were three or four Zoom
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` calls over the last few weeks.
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` Q Okay. Did you meet with anyone other than
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` Mr. Bennett to prepare?
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` A Not in person.
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` Q Okay. How about over Zoom?
`
` A So there was a representative of Novartis
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` present on some of the calls, and I believe -- I'm
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` not -- I don't remember -- I don't have a -- yes, I
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` do remember. At least one of the calls Mr. James
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` was also on the call --
`
` Q Okay. Now --
`
` A -- over Zoom.
`
` Q Oh, okay. So aside from this consulting
`
`www.trustpoint.one
`www.aldersonreporting.com
`
`800.FOR.DEPO
`(800.367.3376)
`Regeneron Exhibit 1208.012
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 12
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` work you're currently doing with the law firm on
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` behalf of Novartis, are you doing any other
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` consulting for Novartis currently?
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` A Well, I was consulting on the antitrust
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` matter through a different law firm, and my
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` understanding is that that has been dismissed and is
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` now under appeal.
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` I think that's it.
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` Q Okay.
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` A I'm also on the District Court case with
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` Allen & Overy -- District Court patent case.
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` Q Aside from litigation consulting, have you
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` done any consulting work on behalf of Novartis?
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` A Not to the best of my recollection.
`
` Q Okay. All right. So -- now, I understand
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` right now you're a practicing ophthalmologist; is
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` that right?
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` A Yes.
`
` Q Okay. And do you currently see patients as
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` part of your practice?
`
` A Yes.
`
` Q Okay. When did you first start seeing
`
`www.trustpoint.one
`www.aldersonreporting.com
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`800.FOR.DEPO
`(800.367.3376)
`Regeneron Exhibit 1208.013
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 13
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` patients in your ophthalmology practice?
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` A 1993, after I finished my residency.
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` Q Okay. Do you recall when you first
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` performed intravitreal injection?
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` A During residency.
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` Q Okay. And what years would that have taken
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` place?
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` A 1990 to 1993.
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` Q Okay. And what was the drug product you
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` were injecting, if you recall?
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` A At that time, it was primarily antibiotics
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` for infections, and there may have been some steroid
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` injections as well.
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` Q Okay. Can you recall when the first time
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` you performed an intravitreal injection of a VEGF
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` antagonist?
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` A 2005.
`
` Q Okay. And do you recall what drug product
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` that was?
`
` A Yes.
`
` Q What was it?
`
` A Avastin.
`
`www.trustpoint.one
`www.aldersonreporting.com
`
`800.FOR.DEPO
`(800.367.3376)
`Regeneron Exhibit 1208.014
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 14
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` Q Okay. And after Avastin, what was the next
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` drug product that you administered intravitreally
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` that was a VEGF antagonist?
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` A Lucentis.
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` Q In what year did you first administer
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` Lucentis?
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` A You know, I don't remember exactly.
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` Q Okay. And would that have been Lucentis in
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` a vial presentation?
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` A Yes.
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` Q And have you administered Lucentis in a
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` prefilled syringe presentation?
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` A Yes.
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` Q Okay. Do you recall when you first did
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` that?
`
` A It would have been shortly after its
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` approval, which I believe was 2016.
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` Q Okay.
`
` A Usually, what happens -- and I don't
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` remember if it was 2016 or 2017 that it actually
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` became available because usually the availability is
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` a few months after the approval.
`
`www.trustpoint.one
`www.aldersonreporting.com
`
`800.FOR.DEPO
`(800.367.3376)
`Regeneron Exhibit 1208.015
`Regeneron v. Novartis
`IPR2021-00816
`
`
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`Andrew F. Calman, M.D., Ph.D.
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`4/5/2022
`Page 15
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` Q Okay. Have you ever injected Eylea?
`
` A Yes.
`
` Q Okay. And did you ever inject Eylea in a
`
` vial presentation?
`
` A Yes.
`
` Q And do you recall what year that would have
`
` taken -- first taken place?
`
` A Shortly after its approval. And, you know,
`
` forgive me. I think it was 2011 or 2012, but I'd
`
` have to look it up.
`
` Q Okay. Have you ever administered Eylea in
`
` a prefilled syringe presentation?
`
` A Yes.
`
` Q Okay. Do you recall the first time that
`
` occurred?
`
` A Shortly after it was introduced, which I
`
` believe was towards the end of 2019.
`
` Q Have you ever administered Macugen?
`
` A No.
`
` Q No? Are you familiar with Macugen?
`
` A Yes.
`
` Q Okay. But in your career, you've never
`
`www.trustpoint.one
`www.aldersonreporting.com
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`
`
`Andrew F. Calman, M.D., Ph.D.
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`4/5/2022
`Page 16
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` administered it?
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` A Correct.
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` Q Have any of your colleagues, to your
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` knowledge, administered Macugen?
`
` A In the past, yes.
`
` Q Okay. Do you recall when that took place?
`
` A Well, Macugen was approved in 2004, so it
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` would have been that -- if I recall correctly, it
`
` would have been around that time frame, and the use
`
` of Macugen rapidly declined after 2005, 2006
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` timeframe when anti-VEGF antibody-type molecules
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` became available.
`
` Q Okay. Have you ever administered Beovu?
`
` A Yes.
`
` Q Okay. And do you recall when you first did
`
` that?
`
` A Shortly after it was approved, which was --
`
` I don't remember exactly, but approximately 2020.
`
` Q Okay. And of the treatments that you've --
`
` or anti-VEGF treatments that you have used, which
`
` ones are you currently still administering?
`
` A Avastin, Lucentis, Eylea, and Beovu.
`
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`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 17
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` Q Okay. And of those treatments, is there
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` one that you tend to administer more than the
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` others?
`
` A I would say there are two that I tend to
`
` administer more than the others.
`
` Q Okay. And which are those?
`
` A Avastin and Eylea.
`
` Q Okay. Now, do you have a sense of what
`
` portion of your current practice involves
`
` administering Beovu?
`
` A It's a small number. It's a small
`
` percentage.
`
` Q Okay. Like, less than 10 percent?
`
` A Yes.
`
` Q Now, would you be more likely to administer
`
` Beovu if it was available in a prefilled syringe?
`
` A On balance, it would be a net positive, so,
`
` it would -- yeah, I don't think it would make a
`
` major impact, but that would be a net positive.
`
` Q Now, with respect to your experience, what
`
` experience do you have working on the development of
`
` drug products for ophthalmologic applications?
`
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`Andrew F. Calman, M.D., Ph.D.
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`4/5/2022
`Page 18
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` A I have participated as a clinical
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` investigator for a number of Stage III clinical
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` trials, as outlined in my CV. I've also done some
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` Stage IV clinical trials, and I've done some
`
` development work on devices that were not directly
`
` involved with pharmaceuticals.
`
` Q Okay. And what kinds of devices have you
`
` worked on the development of?
`
` A Surgical instruments and some diagnostic
`
` devices for retinal disease and also for -- for
`
` other ocular conditions.
`
` Q Okay. Have you done any product
`
` development work for syringes for intravitreal
`
` injection?
`
` A No.
`
` Q And with respect to your drug product
`
` development experience, were any of those intended
`
` for intravitreal injection?
`
` A No.
`
` Q And so what -- for the drug products that
`
` you've worked on in terms of product development,
`
` how were they administered to the patient?
`
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`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 19
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` A I don't have my CV in front of me, but the
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` majority of them were eyedrops, but there were also
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` some systemic drugs, where we were looking for
`
` ocular responses to the drugs.
`
` Q Okay. What do you mean by systemic drugs?
`
` A Again, it's been many years, and I'd have
`
` to look at my CV to give you the details, but there
`
` were some insulin drugs for diabetics where we were
`
` looking at diabetic retinopathy. There were some
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` oral drugs that were being used for other conditions
`
` where we were looking for ocular responses.
`
` So systemic meaning they were taken, you
`
` know, orally or parenterally for the whole body.
`
` Q Okay. But you were looking at them with
`
` respect to whether they would have any ocular side
`
` effects?
`
` A Or ocular beneficial effects.
`
` Q Okay. Okay. In your current practice --
`
` well, strike that.
`
` Historically -- and this may be a difficult
`
` question to answer, but on average, how many
`
` intravitreal injections do you think you perform
`
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`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 20
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` annually since, let's say, 2010?
`
` MR. BENNETT: Objection to form.
`
` THE WITNESS: So, historically, I've
`
` probably done, you know, roughly -- and it varies by
`
` the year, but roughly about a hundred a year.
`
` BY MR. PEPE:
`
` Q Okay.
`
` A And that's probably a low-ball estimate.
`
` Q Now, in your declaration, if you'd go to
`
` paragraph 68. Are you there?
`
` A Yes.
`
` Q Okay. And in that paragraph, I believe
`
` it's the last sentence. It says: "Excessive force
`
` might be exerted by an ophthalmologist if, for
`
` example, the break loose or slide force for the PFS
`
` are too high."
`
` Do you see that?
`
` A I do.
`
` Q So in your experience, have you ever had a
`
` situation where, you know, a particular PFS had a
`
` break loose or slide force that was too high such
`
` that it affected your injection technique?
`
`www.trustpoint.one
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`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 21
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` A So I guess it would depend on your
`
` definition of too high. What I would say is that
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` there are differences between the break loose and
`
` slide forces between the different products, and
`
` there's one in particular that has high forces that
`
` I can perceive, and we can talk about the literature
`
` on that if you want to, where it definitely, you
`
` know, initially was a little surprising.
`
` I'm not sure if I understand your -- I'm
`
` not sure if I'm remembering your question precisely.
`
` Q Okay. What product is that?
`
` A That's the Eylea PFS.
`
` Q Okay. So in your experience, the forces
`
` were -- the higher break loose force was a little
`
` surprising?
`
` A The higher forces in general were initially
`
` surprising compared to what I was used to from other
`
` products.
`
` Q Okay. And did that negatively impact your
`
` ability to perform an intravitreal injection with
`
` Eylea PFS?
`
` A Not really. One adapts. It's like
`
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`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 22
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` learning to use a different surgical instrument.
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` Pretty rapidly you do adapt.
`
` Q Okay. And with respect to Eylea PFS, do
`
` you find the forces to be consistent in terms of
`
` break loose and slide force?
`
` A Generally speaking, yes --
`
` Q Okay.
`
` A -- consistent from one Eylea syringe to
`
` another.
`
` Q Okay. And if you'd go back to, I think,
`
` paragraph 68 of your declaration, you know, the next
`
` part of that last sentence says: "...or if the
`
` forces are unpredictable such that the
`
` ophthalmologist not able to determine based on prior
`
` experience how much force will be required for a
`
` given injection."
`
` Do you see that?
`
` A I see that.
`
` Q Have you had any products you've used where
`
` you've experienced unpredictable break loose and
`
` glide forces?
`
` A Not that I can recall.
`
`www.trustpoint.one
`www.aldersonreporting.com
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`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 23
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` Q Now, with respect to intravitreal injection
`
` using vial presentations versus PFS, have the forces
`
` been comparable between the two in your experience?
`
` A No.
`
` Q No? In what way are they different?
`
` A There is a distinct increase in the forces
`
` in the Eylea PFS compared to the syringe combination
`
` provided with the Eylea vial.
`
` Q Okay.
`
` A The Lucentis, I think, there's probably a
`
` slight increase in forces with the PFS compared to
`
` the vial, but if I recall correctly, Lucentis didn't
`
` actually include a syringe, so that might depend on
`
` which syringe the ophthalmologist used.
`
` Q And in your experience, how did the forces
`
` for administering Avastin differ relative to
`
` Lucentis PFS, for example?
`
` A So Avastin is a little different because it
`
` comes as a prefilled syringe from various 503B bulk
`
` outsourcing facilities, and every facility does it a
`
` little differently and they use a slightly different
`
` syringe. So there are some differences between 503B
`
`www.trustpoint.one
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`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 24
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` bulk sourcing facilities, but in my experience,
`
` generally speaking, the Avastin forces are quite
`
` low.
`
` Q Okay. But are you able to tell a
`
` difference from syringe to syringe using Avastin if
`
` you're given a different syringe from -- from the
`
` bulk source facilities?
`
` MR. BENNETT: Objection to form.
`
` THE WITNESS: Yeah, I'm not sure I
`
` understand your question.
`
` BY MR. PEPE:
`
` Q Sure. So in your previous answer, you
`
` indicated that Avastin comes from bulk outsourcing
`
` facilities, right?
`
` A Well, Avastin ultimately comes from
`
` Genentech in a vial, and then the bulk outsourcing
`
` facilities aliquot the vial into multiple syringes
`
` in a laminar flow hood under Section 503B, so then
`
` they ship them to the ophthalmologist.
`
` Q Okay. And is it correct that you don't
`
` always receive Avastin in the same model of syringe?
`
` A Well, in my experience and my -- and I
`
`www.trustpoint.one
`www.aldersonreporting.com
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`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 25
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` haven't worked with every 503B, but I've worked with
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` at least three of them. Each 503B tends to
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` consistently use their own preferred syringe. So
`
` the differences that I'm talking about would not be
`
` between syringes within the same batch received from
`
` a bulk sourcing facility nor between different
`
` batches received on different dates from the same
`
` outsourcing facility; however, the -- you know, the
`
` syringe used by bulk or outsourcing facility A may
`
` be different from the one used by bulk outsourcing
`
` facility B.
`
` And there also have been some -- some of
`
` these facilities that have changed their syringe
`
` over time. But, generally, you know, they tend to
`
` be consistent.
`
` Q Okay. But if you are injecting one week
`
` with a syringe from facility A and a few weeks later
`
` injecting using a syringe from facility B, are you
`
` able to tell the difference in break loose and slide
`
` force?
`
` MR. BENNETT: Objection to form.
`
` THE WITNESS: Well, I think there may --
`
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`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 26
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` you know, I can't say that that would never occur
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` because I haven't used every 503B, but in my
`
` experience having used at least three of them,
`
` generally speaking, the syringe may be different,
`
` but it -- break loose and slide forces for these
`
` Avastin syringes tend to be all comparable and low.
`
` BY MR. PEPE:
`
` Q Now, looking back at paragraph 68 of your
`
` declaration where you refer to excessive force.
`
` Do you see that?
`
` A I do.
`
` Q Can you tell me what, you know, magnitude
`
` of force you would find to be excessive?
`
` MR. BENNETT: Objection to form.
`
` THE WITNESS: Well, this kind of goes a
`
` little bit beyond what's in the record, but there is
`
` a recent publication ahead of print by Lee,
`
` publication date 2022, that looks patients who had
`
` discomfort with intraocular injections, and they
`
` looked at the forces that were exerted at different
`
` speeds of injection with different prepackaged
`
` syringes.
`
`www.trustpoint.one
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`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 27
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` And they specifically looked at Lucentis,
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` Eylea -- Lucentis PFS, Eylea PFS, and I don't
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` remember the source for the Avastin PFS, and they --
`
` you know, they found, generally speaking, Eylea had
`
` the highest forces and, I believe, Avastin had the
`
` lowest forces, and the forces went up with increased
`
` injection speed and tended to go up towards the end
`
` of the piston travel or stopper travel, travel under
`
` travel.
`
` And the ranges were generally -- and you'd
`
` have to look at the data, but, generally speaking,
`
` the ranges for the Lucentis syringe tended to be in
`
` the 2 to 4 Newton range and the ranges for the Eylea
`
` syringe tended to be higher, in the 3 to 10 Newton
`
` range, again, reaching those higher values with
`
` higher injection speeds and/or towards the end of
`
` the plunger travel.
`
` BY MR. PEPE:
`
` Q Okay. So based on that, is your belief
`
` that 10 Newtons would be an excessive force?
`
` A Well, I didn't say --
`
` MR. BENNETT: Objection to form.
`
`www.trustpoint.one
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`Regeneron v. Novartis
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`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 28
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` THE WITNESS: I didn't say that. I'm not
`
` sure -- I'm not sure -- I wouldn't say that. I
`
` don't know -- it would depend how I define
`
` excessive, I suppose. I guess what I was trying to
`
` do by referencing this recent publication is give
`
` you some quantification of what I perceive as a
`
` clinician, you know, when I give these injections.
`
` BY MR. PEPE:
`
` Q Okay. So I may have missed it on the
`
` realtime. Do you recall what the range was for
`
` Eylea?
`
` A I don't have the paper in front of me, but,
`
` you know, what I recall, from having looked at the
`
` paper, is that the -- at the higher speeds of
`
` injection and particularly toward the end of the
`
` plunger travel, toward the end of the injection, the
`
` forces with Eylea prefilled syringe approached 10
`
` Newtons.
`
` They may have gone beyond 10 Newtons. I
`
` don't remember. You know, and there of course were
`
` error bars and, you know, confidence intervals. So,
`
` you know, it's not one hard number.
`
`www.trustpoint.one
`www.aldersonreporting.com
`
`800.FOR.DEPO
`(800.367.3376)
`Regeneron Exhibit 1208.029
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`Andrew F. Calman, M.D., Ph.D.
`
`4/5/2022
`Page 29
`
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` Q Okay. But you don't have an opinion as to
`
` whether 10 Newtons would be an excessive force?
`
` MR. BENNETT: Objection.
`
` THE WITNESS: I think it would depend on
`
` how you define excessive. And I think what I'v
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