throbber
Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 1 of 125 PageID #:5711
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`
`672
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`IN THE UNITED STATES DISTRICT COURT
`NORTHERN DISTRICT OF ILLINOIS
`EASTERN DIVISION
`
`1 2 3 4 5 6 7 8 9
`
`Docket Nos. 16 C 651
` 17 C 7903
`
`Chicago, Illinois
`July 19, 2018
`1:30 p.m.
`
`)))))))))
`
` HOSPIRA, INC.,
`
`Plaintiff,
`
`vs.
`
` FRESENIUS KABI USA, LLC,
`
`Defendant.
`
`VOLUME 4B
`TRANSCRIPT OF PROCEEDINGS - Bench Trial
`BEFORE THE HONORABLE REBECCA R. PALLMEYER
`
`APPEARANCES:
`
`For the Plaintiff:
`
`For the Defendant:
`
`Court Reporter:
`
`JENNER & BLOCK LLP
`BY: MR. BRADFORD P. LYERLA
`MR. YUSUF ESAT
`MR. AARON A. BARLOW
`MR. REN-HOW H. HARN
`MS. SARA T. HORTON
`353 North Clark Street
`Chicago, Illinois 60654
`
`SCHIFF HARDIN LLP
`BY: MR. IMRON T. ALY
`MR. JOEL M. WALLACE
`MS. TARA L. KURTIS
`MR. KEVIN M. NELSON
`233 South Wacker Drive, Suite 6600
`Chicago, Illinois 60606
`
`SCHIFF HARDIN LLP
`BY: MR. AHMED M.T. RIAZ
`666 Fifth Avenue, 17th Floor
`New York, New York 10103
`
`FRANCES WARD, CSR, RPR, RMR, FCRR
`Official Court Reporter
`219 S. Dearborn Street, Suite 2144D
`Chicago, Illinois 60604
`(312) 435-5561
`frances_ward@ilnd.uscourts.gov
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 2 of 125 PageID #:5712
`
`
`673
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`Also Present:
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`Mr. Michael P. Bauer, Hospira
`Mr. Ryan Daniel, Fresenius Kabi
`Mr. Ali Ahmed, Fresenius Kabi
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 3 of 125 PageID #:5713
`Seaton - cross by Mr. Nelson
`
`674
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`(Proceedings heard in open court:)
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`THE COURT: All right. We can proceed.
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`R. CHRISTOPHER SEATON, PLAINTIFF'S WITNESS, PREVIOUSLY SWORN.
`
`CROSS-EXAMINATION (Resumed)
`
`BY MR. NELSON:
`
`Q. Good afternoon, Mr. Seaton.
`
`A. Good afternoon.
`
`Q. Can you please turn to JTX 109, the separation and
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`distribution agreement, please.
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`And what is the date of the separation and
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`distribution agreement?
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`A. April 12th, 2004.
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`Q. Can you turn to JTX 109 at page 12, please.
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`And you see the section entitled, "Ancillary
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`Agreements." It's about the third, fourth one down?
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`A. Yes, sir.
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`Q. There's a series of agreements listed there. Those
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`agreements were entered into between Abbott and Hospira before
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`the effective date of this agreement, correct?
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`A. Yes, sir.
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`Q. And if you can turn to page 51 of this agreement. That's
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`JTX 109.51. And if we look at the section that's entitled,
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`"Advisors." Do you see that?
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`A. Yes, sir.
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`Q. And this section says that the attorneys that represented
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 4 of 125 PageID #:5714
`Seaton - cross by Mr. Nelson
`
`675
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`Abbott in this agreement were not the same law firms that
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`represented Hospira, correct?
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`A. Correct.
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`Q. So, the parties had separate law firms when they were
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`negotiating this agreement, correct?
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`A. Correct.
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`Q. And you'd agree with me that Abbott actually transferred
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`the IND to Hospira after the effective date of this agreement,
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`correct?
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`A. I believe that's correct.
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`Q. Can you please turn to JTX 40. It's in your binder.
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`Are you there, sir?
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`A. Yes, sir.
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`Q. Good. This is a letter from Hospira dated May 10th, 2004,
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`to FDA, correct?
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`A. Correct.
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`Q. So, that's after the effective date of the agreement,
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`correct?
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`A. Yes, sir.
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`Q. And here, this agreement -- and we might disagree with the
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`wording, but it does say that there's a transfer of ownership
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`in the general correspondence regarding line, correct?
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`A. It does say that, yes.
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`Q. And if we look down at that first paragraph, it says,
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`"On this date, Abbott transferred ownership of the
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 5 of 125 PageID #:5715
`Seaton - redirect by Mr. Lyerla
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`676
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`above-referenced IND to Hospira." And the above-referenced
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`IND is the IND we've been looking at, correct?
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`A. That is correct, sir.
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`Q. And if we look at that second paragraph, the last sentence
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`there says that, "This letter assures that all legal and
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`regulatory obligations will continue to be met and that
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`Hospira accepts all rights and responsibilities associated
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`with the sponsorship of this IND effective May 3rd, 2004,"
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`correct?
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`A. Yes, sir.
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`Q. So, here, Hospira is communicating to FDA that it is
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`accepting all rights and responsibilities associated with
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`sponsorship, isn't that right?
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`A. That is correct.
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`MR. NELSON: Your Honor, may I have one minute to
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`confer with my colleagues?
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`THE COURT: Sure.
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`MR. NELSON: Nothing further, your Honor.
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`THE COURT: Any redirect?
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`MR. LYERLA: I guess I'll ask one question.
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`REDIRECT EXAMINATION
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`BY MR. LYERLA:
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`Q. Can you explain why you said the spin-off occurred after
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`the agreement and what the significance of that is to your
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`opinions?
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 6 of 125 PageID #:5716
`Seaton - redirect by Mr. Lyerla
`
`677
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`A. Well, the actual spin-off occurred after the agreement
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`between Abbott and Hospira; but let's be clear, Hospira was a
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`wholly-owned subsidiary of Abbott up until the actual
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`spin-off.
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`So, whether they had a separate board of directors,
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`whether they had separate representation, these are all good
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`things; but at the end of the day, if the agreement had not
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`been in accordance with Abbott's wishes, it wouldn't have gone
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`forward with it or had to go forward with it or allowed
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`Hospira to go forward with it.
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`Abbott controlled and had sole ownership of Hospira
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`prior to the spin-off.
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`Q. And so at the time the IND was transferred to Hospira,
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`they were commonly-owned companies?
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`A. No. The transfer occurred after the spin-off, but it was
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`pursuant to the agreement made before the spin-off.
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`MR. LYERLA: All right. Thank you. Nothing further.
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`MR. NELSON: Nothing, your Honor.
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`THE COURT: The witness may step down.
`
`(Witness excused.)
`
`THE COURT: Okay. Your next witness?
`
`MR. BARLOW: For Hospira's next witness, we call --
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`MR. LYERLA: Your Honor, could I interrupt? Mr. Aly
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`and I wanted to ask a quick question.
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`THE COURT: Okay.
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 7 of 125 PageID #:5717
`Seaton - redirect by Mr. Lyerla
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`678
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`MR. LYERLA: This is just a procedural -- does your
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`Honor want closing arguments, and if so, when?
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`MR. ALY: We're ready to do it tomorrow afternoon.
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`This was talked about at the pretrial conference. And it
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`looks like we'll have time then, but we still wanted to make
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`sure if that's what your Honor preferred.
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`THE COURT: I think I would like to hear very short
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`closing arguments, but they're not going to be -- I suspect
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`I'll still want briefs.
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`MR. ALY: Of course.
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`MR. LYERLA: So, I have a funny view on this, your
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`Honor, if I could just suggest this.
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`THE COURT: Go right ahead.
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`MR. LYERLA: I think this is very, very dense
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`information to process on the fly, and I've always thought
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`that it might be more helpful for courts to have us brief, and
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`then an oral argument when the briefs are closed.
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`And I would -- I'm just posing that as a possibility
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`because I think that might actually be far more helpful than
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`continuing the trial and having closing tomorrow afternoon.
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`And that's just a suggestion, your Honor. I know
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`that people have their preferences, and that may not be the
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`Court's.
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`MR. ALY: We have a view and a suggestion as well,
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`your Honor.
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 8 of 125 PageID #:5718
`Seaton - redirect by Mr. Lyerla
`
`679
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`THE COURT: What is your suggestion, Mr. Aly?
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`MR. ALY: The suggestion is to have short closings
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`tomorrow, if for no other reason than to identify what are
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`those key issues that would be the focus of the briefing
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`instead of the other way around, so that we would know these
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`are the issues to be addressed. And, in fact, that would
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`accelerate the briefing schedule timing because we would know
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`these are the issues to be addressed.
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`THE COURT: Well, to identify the -- to --
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`MR. ALY: By seeing each other, for example, and what
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`we're focusing upon.
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`THE COURT: Yeah, to accomplish that mission, I just
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`want to make sure that it doesn't extend for a long time
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`because I will -- I'll lose focus. Will we finish the
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`evidence tomorrow?
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`MR. ALY: Yes.
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`THE COURT: Start there.
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`MR. LYERLA: Yes.
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`THE COURT: That's a yes? You know what, I think we
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`should spend 10 or 15 minutes on each side with very brief
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`arguments. We'll still have -- we'll still have to do
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`closing -- briefs, and I may have you back in.
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`MR. LYERLA: All right, your Honor. Thank you.
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`THE COURT: All right. Thanks.
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`MR. NELSON: And, your Honor, there's one issue with
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 9 of 125 PageID #:5719
`Seaton - redirect by Mr. Lyerla
`
`680
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`the coming witness that we'd like to address.
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`THE COURT: Yes.
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`MR. NELSON: We informed counsel about this last
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`night. Your Honor, the issue with this witness here is this
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`witness is a rebuttal witness, Dr. Ramsay. But Hospira chose
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`when they did their rebuttal expert report to only focus this
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`witness's testimony on Claim 6 in the '527 patent. That's the
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`method of use patent.
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`THE COURT: Right.
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`MR. NELSON: That patent is no longer part of this
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`case. Every single opinion relates to Claim 6 of the '527
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`patent, including what's relevant to his testimony, which is
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`the ready for patenting issue. That's that last opinion
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`there, right here. It says, "Ready for patenting within the
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`limitations of Claim 6." That claim again is no longer here.
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`So, your Honor, we asked them, we asked Hospira,
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`"Can you identify paragraphs for us that he's going to testify
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`about that relate to anything other than Claim 6?"
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`We got, first of all, his ready for patenting
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`opinions; but again, all of them, you can see, are Claim 6.
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`And if we go to the last paragraph, the summary paragraph of
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`that section, again, it's Claim 6. You can see that says,
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`"Summary Paragraph," right here.
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`THE COURT: Yes.
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`MR. NELSON: All of the other paragraphs that they
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 10 of 125 PageID #:5720
`Seaton - redirect by Mr. Lyerla
`
`681
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`mentioned are in his anticipated or obviousness section.
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`Again, those are related to Claim 6, which again is out.
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`And counsel said during his deposition he's not going
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`to provide any anticipation or obviousness arguments relating
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`to other patents. But put that aside. Anticipation and
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`obviousness has nothing to do with ready for patenting. Ready
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`for patenting is on the on-sale issue that we've been looking
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`at.
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`Finally, your Honor, they have other experts that are
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`going to testify about ready for patenting for the asserted
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`claims that still remain in this case. Dr. Ramsay, he was
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`never provided for that position for patents that are still
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`asserted in this case. We never asked him questions in his
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`deposition, either, on that.
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`THE COURT: Response?
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`MR. BARLOW: Could I use the document?
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`MR. NELSON: Yes, please, absolutely.
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`MR. BARLOW: So, this is a rebuttal witness to
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`Dr. Maile. He's responding to what Dr. Maile said on ready
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`for patenting. And in his report, one of the statements he
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`said, "The documents submitted in relation to IND 32934 do
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`not disclose a ready-to-use dexmedetomidine formulation that
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`was ready for patenting."
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`And many of the statements talk about product within
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`the limitations of Claim 6. Claim 6 is a method claim, and
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 11 of 125 PageID #:5721
`Seaton - redirect by Mr. Lyerla
`
`682
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`the product is the same as the product in the '924, except for
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`certain limitations. It's the same as the product claimed in
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`the '106, except for the 2 percent limitation.
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`But he is only responding to Dr. Maile. And here's
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`Dr. Maile's -- the materials he considered in his report. The
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`'106 and the '094 are not on here. He considered the '527.
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`He considered the prosecution history for it, and he
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`considered some prior art.
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`So, our witness is responding solely to the exact
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`same opinion about whether a specific formulation is ready for
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`patenting that Dr. Maile testified about.
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`THE COURT: How long is this witness going to be on
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`the stand?
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`MR. BARLOW: I would say a half hour of direct.
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`MR. NELSON: Your Honor, if I just might respond very
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`briefly to that point, the reason is Dr. Maile provided
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`testimony generally. Dr. Ramsay was testifying very
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`specifically about that the method wasn't used. Again, that's
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`out of this case. We're no longer talking about whether the
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`method was experimental or not, whether they had enough data
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`or it was safe enough, all of that other stuff. And it's
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`irrelevant here.
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`MR. BARLOW: No, I just showed your Honor quotes that
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`said he was talking about whether the formulation was ready
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`for patent.
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 12 of 125 PageID #:5722
`Ramsay - direct by Mr. Barlow
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`683
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`MR. NELSON: And if you saw the paragraph above, it
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`was specifically referenced to Claim 6.
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`THE COURT: I'm going to allow it.
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`MR. BARLOW: Hospira calls Dr. Michael Ramsay to the
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`stand.
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`MR. NELSON: Your Honor, while the witness is coming
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`up, if it helps move things along, we're willing to stipulate
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`that this witness is an expert and to his qualifications.
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`MR. BARLOW: Oh, it does. Thank you.
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`THE COURT: Thank you. Let me ask you to raise your
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`right hand.
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`(Witness sworn.)
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`THE WITNESS: I do.
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`THE COURT: All right. And why don't we make sure
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`that stipulation is in the record. The parties have
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`stipulated that this witness is an expert with respect to the
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`interpretation of this patent?
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`MR. BARLOW: Well, we were going to offer him as an
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`expert in anesthesiology with experience prescribing and
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`administering sedatives, including dexmed.
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`MR. NELSON: And we agree to that.
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`THE COURT: That's fine. All right. So noted.
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`MICHAEL ANTHONY RAMSAY, PLAINTIFF'S WITNESS, DULY SWORN.
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`DIRECT EXAMINATION
`
`BY MR. BARLOW:
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 13 of 125 PageID #:5723
`Ramsay - direct by Mr. Barlow
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`684
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`Q. So, I will just very quickly -- Dr. Ramsay, could you
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`please state your name for the record.
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`A. Michael Anthony Ramsay, R-A-M-S-A-Y.
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`Q. And you should have in your binder an Exhibit 141,
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`JTX 141. Is that your current CV?
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`A. Yes, it is.
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`Q. And what is your current position?
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`A. I'm chair of the Department of Anesthesiology at Baylor
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`University Medical Center, and I'm president of the Baylor
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`Research Institute.
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`Q. And how long have you been an anesthesiologist?
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`A. At least 40 years.
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`Q. And there's something called the Ramsay Sedation Scale.
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`What's that?
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`A. That's a scoring system of depth of sedation that I put
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`together, again, about 40 years ago.
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`Q. All right. And how -- have you ever used Precedex?
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`A. Yes, I have.
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`Q. For how long have you been using Precedex?
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`A. Since about 2002, something like that.
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`Q. Okay. All right. Now, Dr. Ramsay, were you here when
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`Dr. Maile testified?
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`A. I was.
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`Q. Did you hear him testify that in his opinion, the
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`20-microgram-per-milliliter formulation described in the
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 14 of 125 PageID #:5724
`Ramsay - direct by Mr. Barlow
`
`685
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`Shafer protocol contained in the IND was ready for patenting
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`as a ready-to-use dexmedetomidine formulation?
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`A. I did hear that, yes.
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`Q. Do you agree with that opinion?
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`A. No, I don't.
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`Q. Can you briefly explain why not? And I believe we have a
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`slide.
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`A. Yes.
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`Q. Can you briefly explain why you disagree with Dr. Maile?
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`A. Because this IND, as we heard explained earlier, was
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`purely an experimental study. It was looking at fit, healthy
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`volunteers. It was using a very high concentration of
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`dexmedetomidine that never progressed beyond those trials, in
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`fact, was stopped and was not produced beyond that point.
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`It's not clinically relevant concentration of dexmedetomidine,
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`so it wasn't ready-to-use.
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`Q. All right. Now, could I have the next slide? Were you
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`asked -- skip that one. Sorry. Can I have the slide with
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`legal standards? Thank you.
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`Were you asked to assume certain legal standards in
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`forming your opinion?
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`A. Yes, I was.
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`Q. And could you -- I've put the standards we've asked you
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`to assume on a slide. Could you explain your understanding
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`of what those standards are?
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`A. That -- basically, that the -- an experiment using the
`
`product had to be very clear and be ready for use clinically,
`
`and that would then make it ready for patenting.
`
`Q. Okay. Now, before going into the details of your opinion,
`
`have you -- have you ever worked on an IND?
`
`A. Yes, I have.
`
`Q. How many times?
`
`A. Probably three or four.
`
`Q. Have you ever been a principal investigator on an IND?
`
`A. Yes, I have.
`
`Q. And what was the subject matter of that?
`
`A. One was inhaled nitric oxide, and another one was on a
`
`drug that promotes blood clotting.
`
`Q. Okay. And was -- which one was -- you were a principal
`
`investigator on both?
`
`A. No, on the inhaled nitric oxide.
`
`Q. And did that eventually receive FDA approval?
`
`A. Not for the field of use that we were testing it for.
`
`Q. All right. Now, you're familiar with the IND involved in
`
`this case, IND No. 32934, is that right?
`
`A. Yes.
`
`Q. Were you involved with this IND?
`
`A. No, I was not.
`
`Q. Okay. You should have in your binder an Exhibit DTX 436,
`
`and we'll put it on the screen. Is this one of the documents
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 16 of 125 PageID #:5726
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`you reviewed in forming your opinions?
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`A. Yes, it is.
`
`Q. And what is this document?
`
`A. This is the IND application form.
`
`Q. And after the form, there's a number of materials that
`
`were submitted?
`
`A. Yes.
`
`Q. What's the date of -- this form was submitted to the FDA?
`
`A. March 17th, 1989.
`
`Q. Were you practicing medicine as an anesthesiologist in
`
`1989?
`
`A. Yes, I was.
`
`Q. Did you know about dexmedetomidine in 1989?
`
`A. No, I did not.
`
`Q. In 1989, would dexmedetomidine have been considered a new
`
`compound in anesthesiology?
`
`A. Yes.
`
`Q. I'd like to look at a later filing of the IND, which is
`
`JTX 38 in your binder. And I'd like to direct your attention
`
`to page 3 of this exhibit.
`
`A. Yes.
`
`Q. Is this -- this is a clinical protocol, principal
`
`investigator Steven Shafer, pharmacokinetics and
`
`pharmacodynamics of dexmedetomidine hydrochloride in adult
`
`volunteers.
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 17 of 125 PageID #:5727
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`Are you familiar with this document?
`
`A. Yes, I am.
`
`Q. Is this the document that Dr. Maile testified about
`
`yesterday that we've been calling the Shafer protocol?
`
`A. It is.
`
`Q. Now, I'd like you to look to page 6 of JTX 38 --
`
`A. Yes.
`
`Q. -- and ask you -- direct you to the second paragraph. I
`
`would like you to explain what the purpose of this protocol
`
`was.
`
`A. The purpose of the protocol was to investigate the
`
`pharmacokinetics of the new drug, and that's what a Phase I
`
`trial does is you're trying to work out, number one, is it
`
`safe? Number two, what's the dosing of the drug? In other
`
`words, how much do you give to get certain blood levels that
`
`might be clinically effective?
`
`Q. And why did this protocol -- why was this protocol looking
`
`at the pharmacokinetics of dexmedetomidine?
`
`A. Because you have to determine the safe dose of the drug.
`
`Q. What is pharmacokinetics?
`
`A. It's basically the concentration of the drug following the
`
`injection in various body compartments, particularly the
`
`plasma.
`
`Q. And what dose was used in this study?
`
`A. It was a 2 mic's per kilogram body weight.
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 18 of 125 PageID #:5728
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`Q. Is that a safe dose of dexmedetomidine for patients
`
`undergoing surgery?
`
`A. It's a high dose.
`
`Q. Are there -- what could happen with a high dose of
`
`dexmedetomidine?
`
`A. You could get adverse reactions occurring in the patients,
`
`particularly slowing of the heart rate, cardiac arrest,
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`hyper -- high blood pressure or low blood pressure, extremely
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`low blood pressure.
`
`Q. Now, when you sedate a patient with an anesthesia --
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`during anesthesia, don't you want to slow the heartbeat?
`
`A. To slow it reasonably is certainly one of the goals, but
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`not to the point that it reduces cardiac output and would
`
`cause a lack of profusion of major organs like the heart or
`
`the brain.
`
`Q. All right. What was the study population in this
`
`protocol? That's on -- I think that's described in page 6,
`
`paragraph 3 of page 6.
`
`A. It was fit, healthy male volunteers.
`
`Q. And why were fit, healthy male volunteers used for this
`
`study?
`
`A. Because the risks were not known on this new drug, and so
`
`you want patients who can sustain certain adverse events
`
`without undue harm to be the ones to undertake this study; but
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`they would know there's significant risk attached during a
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 19 of 125 PageID #:5729
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`Phase I study.
`
`Q. Let's look at page 11 of JTX 38. There's a section
`
`called, "Criteria For Inclusion." Do you see that?
`
`A. Yes, I do.
`
`Q. What are criteria for inclusion?
`
`A. These are parameters that the volunteers must meet to be
`
`able to meet the criteria to enter the study.
`
`Q. All right. And there's one 5.28. It says, "No history of
`
`chronic or current cardiac problems." Why -- why doesn't this
`
`study want to include volunteers with chronic or current
`
`cardiac problems?
`
`A. Because there's a significant chance with a drug like dex
`
`or any new drug that you still haven't used in humans that you
`
`might get significant cardiovascular changes, hemodynamic
`
`changes; and you want somebody who's got a strong heart,
`
`normal heart without disease in it that should be able to
`
`tolerate it better than somebody with a diseased or a sick
`
`heart.
`
`Q. Okay. Now, let's look at -- I want to look at the
`
`previous page, page 10, and ask you to explain how the
`
`dexmedetomidine was supplied for this study. And I'll direct
`
`you to the top of the page.
`
`A. Okay.
`
`Q. Page 10 of JTX 38.
`
`A. It was supplied in individual ampules containing 100 mic's
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 20 of 125 PageID #:5730
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`691
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`of dexmedetomidine in 5 milliliters of .9 percent of sodium
`
`chloride.
`
`Q. And then in the second paragraph, it says, "The ampules
`
`for this open label study will be labeled with the appropriate
`
`protocol number, product name, lot number," et cetera, "and
`
`the statement, 'Caution: New drug. Limited by U.S. law to
`
`investigational use.'"
`
`Do you see that?
`
`A. Yes, I do.
`
`Q. Why was that label included?
`
`A. Because there's certain risks associated with -- well
`
`first of all, you've got to label every single syringe that
`
`you draw up with a drug. But this particular drug, there are
`
`certain risks associated with it, certain unknown risks
`
`associated with it, so you don't want someone inadvertently to
`
`administer it to somebody not in the trial.
`
`Q. Was this study an experiment, in your opinion?
`
`A. Yes, it was.
`
`Q. Why do you say that?
`
`A. Because it was an experiment. That's what a Phase I trial
`
`is is an experiment to figure out the right dosing of the drug
`
`and to figure out is it safe or isn't it safe.
`
`Q. Thank you. I'd like to now turn to the investigator's
`
`brochure. That's part of the original IND filing in DTX 436,
`
`and Dr. Maile talked about that yesterday.
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 21 of 125 PageID #:5731
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`I'll direct your attention to page 13 of DTX 436.
`
`A. Yes.
`
`Q. So, is this a document you've reviewed in formulating your
`
`opinions here?
`
`A. Yes.
`
`Q. Have you had your own experience with investigator's
`
`brochures in the past?
`
`A. Yes, I have.
`
`Q. About how many times?
`
`A. Just about every clinical trial I've done has had an
`
`investigator's brochure.
`
`Q. All right. And in 1989, would a clinician regard -- in
`
`your opinion, regard DTX 46 as confidential?
`
`A. You certainly would, as this one is labeled confidential;
`
`but certainly on a Phase I or II trial, you'd take them as --
`
`they'd all be confidential.
`
`Q. Now, yesterday, Dr. Maile testified that -- well, let me
`
`back up. Let me go to page 7 -- no, I'm sorry, page 16 of
`
`DTX 436. It's the introduction to the investigator's
`
`brochure.
`
`And here, it states that, "Clonidine and medetomidine
`
`are both alpha-2 adrenoceptor agonists." Do you see that?
`
`A. Yes, I do.
`
`Q. Do you recall Dr. Maile testified yesterday that knowing
`
`the action of Clonidine and medetomidine would give a
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 22 of 125 PageID #:5732
`Ramsay - direct by Mr. Barlow
`
`693
`
`clinician a fairly good idea of the action of dexmedetomidine?
`
`Do you recall that?
`
`A. Yes, I do.
`
`Q. Do you agree with that?
`
`A. No, I don't.
`
`Q. Why is that?
`
`A. Because the alpha-2 adrenoceptor is a series of receptors.
`
`They're various types of receptors, and these drugs act --
`
`there's A, B, C that are known right now. There may be more.
`
`And these different drugs act primarily on different
`
`receptors.
`
`For instance, Clonidine, it's used to control
`
`hypertension. Its main action is to reduce your blood
`
`pressure. Medetomidine is a mix, and it really doesn't --
`
`it's not used in humans. It's not approved in humans and --
`
`because it's not specific enough for humans.
`
`Q. All right. Now, you said medetomidine was a mix. What
`
`did you mean by that?
`
`A. It's got both the two isomers that are involved in this
`
`molecule, the levo and the dextro, and so it hits various
`
`receptors. And it's not a pure -- what we want is a pure dex
`
`isomer drug to be clinically effective.
`
`Q. Now, do you recall Dr. Maile also testified about the
`
`animal studies disclosed in this brochure?
`
`A. Yes.
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 23 of 125 PageID #:5733
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`694
`
`Q. Are animal studies on medetomidine or dexmedetomidine
`
`indicative of the efficacy of dexmedetomidine in humans?
`
`A. They can give you some guide, but they're really not
`
`indicative. I mean, we do animal studies first so that we can
`
`at least look at the safety and look at the bad things that
`
`might happen to animals.
`
`But certainly, like in my research institute, we can
`
`cure cancer in mice. We can't cure it in humans. So, you
`
`can't cross over.
`
`The nearer you get to humans with non-human primates
`
`would certainly be an area where you might get much more idea
`
`of the adverse effects that might affect humans, but it's
`
`really not appropriate to do that on those types of animals.
`
`Q. If drugs are found to be safe in animals, are they always
`
`safe in humans?
`
`A. No, they're not.
`
`Q. Let's look at page 51 of DTX 436. Here is a discussion of
`
`some Phase I and Phase II studies with medetomidine. Do these
`
`studies show that medetomidine was safe and effective in
`
`humans?
`
`A. No. I believe they -- they show some significant adverse
`
`events.
`
`Q. All right. Let's -- let's look back to page 47 of
`
`DTX 436. Section 6.4 refers to some ongoing studies with
`
`dexmedetomidine; and if you see in the last sentence, it
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 24 of 125 PageID #:5734
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`695
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`mentions three cases of bradycardia. Do you see that?
`
`A. Yes, I do.
`
`Q. What is bradycardia?
`
`A. Bradycardia is a slowing of the heart rate.
`
`Q. Is it the kind of slowing of the heart rate you want in
`
`sedated patients?
`
`A. Some slowing of the heart rate is fine. It's a matter of
`
`whether it becomes clinically significant; and I think in
`
`these instances, they were clinically significant, in that
`
`they caused severe symptoms.
`
`Q. And what kind of symptoms can you get with clinically
`
`significant symptomatic bradycardia?
`
`A. I guess the worst one would be cardiac arrest.
`
`Q. Now, Dr. Maile said yesterday that bradycardia would be
`
`expected for any drug in the class of medications that effect
`
`the flight-or-fight portion of the nervous system. Do you
`
`recall that?
`
`A. Yes.
`
`Q. Do you agree with that?
`
`A. You can certainly see slowing of the heart rate, but not
`
`to the degree that we're seeing here in this initial trial.
`
`That would not be expected, and it certainly would not be
`
`acceptable in clinical practice.
`
`Q. All right. Now, I'd like to go back to the investigator's
`
`brochure and go through these three cases of bradycardia that
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 25 of 125 PageID #:5735
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`696
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`are referred to. I believe the first one is described on
`
`page 48 of DTX 436.
`
`A. Yes.
`
`Q. Do you see -- try to blow that up.
`
`Do you see it refers to very -- "Patient received" --
`
`"experienced very sudden cardiovascular collapse and lost
`
`consciousness and voided spontaneously"? Do you see that?
`
`A. Yes, I do.
`
`Q. What does very sudden cardiovascular collapse mean in
`
`layman's terms?
`
`A. It basically means a cardiac arrest. It means that your
`
`cardiac output's dropped down to non-profusing major organs.
`
`Q. Like a heart attack?
`
`A. Could be with a heart attack, yeah.
`
`Q. I guess what's the difference between cardiac arrest and a
`
`heart attack?
`
`A. Cardiac arrest is the heart stopped beating. A heart
`
`attack, your heart may not stop beating, hopefully.
`
`Q. Okay. What does voided spontaneously mean?
`
`A. It just means they wet themselves.
`
`Q. All right. The second -- let's look at the second case
`
`on page 49. It refers to -- it reports that the subject's
`
`heart rate dropped to 38 beats per minute. This is in the
`
`second full paragraph on the page.
`
`"The subject's heart rate dropped to 38 beats per
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`Case: 1:16-cv-00651 Document #: 142 Filed: 08/07/18 Page 26 of 125 PageID #:5736
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`minute, complained of pain, nausea, and visible disturbance."
`
`What are the clinical concerns w

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