throbber
Case: 1:16-cv-00651 Document #: 140 Filed: 08/07/18 Page 1 of 102 PageID #:5509
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`472
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`IN THE UNITED STATES DISTRICT COURT
`NORTHERN DISTRICT OF ILLINOIS
`EASTERN DIVISION
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`1 2 3 4 5 6 7 8 9
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`Docket Nos. 16 C 651
` 17 C 7903
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`Chicago, Illinois
`July 18, 2018
`1:05 p.m.
`
`)))))))))
`
` HOSPIRA, INC.,
`
`Plaintiff,
`
`vs.
`
` FRESENIUS KABI USA, LLC,
`
`Defendant.
`
`VOLUME 3B
`TRANSCRIPT OF PROCEEDINGS - Bench Trial
`BEFORE THE HONORABLE REBECCA R. PALLMEYER
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`APPEARANCES:
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`For the Plaintiff:
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`For the Defendant:
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`Court Reporter:
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`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
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`SCHIFF HARDIN LLP
`BY: MR. AHMED M.T. RIAZ
`666 Fifth Avenue, 17th Floor
`New York, New York 10103
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`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 #: 140 Filed: 08/07/18 Page 2 of 102 PageID #:5510
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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 #: 140 Filed: 08/07/18 Page 3 of 102 PageID #:5511
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`THE COURT: All right. Are we -- we're ready to
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`resume our video? Okay. Chip, this is a video so you don't
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`need to take the next, like, 30, 40 minutes.
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`(The videotaped deposition of Rao Tata-Venaka resumed
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`playing in open court.)
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`MR. WALLACE: That concludes the testimony of
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`Dr. Tata-Venaka.
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`THE COURT: Thank you. Your next witness, or is that
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`your final witness?
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`MR. WALLACE: No, we have one more live witness, your
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`Honor.
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`THE COURT: Okay.
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`MR. WALLACE: We call to the stand Dr. Michael Maile.
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`THE COURT: Sir, can I ask you to step forward,
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`please. Would you raise your right hand.
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`(Witness sworn.)
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`MR. WALLACE: May I approach, your Honor, with a
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`binder?
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`MICHAEL DAVID MAILE, DEFENDANT'S WITNESS, DULY SWORN.
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`DIRECT EXAMINATION
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`BY MR. WALLACE:
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`Q. Good afternoon, Dr. Maile.
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`A. Good afternoon.
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`Q. Could you state your name and address for the record?
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`A. Michael David Maile, 4563 Morningstar Way, Ann Arbor,
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`Michigan, 48103.
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`Q. And where are you currently employed?
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`A. The University of Michigan.
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`Q. And what's your job title?
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`A. Assistant professor.
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`Q. In what department?
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`A. The Department of Anesthesiology.
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`Q. And, Dr. Maile, what have you been asked to testify about
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`today?
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`A. I've been asked to provide information from a clinician's
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`point of view about the drug dexmedetomidine and to review the
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`IND and determine whether there's a ready-to-use formulation
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`in the IND that's ready for patent.
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`Q. Let's first talk about your qualifications. Where did you
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`attend undergraduate?
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`A. Michigan State University.
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`Q. And what degree did you receive?
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`A. A Bachelor of Science degree in biochemistry.
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`Q. And what year was that?
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`A. I graduated in 2002.
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`Q. What did you do after undergraduate?
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`A. I attended medical school.
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`Q. And where did you attend medical school?
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`A. Penn State University.
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`Q. When did you complete that?
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`A. 2006.
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`Q. After medical school, did you continue your medical
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`training?
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`A. I did.
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`Q. What additional training did you receive?
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`A. I completed a residency program in anesthesiology.
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`Q. And where was that?
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`A. That was at the University of Michigan.
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`Q. And how long was that program?
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`A. That's a four-year program.
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`Q. And what types of training do you receive in a residency
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`in anesthesiology?
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`A. So, a lot of the training is pertaining to taking care of
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`patients in the operating room, but we also take care of
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`patients on the floor and in the intensive care units at
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`different points, and in the pain clinics.
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`Q. And when did you complete that residency?
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`A. 2010.
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`Q. And during this residency program, were you actually
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`seeing patients?
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`A. Yes, most of the time.
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`Q. And what was the end point of your residency?
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`A. Board certification in anesthesiology.
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`Q. And after your residency, did you receive additional
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`training?
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`A. I did.
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`Q. At what time?
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`A. So, after residency, I completed a critical care medicine
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`fellowship.
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`Q. Now, what is critical care medicine?
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`A. Critical care medicine is a subspecialty that focuses on
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`the care of patients who are typically located in an intensive
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`care unit, who are suffering from some sort of severe disease
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`process that requires minute-to-minute titration of
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`diffusions, frequent monitoring, organ support of daily organ
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`systems.
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`Q. Why did you pursue a fellowship in critical care medicine?
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`A. So, ever since medical school, I was very interested in
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`critical care, and it was part of my decision to pursue
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`training in anesthesiology. The physiology and disease
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`processes involved were fascinating to me.
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`I feel the care of those patients and their families
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`is satisfying, and there's a lot we still don't understand
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`about those, the problems we encounter, which is -- matches my
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`interest in research as well.
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`Q. Now, did you receive additional certification as part of
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`your fellowship?
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`A. Yes. There is a board certification in critical care
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`medicine.
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`Q. Have you received any additional board certifications?
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`A. Yes.
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`Q. What is that?
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`A. I also received board certification in perioperative use
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`of transesophageal echocardiography.
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`Q. And what is that?
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`A. That is a competence in using ultrasound to examine the
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`heart function by placing an ultrasound probe in the
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`esophagus, which is located directly behind the heart.
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`Q. And in what settings is that procedure used?
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`A. In the operating room or in the intensive care units.
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`Q. Now, what type of position did you obtain after completing
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`your fellowship?
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`A. So, after fellowship, I joined the faculty of the
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`University of Michigan.
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`Q. And what were your responsibilities as faculty at the
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`University of Michigan?
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`A. So, my responsibilities there included education of the
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`medical students, residents, fellows. Clinical activity
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`included care of patients in the operating rooms and the
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`intensive care units, research, and some administrative tasks.
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`Q. Now, during your time as faculty at the University of
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`Michigan, were you asked to take on further responsibilities?
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`A. I was.
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`Q. And what were those responsibilities?
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`A. So, after a couple of years as faculty, I was appointed as
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`the program director of our critical care medicine fellowship
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`and also became the co-director of our cardiovascular center
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`intensive care unit.
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`Q. Now, let's talk first about the program director for
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`critical care. What responsibilities did you have in that
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`role?
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`A. So, the program director of any training program is
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`responsible for basically everything that has to do with the
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`training program. So, that would involve supervising the
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`faculty who are working with the fellows, setting the
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`curriculum of the fellowship program, making sure all the
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`fellows are progressing through their training in a great way,
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`and, you know, administrative tasks such as satisfying the
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`paperwork requirements of the ACGME.
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`Q. And you also said you were the co-director of the
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`cardiovascular center?
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`A. Correct.
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`Q. What were your responsibilities there?
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`A. So, that would involve modifying protocols we had in
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`place, developing new protocols, dealing with any issues that
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`came up with any of the trainees or faculty or nurse
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`practitioners, patients who we're taking care of in the unit,
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`various other -- reviewing quality data that is generated by
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`the unit.
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`Q. And have you been awarded any grants, Dr. Maile?
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`A. Research grants? Yes.
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`Q. And could you tell us more about your research grants?
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`A. So, currently, I'm supported by a grant from the Michigan
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`Institute For Clinical Health Research, which is funded by the
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`National Institutes of Health. That's to study heart damage
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`that occurs in critical illness.
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`Prior to that, I had finished a grant that was
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`focused on investigating the relevance of the plasma lipidome
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`to mortality in patients with ARDS.
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`Q. And is your research funded by pharmaceutical companies?
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`A. It is not.
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`Q. Have you ever received funding from a pharmaceutical
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`company?
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`A. I have not.
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`Q. Have you published your research, Dr. Maile?
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`A. Yes.
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`Q. About how many times?
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`A. Probably about 40 times.
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`Q. And have you presented your research in meetings to other
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`physicians?
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`A. I have.
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`Q. About how many times?
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`A. Probably 10 times.
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`Q. Have you ever presented a talk related to dexmedetomidine?
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`A. I have.
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`Case: 1:16-cv-00651 Document #: 140 Filed: 08/07/18 Page 10 of 102 PageID #:5518
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`Q. Could you tell us a little more about that?
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`A. It was a talk that was a while ago, but it was focused on
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`the care of patients who are being treated with Suboxone,
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`which is a medication that can block the receptors that are
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`used by medications such as morphine to treat pain, so those
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`parents can be difficult to manage; and that involved the use
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`of dexmedetomidine to help alleviate pain.
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`Q. And who was the audience for that presentation?
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`A. That would have been primarily board-certified
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`anesthesiologists.
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`Q. And have you used dexmedetomidine, Dr. Maile?
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`A. I have.
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`Q. About how many times have you used dexmedetomidine?
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`A. I don't have an exact number, but hundreds of times.
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`Q. And were you trained about the use of dexmedetomidine
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`during your medical training?
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`A. Yes.
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`MR. WALLACE: At this time, Fresenius Kabi moves that
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`Dr. Michael Maile be admitted as an expert in the fields of
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`anesthesiology and critical care medicine.
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`MR. BARLOW: No objection, your Honor.
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`THE COURT: So noted.
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`BY MR. WALLACE:
`
`Q. So, what is dexmedetomidine?
`
`A. Dexmedetomidine is a sedative medication.
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`Q. And what do you mean by a sedative?
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`A. A sedative is a medication that can -- will calm a patient
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`who receives it.
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`Q. And how does it work in the body?
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`A. Dexmedetomidine works by stimulating alpha-2 adrenergic
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`receptors.
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`Q. And what are those?
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`A. So, these are receptors located throughout the body. The
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`one -- the part that's involved in sedation are located in the
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`central nervous system, in the brain stem.
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`And by activating this portion of your central
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`nervous system, that in turn decreases the activity of the
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`kind of fight-or-flight portion of your autonomic nervous
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`system, which leads to sedation, lower blood pressure,
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`decreased heart rate.
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`Q. Now, are these alpha-2 adrenergic receptors, are those
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`unique to humans?
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`A. No.
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`Q. What other types of animals have these receptors?
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`A. I believe most mammals do. There are probably other
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`species as well.
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`Q. Now, how is dexmedetomidine administered to patients?
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`A. So, we administer dexmedetomidine by IV infusion.
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`Q. What's an infusion?
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`A. An infusion is where you use a device to give a constant
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`Case: 1:16-cv-00651 Document #: 140 Filed: 08/07/18 Page 12 of 102 PageID #:5520
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`rate of the medication.
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`Q. And why would a doctor use an infusion to administer a
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`drug?
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`A. So, a couple of potential reasons would be either you
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`wanted to administer it slowly so you could monitor for any
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`side effects. If the drug -- if you wanted the drug effect to
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`last for a long time and it would otherwise wear off, using an
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`infusion, you could keep the effect for as long as you wanted.
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`Q. And dexmedetomidine, that's not the only sedative
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`available to doctors, is it?
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`A. No, it is not.
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`Q. What are some other common sedatives that are used by
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`injection in the operating room or ICU setting?
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`A. So, some of the most commonly used sedatives include
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`Propofol and also some of the benzodiazepines such as
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`Midazolam.
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`Q. Now, were these other sedatives available before January
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`2012?
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`A. Yes.
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`Q. And let's first look at Propofol. Let's talk about
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`Propofol. How is Propofol provided to clinicians?
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`A. It's provided in glass ampules or glass vials.
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`Q. And was that true before January 2012?
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`A. It was.
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`Q. And once you get the Propofol, how is it prepared before
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`being administered to a patient?
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`A. It can either -- if you're using an infusion pump in which
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`you can take it directly from the vial, it could be given that
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`way; or you can draw it out into a syringe and administer it
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`from the syringe.
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`Q. Is dilution required for Propofol?
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`A. No.
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`Q. Now, you also mentioned some benzodiazepines, Midazolam.
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`How is Midazolam provided to physicians?
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`A. In a glass vial.
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`Q. And what's the preparation steps for Midazolam?
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`A. That can also be withdrawn from the vial and given
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`directly to patients.
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`Q. As of January 2012, among the commonly used injectable
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`sedatives, how many came in glass vials?
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`A. All of them.
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`Q. And as of January 2012, for the commonly used sedatives,
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`how many required dilution?
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`A. Just dexmedetomidine.
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`Q. Now, you said dexmedetomidine requires dilution. How
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`would a physician know how to dilute the drug before
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`administration?
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`A. If they were unfamiliar with the process, they would look
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`at the label.
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`Q. So, let's look at the label together. Could you please
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`pull up JTX 15. And go to page 2.
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`And is this the label that you looked at, Dr. Maile?
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`A. It is.
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`Q. And so where in a label would you expect to find
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`instructions on how to prepare the medication?
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`A. There's a section on administration and preparation.
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`Q. Let's look at page 13 of JTX 15 and look at the dilution,
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`below that, the dilution instructions.
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`So, how does the label instruct a physician to
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`prepare Precedex concentrate?
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`A. So, it states you should withdraw the 2 milliliters of
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`Precedex and add that to 48 milliliters of .9 percent sodium
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`chloride to make a total of 50 milliliters.
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`Q. And what will the concentration of dexmedetomidine be
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`after the preparation?
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`A. 4 micrograms-per-milliliter.
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`Q. I want to turn back to the first page of -- or page 2 of
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`JTX 15. Sorry. Go to that section at the top, the
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`description.
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`Now, what pH was the Precedex concentrate product
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`provided at?
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`A. So, it shows a pH of 4.527.
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`Q. And why would a physician care about the pH of a drug
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`being administered?
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`A. We prefer medications to be the physiologic pH, which
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`Case: 1:16-cv-00651 Document #: 140 Filed: 08/07/18 Page 15 of 102 PageID #:5523
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`would be about 7.4. If you have pHs on the extreme, either
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`extremely acidic or extremely alkaline, it can be irritating
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`or damaging to the tissues, such as the veins or skin.
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`Q. And if we can turn to page 7 of JTX 15. We have a section
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`called, "Indication." What is the indication in a label
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`generally?
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`A. It tells you for what reasons the FDA has approved
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`physicians to use this drug for patients.
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`Q. And for what reason was Precedex approved in patients?
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`A. For the sedation of initially intubated and mechanically
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`ventilated patients during treatment in an intensive care
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`setting.
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`Q. Now, there's a statement after that about not to exceed
`
`24 hours. Do you see that, Dr. Maile?
`
`A. I do.
`
`Q. And why were physicians not to -- why were they instructed
`
`not to administer the drug for more than 24 hours?
`
`A. So, there's a concern that continuing the infusion for
`
`greater than 24 hours could lead to rebound hypertension when
`
`it was discontinued.
`
`Q. And what is rebound hypertension?
`
`A. So, basically, the body gets used to the suppression of
`
`the fight-or-flight part of the autonomic nervous system that
`
`I mentioned, so when you take it away, it's kind of -- instead
`
`of being at your normal blood pressure, it would be at the
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`Case: 1:16-cv-00651 Document #: 140 Filed: 08/07/18 Page 16 of 102 PageID #:5524
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`higher blood pressure. And that's typical of this class of
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`medications.
`
`Q. Now, you were asked to provide opinions about the
`
`dexmedetomidine IND, correct?
`
`A. Correct.
`
`Q. And what issue were you asked to analyze?
`
`A. Whether or not the IND described a ready-to-use
`
`formulation that was ready for patenting.
`
`Q. And what was your conclusion that you reached?
`
`A. I thought that it did.
`
`Q. And were you provided a legal standard from counsel to
`
`analyze this issue?
`
`A. I was.
`
`Q. And did you prepare a demonstrative to describe that
`
`standard?
`
`A. I did.
`
`Q. Let's look at DDX 302.
`
`So, what legal standard did you apply, Dr. Maile,
`
`when analyzing the issue of ready for patenting?
`
`A. So, either it was described in sufficient detail for a
`
`POSA to make, use, or practice the product or method, or the
`
`product or method was actually made or practiced.
`
`Q. So, this is an "or." Which of these did you find in your
`
`analysis of the IND?
`
`A. I thought that both of these were satisfied.
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`Case: 1:16-cv-00651 Document #: 140 Filed: 08/07/18 Page 17 of 102 PageID #:5525
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`Q. Now, I know we've seen before an IND is a huge document.
`
`What type of information -- did you prepare a summary of the
`
`type of information that was relevant to your analysis?
`
`A. Yes, I did.
`
`Q. Let's look at DDX 303.
`
`So, what categories of information were relevant to
`
`you in analyzing this ready for patenting issue?
`
`A. Well first looking at just the class of medications and
`
`what can be learned from that, and then looking at the
`
`administration and side effects that were described, and
`
`finally looking at animal and human studies that were in
`
`the IND.
`
`Q. So, what portion of the IND did you use to conduct this
`
`analysis?
`
`A. I started with the investigator's brochure.
`
`Q. So, let's look there. Let's start in JTX 35, and let's
`
`start at page 13.
`
`So, first off, Dr. Maile, what is an investigator's
`
`brochure?
`
`A. An investigator's brochure is a collection of information
`
`that a company who's developing a product or someone who's
`
`developing a product would put together to give to the
`
`investigator so they would know everything that was understood
`
`about that drug before they started their clinical trials.
`
`Q. Is it expected that a clinician will review the
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`Case: 1:16-cv-00651 Document #: 140 Filed: 08/07/18 Page 18 of 102 PageID #:5526
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`investigator's brochure before taking part in a trial?
`
`A. It is.
`
`Q. So, who typically prepares an investigator's brochure?
`
`A. The company developing the product.
`
`Q. And for this particular investigator's brochure, who
`
`prepared it?
`
`A. The Farmos Group.
`
`Q. And what's the date of this brochure?
`
`A. It was last amended March 8th of 1989.
`
`Q. If we can step ahead to page 16, the introduction, what is
`
`being communicated in the introduction to physicians?
`
`A. So, this provides information from other medications that
`
`are within the same class, starting with Clonidine, which was
`
`an alpha-2 adrenoceptor agonist that was already available at
`
`the time.
`
`Q. And why would discussion of other drugs be relevant to an
`
`investigator who's going to be using dexmedetomidine in a
`
`trial?
`
`A. Because those medications have a similar mechanism of
`
`action, you would expect the effect to be similar.
`
`Q. And what were the effects of alpha-2 -- or what was the
`
`known effect of alpha-2 adrenoceptor agonists as of the time
`
`of this investigator's brochure?
`
`A. So, lowering of the blood pressure and sedation.
`
`Q. I'm going to turn ahead to the next page, page 20,
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`Case: 1:16-cv-00651 Document #: 140 Filed: 08/07/18 Page 19 of 102 PageID #:5527
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`pharmaceutical data. I'm sorry, page 20.
`
`And so what's being described here, Dr. Maile?
`
`A. This is the -- the drug that's being provided to the
`
`investigators.
`
`Q. And what is the formulation of the drug that's being
`
`provided?
`
`A. So, it's dexmedetomidine hydrochloride at a concentration
`
`of 20 micrograms-per-milliliter in a clear, colorless ampule.
`
`Q. And are ampules still used today in the ICU or operating
`
`room?
`
`A. Yes.
`
`Q. And are they -- are ampules used today for drugs that
`
`don't require dilution?
`
`A. They are.
`
`Q. Could you give us an example?
`
`A. Propofol would be an example.
`
`Q. So, if we turn to the next page, there's a section
`
`entitled, "Animal Pharmacology." Do you see that, Dr. Maile?
`
`A. I do.
`
`Q. If this is a brochure for human studies, why would there
`
`be an inclusion of animal data?
`
`A. So, drugs are always studied in animals before they're
`
`given to humans so we can understand the way they work.
`
`Q. And have you reviewed the data that is described in this
`
`animal pharmacology section?
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`A. I have.
`
`Q. And what was the conclusion about the effects of
`
`dexmedetomidine on animals?
`
`A. I mean, here, they list -- they say, "A variety of effects
`
`including sedation, analgesia, relief of anxiety, hypotension,
`
`bradycardia," et cetera.
`
`Q. Now, besides the animal studies, does this investigator's
`
`brochure provide data about human studies?
`
`A. It does.
`
`Q. So, let's jump ahead to page 44. Let's look at the
`
`introduction on the clinical program.
`
`So, what information is the investigator's brochure
`
`providing to doctors about the status of the clinical program?
`
`A. It's stating that a Phase I study and a pharmacokinetic
`
`study have already been performed and completed, and that
`
`there are ongoing Phase I and Phase II studies.
`
`Q. So, what's the difference between a Phase I and a Phase II
`
`study?
`
`A. Phase I studies are when the study drug is administered
`
`typically to healthy volunteers, and Phase II studies, you
`
`would start administering the drug to patients.
`
`Q. Well, if Phase I is a study on a healthy volunteer, what
`
`can that possibly tell a clinician about a sedative?
`
`A. Healthy volunteers can also become sedated, so in this
`
`case, you could gain some information about how it would work.
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`Case: 1:16-cv-00651 Document #: 140 Filed: 08/07/18 Page 21 of 102 PageID #:5529
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`Q. And is that true for all drugs?
`
`A. If you were doing a Phase I study of something like an
`
`antibiotic and the volunteer didn't have an infection, you
`
`couldn't really evaluate if it was treating the infection.
`
`Q. What, if anything, does the fact that Phase II studies
`
`have started tell a POSA about the progress of
`
`dexmedetomidine?
`
`A. That would tell you that the data they're collecting thus
`
`far is promising, and they're choosing to continue developing
`
`the drug.
`
`Q. So, this is clinical data on dexmedetomidine. Are there
`
`clinical trials reported for any other drug?
`
`A. They do provide some information on medetomidine.
`
`Q. All right. Let's step ahead to page 51 of JTX 35, heading
`
`6.5.
`
`And so what's being communicated here to doctors?
`
`A. This is providing information from three clinical Phase I
`
`studies and one Phase II study with racemic medetomidine.
`
`Q. And why would clinical studies on medetomidine be relevant
`
`to an investigator who's about to start a trial on
`
`dexmedetomidine?
`
`A. So, since medetomidine would kind of be the same class, in
`
`fact, it would contain dexmedetomidine, any data from these
`
`sorts of studies would be very relevant.
`
`Q. So, we've looked at an investigator's brochure. What
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`Case: 1:16-cv-00651 Document #: 140 Filed: 08/07/18 Page 22 of 102 PageID #:5530
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`493
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`other types of information did you look at to analyze ready
`
`for patenting?
`
`A. There were some study protocols that were included in this
`
`document.
`
`Q. Okay. So, within this document, let's jump ahead to
`
`page 63. Is this one of the clinical protocols that you're
`
`talking about, Dr. Maile?
`
`A. It is.
`
`Q. Okay. First, what is a clinical protocol?
`
`A. So, a clinical protocol describes a step -- the steps that
`
`are taken to -- in a study to evaluate a drug.
`
`Q. And are the steps in a protocol optional for the
`
`investigator?
`
`A. No.
`
`Q. And why not?
`
`A. The -- because the study's interested in evaluating the
`
`effect of the drug, if people change the protocol, you could
`
`actually be investigating the changes in the protocol, which
`
`isn't what you're interested in.
`
`Q. So, let's look at the title of this study. What is the
`
`title here, Dr. Maile?
`
`A. A double-blind placebo-controlled Phase I study of
`
`tolerance to dexmedetomidine hydrochloride injection in
`
`healthy human male volunteers.
`
`Q. What is meant by a double-blind study?
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`Case: 1:16-cv-00651 Document #: 140 Filed: 08/07/18 Page 23 of 102 PageID #:5531
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`494
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`A. So, double-blind refers to a situation in which the
`
`subject doesn't know what they're receiving, which -- and
`
`also, the person administering the drug doesn't know what
`
`they're giving.
`
`Q. Okay. And what's the number of this study?
`
`A. The number is FAR NA 88-02-02.
`
`Q. That's a little bit of a mouthful. Is there a shorthand
`
`that we can use to refer to this clinical protocol, Dr. Maile?
`
`A. The Maze protocol, since he's one of the principal
`
`investigators.
`
`Q. Let's turn ahead to page 64. Let's look at the abstract
`
`here within the IND of this Maze protocol.
`
`So, what is Farmos investigating in the Maze
`
`protocol?
`
`A. They state that the purpose of the study is to investigate
`
`the safety of dexmedetomidine in healthy male human
`
`volunteers.
`
`Q. And how are they doing that? What's the structure of this
`
`Maze protocol?
`
`A. So, they're administering a -- several different doses of
`
`the study drug, and one of the doses would be a placebo.
`
`Q. And is this typical or atypical design of a study?
`
`A. It would be typical.
`
`Q. And why is that?
`
`A. In order so you can compare the effect of different doses
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`Case: 1:16-cv-00651 Document #: 140 Filed: 08/07/18 Page 24 of 102 PageID #:5532
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`of the medication.
`
`Q. Now, does this protocol tell a clinician how to administer
`
`dexmedetomidine?
`
`A. It does.
`
`Q. Let's look at that section then. Let's jump ahead to
`
`page 69.
`
`So, in the materials section, what is being provided
`
`to the doctors that are going to be conducting the Maze
`
`protocol?
`
`A. It's 20-microgram-per-milliliter solution of
`
`dexmedetomidine hydrochloride in .9 percent sodium chloride.
`
`Q. And how does this investigational test article compare
`
`with the pharmaceutical data that we saw on the investigator's
`
`brochure?
`
`A. It is the same.
`
`Q. So, doctors are provided these ampules. How are they
`
`supposed to actually administer it to the patient?
`
`A. It would be -- they would follow the instructions in the
`
`methods.
`
`Q. Okay. Let's turn to the next page, the methods,
`
`Section 4.3, page 70 of JTX 35.
`
`How is this drug prepared before administration to
`
`the subjects?
`
`A. So, because the four different doses are determined on the
`
`patient's -- by the patient's weight, there's a table here
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`that has the investigator multiply their weight by a number,
`
`and that would give them the volume that they would need to
`
`withdraw from the ampules to create the dose.
`
`And then that volume would be diluted with normal
`
`saline to create a total volume of 15 milliliters. And then
`
`that would be shaken, and 10 milliliters would be injected
`
`over two minutes, which would give the dose that they were
`
`studying.
`
`Q. Okay. And did you review the court's claim construction
`
`of the term "ready-to-use" as part of your analysis?
`
`A. I did.
`
`Q. Could we please look at DDX 304, please.
`
`And what was the claim construction of "ready-to-use"
`
`that you used in your analysis?
`
`A. Formulated to be suitable for administration to a patient
`
`without dilution or reconstitution.
`
`Q. Okay. And so if we can turn back to page 70.
`
`So, is this Maze protocol, is this a ready-to-use
`
`preparation of dexmedetomidine?
`
`A. It is not.
`
`Q. And why not?
`
`A. Because of the dilution step.
`
`Q. And how do you know this drug has to be diluted?
`
`A. Because it states it in the method section.
`
`Q. Now, is this the only clinical protocol that you looked
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`Case: 1:16-cv-00651 Document #: 140 Filed: 08/07/18 Page 26 of 102 PageID #:5534
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`at, Dr. Maile?
`
`A. It is not.
`
`Q. What was the other?
`
`A. There was a protocol with a principal investigator of
`
`Shafer.
`
`Q. Let's turn to JTX 38, and let's turn to page 3 of this
`
`document, please.
`
`Is this the protocol to which you were referring,
`
`Dr. Maile?
`
`A. It is.
`
`Q. And what's the title of this study?
`
`A. The title is the pharmacokinetics and pharmacodynamics of
`
`dexmedetomidine in adult volunteers.
`
`Q. And what's the study number of this study?
`
`A. It is F-DEX-CL-0690-USA.
`
`Q. Now, is this Shafer protocol, is this part of the IND,
`
`Dr. Maile?
`
`A. It is.
`
`Q. And how do you know that?
`
`A. Because it was provided along with the IND documents.
`
`Q. So, if we look back to the title, what is -- what is meant
`
`by pharmacokinetics?
`
`A. So that's

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