Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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`Page 1
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` UNITED STATES PATENT AND TRADEMARK OFFICE
`
` __________
`
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
` __________
`
` PAR PHARMACEUTICAL, INC.,
` Petitioner,
`
` v.
`
` HORIZON THERAPEUTICS, LLC,
` Patent Owner.
`
` __________
`
` Case IPR2017-01767 (Patent 9,254,278)
` Case IPR2017-01768 (Patent 9,095,559)
` Case IPR2017-01769 (Patent 9,326,966)
`
` __________
`
` Deposition of
`
` GREGORY M. ENNS, M.B., Ch.B.
`
` Wednesday, July 18, 2018
`
`REPORTED BY: JOHN WISSENBACH, RDR, CRR, CRC
`
` CSR 6862
`
`GregoryEdwards, LLC | Worldwide Court Reporting
`GregoryEdwards.com | 866-4Team GE
`
`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 1 of 294
`
`
`
`Page 1
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` UNITED STATES PATENT AND TRADEMARK OFFICE
`
` __________
`
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
` __________
`
` PAR PHARMACEUTICAL, INC.,
` Petitioner,
`
` v.
`
` HORIZON THERAPEUTICS, LLC,
` Patent Owner.
`
` __________
`
` Case IPR2017-01767 (Patent 9,254,278)
` Case IPR2017-01768 (Patent 9,095,559)
` Case IPR2017-01769 (Patent 9,326,966)
`
` __________
`
` Deposition of
`
` GREGORY M. ENNS, M.B., Ch.B.
`
` Wednesday, July 18, 2018
`
`REPORTED BY: JOHN WISSENBACH, RDR, CRR, CRC
`
` CSR 6862
`
`GregoryEdwards, LLC | Worldwide Court Reporting
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`
`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 1 of 294
`
`
`
`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
`
`Page 2
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` INDEX OF EXAMINATIONS
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` Page
`
`WITNESS:
`
`GREGORY M. ENNS, M.B., Ch.B.
`
` Examination by Mr. Silverstein 4
`
` Examination by Mr. Green 284
`
` ****
`
` E X H I B I T S
`
`No. Description Page
`
`Exhibit 1026 Inborn Metabolic Diseases, Diagnosis 4
` and Treatment, 3rd, Revised Edition,
` J. Fernandes, et al.,
` Springer-Verlag; Chapter 17,
` Disorders of the Urea Cycle, J.V.
` Leonard (title pages and pages
` 215-222)
`
` ****
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 2 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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` BE IT REMEMBERED that, pursuant to the laws
`
`governing the taking and use of depositions, on
`
`Wednesday, July 18, 2018, commencing at 8:57 a.m.
`
`thereof, at the offices of Regus, 228 Hamilton Avenue,
`
`3rd Floor, Palo Alto, California, before me, JOHN
`
`WISSENBACH, a Certified Shorthand Reporter, personally
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`appeared GREGORY M. ENNS, M.B., Ch.B., called as a
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`witness by the Petitioner, who, being by me first duly
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`sworn, was thereupon examined as a witness in said
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`action.
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` APPEARANCES OF COUNSEL
`
`For the Petitioner:
`
` AXINN, VELTROP & HARKRIDER LLP
` BY: DAVID H. SILVERSTEIN, Attorney at Law
` 114 West 47th Street
` New York, New York 10036
` (212) 261-5651 dsilverstein@axinn.com
`
` AXINN, VELTROP & HARKRIDER LLP
` BY: AZIZ BURGY, Attorney at Law
` 950 F Street, NW
` Washington, DC 20004
` (202) 721-5417 aburgy@axinn.com
`
`For the Patent Owner:
`
` GREEN, GRIFFITH & BORG-BREEN LLP
` BY: ROBERT F. GREEN, Attorney at Law
` ANN K. KOTZE, Attorney at Law
` 676 North Michigan Avenue, Suite 3900
` Chicago, Illinois 60611
` (312) 883-8080 rgreen@greengriffith.com
` (312) 883-8015 akotze@greengriffith.com
`
` ---o0o---
`
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`
`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 3 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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` (Deposition Exhibit 1026 was marked for
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`identification.)
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` EXAMINATION BY MR. SILVERSTEIN
`
` Q. Good morning, Dr. Enns.
`
` A. Good morning.
`
` Q. My name is David Silverstein. I'll be taking
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`your deposition today. Do you mind stating your full
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`name and address for the record.
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` A. Gregory Mark Enns. Shall I state my home or my
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`work address?
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` Q. Both.
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` A. Okay. My home address is 907 Whitehall Lane,
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`Redwood City, California 94601, and my work address is
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`300 Pasteur Drive, Stanford, California 94305.
`
` Q. I think I've -- I've seen a couple of them, so
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`I know you've been deposed a number of times, and you've
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`testified a number of times; is that correct?
`
` A. Yes.
`
` Q. How many times have you been deposed?
`
` A. Approximately 30 to 35 times.
`
` Q. Okay. And how many of those were patent cases?
`
` A. The patent cases are a handful of times. I
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`don't recall off the top of my head. It would be five
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`or so, I think; maybe more. It's all a bit of a blur.
`
` Q. Have you testified at trial before?
`
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`
`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 4 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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` A. Yes.
`
` Q. How many times?
`
` A. I've testified once for plaintiffs in a medical
`
`malpractice case by a video deposition for a trial. I
`
`was a defense expert in another medical malpractice
`
`case. And recently -- this wasn't a trial; it was an
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`arbitration, so I'm not sure if that counts. But I
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`testified in an arbitration recently.
`
` Q. Testified in any patent cases?
`
` A. No.
`
` Q. In your role as expert witnesses in patent
`
`cases, has it always been on the side of the brand?
`
` A. Yes.
`
` Q. Okay. Have you ever been sued before?
`
` A. Yes.
`
` Q. What was the nature of those matters?
`
` A. It was a single case, several years back now,
`
`related to a genetic test that I had performed in a
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`patient I had seen once, ten years before getting notice
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`of being sued. The case related to a laboratory result
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`being report -- reported as negative, and then ten years
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`later the laboratory redid the test and found out that
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`they had made a mistake.
`
` Q. So was that a medical malpractice case?
`
` A. It was.
`
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 5 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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` Q. And you were a defendant in the case?
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` A. I was, yes.
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` And just for the record, I was dismissed from
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`it, and it was all gone away without a settlement or
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`anything else.
`
` Q. Okay. Just to review briefly the ground rules
`
`for the deposition, if I ask a question and you answer,
`
`I'm going to assume that you understood the question
`
`unless you ask me to clarify or you ask another
`
`question. Do you understand that?
`
` A. Yes.
`
` Q. Okay. For today's deposition, unless I specify
`
`otherwise, I want you to assume that the time frame of
`
`my questions is as of 2011. Do you understand that?
`
` A. Yes.
`
` Q. As you know, for the court reporter, verbal
`
`answers are -- make the record clearer, so "yes"/"no" is
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`better than nodding. If you'd like to take a break, I'm
`
`happy to indulge you, but just as long as there's not a
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`question pending.
`
` What did you do to prepare for today's
`
`deposition?
`
` A. I read my declaration, and I met with counsel
`
`yesterday to go over my declaration, and I reviewed some
`
`of the exhibits related to this matter, as well as
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 6 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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`reading the declaration testimony of Dr. Sondheimer. I
`
`also reviewed the patents in question.
`
` Q. Did you review any other documents?
`
` A. I think that's the totality of what I reviewed.
`
` Q. Okay. Did you review the final written
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`decision in the IPR that Lupin filed on the '559 patent?
`
` A. No.
`
` Q. Have you ever reviewed it?
`
` A. No.
`
` Q. Did you review the final written decision on
`
`the '215 patent?
`
` A. No.
`
` Q. Okay. You understand by "'215 patent," I mean
`
`it's the parent patent of the '559 patent?
`
` A. Yes.
`
` Q. Okay. And just a little point of clarity. So
`
`you said you reviewed your declaration. So this is a
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`consolidated deposition for all three, the '559, '278,
`
`to '966 patent IPRs. Do you understand that?
`
` A. Yes.
`
` Q. And I assume you reviewed all three
`
`declarations, or just one of them?
`
` A. Well, I reviewed the '559 primarily, and I
`
`looked through the other declarations in brief. But
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`they're all dealing with similar material.
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 7 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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` Q. And for ease of today's proceeding, I'll
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`provide you all three, but we'll focus the discussion on
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`the '559. If there's any substantive differences in the
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`other two declarations when I ask a question and you're
`
`answering, please -- please point that out if you feel
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`the need.
`
` A. Okay.
`
` Q. Did you take any notes during your preparation
`
`yesterday with counsel?
`
` A. I took some notes, yes.
`
` Q. Did you -- did you bring them with you?
`
` A. I have some of the notes with me, yes. I'm not
`
`sure if I brought them all. I haven't reviewed them
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`since yesterday.
`
` Q. Okay.
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` A. But I've got my briefcase that I took with me
`
`to the meeting.
`
` Q. Did you bring any other documents with you
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`today?
`
` A. I did. I've got copies of my declarations in
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`hard copy, and I've got a file that I've used in the
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`past for past matters related to Horizon. I also have
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`my computer, and that has the exhibits and other
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`materials on electronic files, as well.
`
` Q. Okay. Did you conduct the search -- searches
`
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 8 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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`for the prior art that you rely on in the '559, '966,
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`and '278 declarations?
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` A. It was a combination, I would say. I, of
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`course, know the literature well, and I conducted
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`searches related to that, but I was also provided
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`materials that had to deal with the prior art.
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` Q. The prior art you do rely on in your
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`declarations, do you believe they're reliable and
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`accurate?
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` A. Well, as far as "reliable and accurate" goes,
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`these are published materials that are in the record. I
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`would have to review each document to determine the
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`extent of the reliability per se. But they're
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`reasonable documents, that have been published in
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`peer-reviewed journals, for the most part, but there are
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`other statements, such as packet inserts and other
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`documents, in there as well, so I would have to -- as a
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`blanket, to say that perhaps one by one I would have to
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`look at it to discuss the precise reliability.
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` Q. Uh-huh. But to your knowledge, are there any
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`prior art references you rely on in these matters that
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`are not reliable?
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` A. Well, reliability, again, is a matter of
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`exactly what -- what is stated in each exhibit, for
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`example. A book is typically not peer reviewed, whereas
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 9 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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`a medical article appearing in a journal would have some
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`peer review, typically, unless it is a review article.
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`Sometimes abstracts have been listed as part of
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`exhibits, and they don't, of course, carry the weight as
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`a -- of -- a peer-reviewed article would, et cetera. So
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`in general these are parts of the prior art that have
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`been published, and depending upon the publication
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`process and the peer review process and the actual, for
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`example, number of patients reviewed, a case report
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`versus a -- a large study involving lots of patients,
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`the reliability is going to vary from subject matter to
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`subject matter.
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` Q. Is it safe to say, though, if you relied on a
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`prior art reference, that in your opinion that reference
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`would be relevant to a POSA in the context of these
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`IPRs?
`
` A. I think overall that would be a safe summary.
`
` Q. What is your current position?
`
` A. I'm a professor of pediatrics in the Department
`
`of Pediatrics in the Division of Medical Genetics at
`
`Stanford University.
`
` Q. And do you treat UCD patients?
`
` A. Yes.
`
` Q. Approximately how many currently?
`
` A. Currently approximately 40, I think.
`
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 10 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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` Q. And what -- what ages?
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` A. Ages range from infants to adults. The oldest
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`adult that I was treating passed away. He was in his
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`seventies or eighties. So generally the adults that I'm
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`currently following are in their fifties, and there's a
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`collection of maybe a handful of infants that I
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`currently follow as well, so in between. The majority
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`would be in the childhood range.
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` Q. The patient that passed away, did they acquire
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`UCD congenitally?
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` A. Yes. This was a congenital abnormality. It
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`was genetic defect.
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` Q. Around 2011, how many UCD patients were you
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`treating?
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` A. 2011, it was probably relatively similar. It
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`comes and goes a little bit with referrals and patients
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`coming in and out of town. One of the most common
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`things that happens in our practice, because we're a
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`known center for this, is patients come in from around
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`the world for liver transplantation, for example. I
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`might follow that patient for a period of time, and then
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`they go back to their home base. But I think it's been
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`fairly steady over the last -- last eight or so years to
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`be following continuously around 40 patients.
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` Q. What is your understanding of treatment of
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 11 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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`chronic UCDs?
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` A. It's a pretty broad question.
`
` Q. Well, let me ask it different: chronic versus
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`acute?
`
` A. Okay.
`
` Q. Would you categorize the types of UCD treatment
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`in those -- with those two labels, or would you use
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`something else?
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` A. Yeah, again, it really depends, because a
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`patient who is on chronic treatment might have a
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`biochemical crisis associated with hyperammonemia that
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`would go into an acute phase, for example. A new
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`patient who has not been treated at all might have an
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`acute metabolic crisis, requiring significant rescue
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`therapy, which would then be transferred into more
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`chronic management.
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` So it's a little bit of a continuum in some
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`ways, and in others -- the general feeling, I would say,
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`is an acute treatment is typically associated with a --
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`a metabolic crisis or a hyperammonemic state that needs
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`some acute intervention. However, chronic management
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`also involves some degree of acute intervention, too, as
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`far as adjusting medication dosages, that might not
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`necessarily require admission to hospital, or changing
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`the diet, that might not necessarily require admission.
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 12 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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`So it's, I think, a bit of a continuum.
`
` Q. In your care of the about 40 UCD patients
`
`currently, do you care for the -- do you chronic -- are
`
`you involved in chronic management of the UCD or acute
`
`treatment?
`
` A. Both. As far as the acute therapy would go, I
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`also have a colleague, who has started within the last
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`couple of years, to my great delight, where I cannot
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`necessarily be involved in the acute management unless
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`I'm specifically on call or if there's a specific
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`question that arises that my colleague might have. So
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`I'm on call as what we call a biochemical backup at
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`least six months of the year, and we share that call
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`with my colleague, who is also a biochemical geneticist.
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` Q. Uh-huh. So other than, I believe you
`
`mentioned, adjusting the dose and changing the diet in
`
`the context of chronic management, what other courses of
`
`action might you take in treating those patients for
`
`chronic UCD?
`
` A. Chronic therapy involves a comprehensive
`
`evaluation of the patient and family. So a patient
`
`would be seen in the context of our biochemical genetics
`
`clinic, and that includes evaluation medically by -- by
`
`me or my colleague. It includes a dietician evaluation
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`of nutritional status and current dietary practices,
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
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`also a nurse evaluation if -- these children typically
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`or often are on G-tube feeds or other things.
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` (Discussion off the record.)
`
` THE WITNESS: G-tube, gastrostomy tube, feeds.
`
` So a nurse is also there and available, as is
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`a -- as is a social worker, who -- who looks at the
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`overall family dynamics and other things.
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` So from that evaluation, we make an assessment
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`of what the needs are of that individual patient.
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`Individual patients will have a range of biochemical
`
`abnormalities associated with their underlying enzyme
`
`defect. A urea cycle patient has a variety of different
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`potential levels of severity, for example. So assessing
`
`the severity of the patient's clinical status is part of
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`what we do.
`
` We provide the patients all with an emergency
`
`management protocol, as well as an emergency letter.
`
`The emergency letter is typically used for, as we were
`
`discussing before, a transition to a more acute phase.
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`If the child is acutely unwell, there would be a need to
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`be evaluated promptly to -- to initiate other therapy,
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`potentially, and we don't want these patients lounging
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`around in the emergency department. We need them to be
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`looked upon quickly.
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` So part of that is, I think, general education,
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 14 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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`et cetera; also, evaluating the state of hospital stays
`
`and neurological status and providing guidance on a
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`variety of different treatments. You mentioned diet and
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`medication therapy, which are part of it, of course.
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`Dietary involvement is also using special nutritional
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`supplements that are not just a low-protein diet, but
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`essential amino acid supplements that are used in
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`treating these disorders. And the other thing, of
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`course, is providing guidance on such things as liver
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`transplantation and how we follow these patients
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`before/after transplantation.
`
` So it's a global interaction, with a lot of
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`inputs and a lot of different people working on the
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`management of these patients.
`
`BY MR. SILVERSTEIN:
`
` Q. So as far as your involvement, though,
`
`everything you listed is what you were involved with
`
`personally, or -- I guess I'm just --
`
` A. I --
`
` Q. The line's a little blurry of --
`
` A. Right.
`
` Q. -- consulting with -- with others versus
`
`what --
`
` A. No, I can -- I can see.
`
` So I would be the -- the sort of person where
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 15 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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`the buck stops. So I -- I would be the one who would be
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`guiding the overall care and evaluation of the patient.
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`Our dietician would provide me with data related to the
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`amount of protein intake, for example, a child is
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`experiencing. We would look at laboratory values, such
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`as amino acids and other values, in order to determine
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`whether protein intake, for example, is adequate for
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`growth. We would be monitoring growth chart, and things
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`like that. So I would interact with that individual,
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`and together we would come up with a reasonable plan,
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`that would have to be okayed in its final form by me.
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`However, there are a lot of different inputs. And
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`that's why you need a team approach here.
`
` Q. It sounds like, if I'm understanding you
`
`correctly, as a physician chronically managing a UCD
`
`patient, you're involved in treatment, diagnosis, and
`
`counseling. Is that right?
`
` A. I think that's fair. We also -- and thank you
`
`for reminding me. We also have genetic counselors, who
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`are seeing patients, as well as our residents in
`
`training and fellows in training, who will also see
`
`these patients. So part of what we're doing is
`
`education. And there are genetic counseling aspects to
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`this as well. However, for the very basic going over
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`inheritance patterns and how things are transmitted down
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`Par Pharmaceutical, Inc. Ex. 1027
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`Page 16 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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`the family line, et cetera, we will often resort to
`
`using our genetic counselors, because they have
`
`tremendous experience in talking to families about this,
`
`et cetera. But --
`
` Q. Right.
`
` A. You know, that's also part of what I do, yes.
`
` Q. As part of chronic management, do you -- let me
`
`back up. So you had mentioned a plan for -- or you say
`
`a guidance -- strike that.
`
` A moment ago, you mentioned as part of the
`
`chronic management you'd offer guidance of liver
`
`transplantation. So just to be clear, liver
`
`transplantation, is that part of chronic management?
`
` A. Well, it's part of seeing a patient who's being
`
`managed chronically. And post transplantation we will
`
`also follow these children to see how they're doing, but
`
`their acute need is much less, because once you've
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`transplanted a liver, the -- there's no longer any
`
`further danger of having elevated ammonia, as long as
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`that liver is functioning well.
`
` So it is a part of chronic management seeing
`
`how the family is doing post transplant, following
`
`alongside our liver transplant team, but that's a much
`
`easier visit for us, because we're no longer prescribing
`
`medications or offering dietary management, because the
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`
`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 17 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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`diet is liberalized once a liver transplantation is in
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`place. However, we have a tendency to provide amino
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`acid supplements, because liver transplantation will not
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`completely correct certain amino acid deficits that are
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`present because of the urea cycle defect in some cases.
`
` Q. Got it. And you'd also mentioned as part of
`
`the chronic treatment or management there's the
`
`emergency management protocol and letter. Is -- are you
`
`saying that emergency management is part of chronic
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`management?
`
` A. I'm saying it's -- education is part of chronic
`
`management. So the -- it's important, when seeing our
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`patients, to make sure that the family or the patient
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`understands the need to be seen acutely and any sort of
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`an illness that can cause catabolism especially, because
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`those are illnesses that can result in a high ammonia
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`level.
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` So we go over with them, typically, an
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`emergency protocol in basic terms and make sure that
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`they understand if -- if it's an adult and you're
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`feeling woozy or lethargic or you're vomiting and not
`
`taking in normal food, that you make sure you be seen
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`quickly. And we also make sure that that individual or,
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`in the case of a child, the family will have an
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`emergency letter that explains the underlying diagnosis,
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 18 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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`that they can use as almost an insurance policy when
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`they're going to their own physician or to the emergency
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`department, so that they're taken into consideration
`
`rapidly and seriously.
`
` Q. If they become acute?
`
` A. If they become acute.
`
` (Discussion off the record.)
`
` MR. SILVERSTEIN: "If they become acute."
`
` THE WITNESS: Correct, if they come -- if they
`
`become acute. But it's -- also part of chronic
`
`management is this educational process, I would say,
`
`making sure patients understand the needs to be seen
`
`rapidly and know that we're always available for them if
`
`need be.
`
`BY MR. SILVERSTEIN:
`
` Q. Okay. The genetic counselors you mentioned,
`
`are they practicing medical doctors?
`
` A. No. No, they typically have master's of
`
`science in genetic counseling, and they -- they're
`
`licensed as certified genetic counselors.
`
` Q. What about the dieticians? Are they medical
`
`doctors?
`
` A. No.
`
` Q. Okay.
`
` A. But they're -- again, the dieticians would be
`
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 19 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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`registered dieticians.
`
` Q. Is blood dialysis part of chronic management?
`
` A. No, typically that would be acute-phase
`
`management. Hemodialysis would -- would be used in the
`
`acute treatment of hyperammonemia, in particular in
`
`cases where there's a very high level of ammonia in a
`
`patient who is lethargic, going into a coma, or
`
`comatose.
`
` Q. And what do you mean by "very high level" of
`
`ammonia?
`
` A. That's a good -- good question.
`
` For dialysis, typically we're invoking
`
`hemodialysis or hemodiafiltration when ammonia levels
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`are above approximately 600 micromolar. If they're
`
`between 200 to 600 micromolar, oftentimes we're
`
`successful in lowering the ammonia level with nitrogen
`
`scavenging medications given IV plus providing high
`
`caloric support given IV as well.
`
` However, the way it works, and the way it
`
`should work, is if a patient is coming in with rising
`
`ammonia and altered mental status, especially over
`
`200 micromolar, the IVs are being placed, and we're
`
`monitoring these patients for their hyperammonemia
`
`situation and their clinic status, and we might be able
`
`to get a response just with what I would say medical
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 20 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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`management without dialysis.
`
` Q. Okay.
`
` A. However, dialysis catheters are often being
`
`placed and the nephrology team is being contacted
`
`simultaneously to be in place just in case this medical
`
`management doesn't work as we would hope it would.
`
` Q. Okay.
`
` A. Sometimes we have a patient who is what we
`
`would say a frequent flyer, who comes in relatively
`
`frequently, and we know what his or her response is
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`likely to be, and likely they will respond to fluid
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`resuscitation with intravenous medications, for example,
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`and we would not need dialysis in that situation or the
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`emergent call to put in a dialysis catheter. We'd
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`typically just alert the team to know that they're
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`coming in, that a patient is coming in; and alerting the
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`team, I mean the nephrology team, to be aware.
`
` So it really depends upon our experience with
`
`the patient, as well. But in general, hemodialysis or
`
`any sort of dialysis is an acute event.
`
` Q. So what about -- you mentioned IV medication.
`
`So those are part of acute treatment. Are they part of
`
`chronic management?
`
` A. Intravenous medications are typically not part
`
`of chronic management, but they can be in -- in some
`
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`Par Pharmaceutical, Inc. Ex. 1027
`Par v. Horizon, IPR2017-01767
`Page 21 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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`situations. We have had the unfortunate experience of
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`having patients be very difficult to treat as far as
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`maintaining a -- ammonia levels in an acceptable range.
`
`And oftentimes, I would say -- "oftentimes." We've had
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`a handful of these patients where they've been sent to
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`our facility because they've had ammonia levels that
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`have been unable to be controlled with the typical
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`management of diet plus enteral, and while waiting for
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`liver transplantation or while being prepared for liver
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`transplantation, we would have to have a handful of
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`patients on IV nitrogen scavengers for a variety of
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`reasons that have lasted for weeks. So in a sense,
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`that's not really acute management; it's -- it's, maybe,
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`subacute on chronic management for period -- periods
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`that can lengthen into several weeks. But those types
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`of situations, fortunately, are relatively rare.
`
` Q. Okay. So you had mentioned for these patients
`
`it's difficult to maintain the ammonia level in, as you
`
`put it, an acceptable range. But what is an acceptable
`
`range for treatment of UCD patients?
`
` A. Right. It really depends upon the patient that
`
`we're talking about, because patients are going to have
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`different enzymatic activities, for example, and
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`different typical severity of disease. However,
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`acceptable range today, that most people shoot for, is
`
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`Par Pharmaceutical, Inc. Ex. 1027
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`Page 22 of 294
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`Gregory M. Enns, M.B., Ch.B. - July 18, 2018
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`often between around 60 to 80 micromolar.
`
` Q. Is that -- is that the same as saying that the
`
`upper limit of normal is 60 to 80 for these patients?
`
` A. No. Upper limit of normal is a laboratory
`
`construct. It's something that laboratories provide
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`related to normative ranges of various laboratory
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`results. An acceptable range would be related to what
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`the physician and team and the patient accepts as being
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`a reasonable treatment goal for a patient, related to
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`ammonia in this case, but t
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