`MD/sp
` ------------------------
` BEFORE THE PATENT TRIAL AND APPEAL BOARD
` ------------------------
` PAR PHARMACEUTICAL, INC.
` Petitioner
` v.
` HORIZON THERAPEUTICS, INC.
` Patent Owner
`
`
`
` PETITION FOR INTER PARTES REVIEW OF U.S. PATENT
` NO. 8,404,215/AND U.S. PATENT NO. 8,642,012
`
`
`
` ------------------------
` This is the Deposition of NEAL SONDHEIMER, held at
` the Offices of VICTORY VERBATIM REPORTING SERVICES, Suite
` 900, 222 Bay Street, Ernst & Young Tower, Toronto-Dominion
` Centre, Toronto, Ontario, on the 10th day of March, 2016.
`
`
`
` ------------------------
`
`
`
` A P P E A R A N C E S:
` DAVID H. SILVERSTEIN} --- for the Petitioner
` AZIZ BURGY }
` Axinn, Veltrop & Harkrider
` 114 West 47th Street
` New York, New York 10036
` EMER SIMIC } --- for the Patent Owner
` ROBERT GREEN}
` Green Griffith
` NBC Tower
` 455 N. Cityfront Plaza Dr.
` Suite 3100
` Chicago, Illinois 60611
` ALSO PRESENT:
` Lauren Stevens
`
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` INDEX OF PROCEEDINGS
`
` PAGE NUMBER
`
`NEAL SONDHEIMER, affirmed
` Examination by:
` Ms. Simic 3 - 188
` Re-Examination by:
` Mr. Silverstein 188 - 233
`
`INDEX OF EXHIBITS 234
`CERTIFICATION 235
`ERRATA 236
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` 1 --- upon convening at 9:00 a.m.
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` 2 --- upon commencing at 9:00 a.m.
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` 3
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` 4 MR. WEINGOTT: Good morning. It is nine
`
` 5 o'clock on the 10th of March, 2016. We're
`
` 6 at the offices of Victory Verbatim. This
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` 7 is the deposition of Neal Sondheimer in the
`
` 8 matter of Par Pharmaceutical v. Horizon
`
` 9 Therapeutics. The reporter today is
`
`10 Matthew Dixon and the videographer is Aaron
`
`11 Weingott. Could I please have the parties
`
`12 introduce themselves and who they act for?
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`13 MS. SIMIC: Emer Simic from Green
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`14 Griffith & Borg-Breen and with me is my
`
`15 colleague, Robert Green, also of Green
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`16 Griffith. We represent Horizon
`
`17 Therapeutics Inc., and also with us today
`
`18 is Lauren Stevens from Horizon Therapeutics
`
`19 Inc.
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`20 MR. SILVERSTEIN: David Silverstein from
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`21 Axinn, Veltrop & Harkrider, representing
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`22 Par Pharmaceutical Inc. in this matter, and
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`23 with me is my colleague, Aziz Burgy, also
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`24 from the Axinn firm.
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`25 MR. DIXON: So I'm just going to
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` 1 administer the oath, sir. Would you just
`
` 2 raise your right hand? Do you solemnly
`
` 3 affirm that the evidence you're about to
`
` 4 give today will the truth, the whole truth
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` 5 and nothing but the truth?
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` 6 MR. SONDHEIMER: I do.
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` 7 MR. DIXON: Very good. Thank you.
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` 8
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` 9 NEAL SONDHEIMER, affirmed
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`10 EXAMINATION BY MS. SIMIC:
`
`11
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`
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`12 Q. Good morning, Dr. Sondheimer.
`
`13 A. Good morning.
`
`14 Q. So Dr. Sondheimer, you have
`
`15 submitted an expert declaration in the inter partes
`
`16 review concerning U.S. patent number 8,642,012. Is
`
`17 that right?
`
`18 A. That's correct.
`
`19 Q. Okay. I will give you a copy of
`
`20 your declaration. It has been marked pursuant to
`
`21 the IPR, Exhibit 1002. So Dr. Sondheimer, in your
`
`22 declaration, Exhibit 1002, at page 33 you state
`
`23 that, "A person of ordinary..." At paragraph 66:
`
`24 "...A person of ordinary skill in the art
`
`25 would have recognized that the experiments
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` 1 in Brusilow '91 by themselves were
`
` 2 insufficient to completely determine the
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` 3 excretion rate of PAGN after a dose of PAA,
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` 4 and would have sought additional
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` 5 information, such as that contained in
`
` 6 Shiple and Sherwin to identify the true
`
` 7 rate of conversion..."
`
` 8 Correct?
`
` 9 A. That's correct. I will be calling
`
`10 it Shiple.
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`11 Q. Sorry, how do you pronounce...
`
`12 A. Shiple.
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`13 Q. Shiple, okay, me too, then. So both
`
`14 Sherwin and Shiple report on the conversion rate of
`
`15 PAA to PAGN in healthy subjects, correct?
`
`16 A. That's correct. They are normal
`
`17 subjects.
`
`18 Q. Okay, and so they're not reporting
`
`19 on conversion of PAA to PAGN in UCD patients. Is
`
`20 that right?
`
`21 A. That's correct.
`
`22 Q. Okay, and prior to August, 2008, a
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`23 POSA would not have expected the amount of
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`24 conversion of PAA to PAGN in healthy subjects to be
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`25 the same as that in a urea cycle disorder patient.
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` 1 Is that right?
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` 2 MR. SILVERSTEIN: Objection, form.
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` 3 THE DEPONENT: No, that's incorrect.
`
` 4 They would have expected it to be roughly
`
` 5 the same based on the evidence in Shiple.
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` 6
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` 7 BY MS. SIMIC:
`
` 8 Q. And when you said "based on the
`
` 9 evidence in Shiple", what do you mean by that?
`
`10 A. So it would be easiest to discuss in
`
`11 looking at the section on Shiple.
`
`12 Q. Is that page 21?
`
`13 A. So we will be looking at the
`
`14 description on page 21, and also referring at times
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`15 to the table, which is given on page 29, which is
`
`16 from Shiple.
`
`17 Q. Okay, and how does Shiple support
`
`18 the statement that you made that the data would be
`
`19 roughly the same in terms of PAA conversion to PAGN
`
`20 between healthy patients and urea cycle disorder
`
`21 patients?
`
`22 A. Sure. So I'll be comparing the
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`23 conversion...actually, the urea synthesis that
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`24 occurs in Shiple with the urea synthesis that occurs
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`25 in Brusilow '91.
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` 1 Q. Okay.
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` 2 A. So in Shiple there was an experiment
`
` 3 where a normal individual was given PAA or benzoate
`
` 4 in varying amounts over the course of a seven-day
`
` 5 experiment. The experiment is listed on page 29
`
` 6 with its data.
`
` 7 So if you look at the first three periods,
`
` 8 which are 24-hour periods, these are full days in
`
` 9 which the individual was given no medication. So
`
`10 you can see what normal ureagenesis would look like
`
`11 in that individual.
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`12 So if you look, for instance, at the
`
`13 percentage of total nitrogen during the periods 1, 2
`
`14 and 3, it's approximately 75 percent of the total
`
`15 nitrogen that's excreted is urea nitrogen.
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`16 After the first three 24-hour periods,
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`17 Shiple is giving either benzoate or phenyl acetate
`
`18 at different amounts in different sub-segments of
`
`19 those periods. So for example, if you look in
`
`20 period 4, when benzoate is provided in several of
`
`21 the segments the urea synthesis as a percentage of
`
`22 total nitrogen drops, and you see glycocoll
`
`23 appearing in the urine. Glycocoll is an older name
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`24 for the amino acid glycine.
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`25 In the first three periods neither glycine
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` 1 nor glutamine will appear in the urine because the
`
` 2 kidneys don't excrete amino acids typically. Only
`
` 3 after giving either benzoate, which conjugates
`
` 4 glycocoll or glycine to form hippurate or
`
` 5 phenylacetic acid which conjugates glutamine to make
`
` 6 phenylacetal glutamine, will you see glycine or
`
` 7 glutamine appear.
`
` 8 If you look now down at the period 7,
`
` 9 which is a period in which benzoate wasn't
`
`10 given...only phenylacetate was given, and it was
`
`11 given in doses that approximate on a molar basis a
`
`12 relevant amount that would be given to a patient
`
`13 with urea cycle defect.
`
`14 If you look at what happens to urea as a
`
`15 percentage of total nitrogen, it drops down to a low
`
`16 figure of 12 percent of total nitrogen excreted,
`
`17 whereas glutamine rises up to a total of 52 percent.
`
`18 What this indicates is that there is a shifting of
`
`19 nitrogen excretion from urea synthesis to excretion
`
`20 in phenylacetal glutamine.
`
`21 It may help now to look at earlier in the
`
`22 declaration at page 11, which is a figure of how
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`23 amino acids flow into the urea cycle. So you can
`
`24 see that glutamine and glycine are donors into an
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`25 ammonia pool which has to be processed through the
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` 1 urea cycle.
`
` 2 The role of medications like PAA prodrugs
`
` 3 or benzoate is to divert those amino acids so that
`
` 4 ammonia is not formed.
`
` 5 What Shiple found is that urea synthesis
`
` 6 is remarkably suppressed in a healthy individual who
`
` 7 is given PAA in pharmacologically relevant doses.
`
` 8 In this case it's falling in a period after a
`
` 9 medically relevant dose to about 12 percent of
`
`10 nitrogen excretion.
`
`11 You can compare that to the residual urea
`
`12 synthesis capacity, for example, in Brusilow. So
`
`13 I...
`
`14 Q. Would you like to refer to Brusilow?
`
`15 A. Yes, if I could have Brusilow '91.
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`16 Q. I'm handing Dr. Sondheimer Brusilow
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`17 '91, which is Exhibit 1012 in the IPR.
`
`18 A. So we will turn here to table 2,
`
`19 which is on page 148. We're looking at the urea
`
`20 synthesis in a urea cycle defect patient who is
`
`21 being given doses of either phenylacetate or sodium
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`22 phenylbutyrate, and you will see that the ratio
`
`23 between the urea nitrogen and the total nitrogen
`
`24 excretion is within the same range of that that is
`
`25 being observed in Shiple in the patient who is
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` 1 treated.
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` 2 What that means is that for urea cycle
`
` 3 defect patients, most of them have residual urea
`
` 4 synthesis capacity, and that urea synthesis capacity
`
` 5 roughly matches what happens to a normal individual
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` 6 who is given pharmacologically relevant doses.
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` 7 That's not surprising because that's the
`
` 8 reason that these medications are used. There is a
`
` 9 diversion of nitrogen away from the urea cycle
`
`10 through the use of these medications.
`
`11 Therefore, data that is established in
`
`12 references like Sherwin and Comte, which are
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`13 obtained in normal individuals, also Collins, are
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`14 relevant to the evaluation of the conversion of PAA
`
`15 to PAGN in patients with urea cycle defects because
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`16 the degree of diversion is roughly the same.
`
`17 Q. Okay. So just so I understand, your
`
`18 ultimate conclusion is that data concerning PAA to
`
`19 PAGN conversion in healthy subjects is relevant to
`
`20 the determination of what PAA to PAGN conversion
`
`21 would be in urea cycle disorder subjects. Is that
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`22 right?
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`23 A. It provides relevant information to
`
`24 a person of ordinary skill in the art. There are
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`25 variations in every experiment that is performed and
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` 1 in every clinical study, but it does provide useful
`
` 2 information.
`
` 3 Q. And the references that you rely on
`
` 4 in your report, Sherwin, Exhibit 1016, and Shiple,
`
` 5 Exhibit 1017, those references both concern healthy
`
` 6 subjects, correct?
`
` 7 MR. SILVERSTEIN: Objection, form.
`
` 8 THE DEPONENT: So Sherwin and Shiple are
`
` 9 both presumably healthy subjects. That's
`
`10 how the authors describe them.
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`11
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`
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`12 BY MS. SIMIC:
`
`13 Q. Just to follow up on one point, I
`
`14 believe it's at page 29 of your report. With
`
`15 respect to the Shiple reference you provide a table
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`16 2 from Shiple on page 29. Is that right?
`
`17 A. That's correct.
`
`18 Q. And you mentioned on day 7 of the
`
`19 study that four grams of phenylacetic acid were fed
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`20 to the patient at, I believe, four hours. Is that
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`21 right?
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`22 A. So it's...it would be helpful...do
`
`23 you have Shiple?
`
`24 Q. I do.
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`25 A. I just want to be sure that I'm
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` 1 stating this correctly.
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` 2 Q. Sure. I am handing to the witness
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` 3 the reference we're referring to as Shiple, which is
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` 4 Exhibit 1017.
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` 5 A. So if you look at page 621 of
`
` 6 Shiple, in the second paragraph, complete paragraph,
`
` 7 starting in table 2, Shiple describes how the
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` 8 medication is provided to the subject. So the days
`
` 9 of feeding have been divided into sub-periods of
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`10 varying length, and the acid, either phenylacetic
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`11 acid or benzoic acid, is ingested during a certain
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`12 sub-period and was always taken at the beginning of
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`13 the sub-period.
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`14 So that is where he is describing sort of
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`15 how to read table 2.
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`16 Q. Okay. So for day 7...
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`17 A. M'hm.
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`18 Q. ...four grams of phenylacetic acid
`
`19 were administered to the patient at the beginning of
`
`20 the period. Is that right?
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`21 MR. SILVERSTEIN: Objection, form.
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`22 THE DEPONENT: That appears to be what
`
`23 Shiple is describing.
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`24
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`
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`25 BY MS. SIMIC:
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` 1 Q. Okay, and later in the day, on day
`
` 2 7, six grams of phenylacetic were administered to
`
` 3 that same patient. Is that right?
`
` 4 MR. SILVERSTEIN: Objection, form.
`
` 5 THE DEPONENT: That's correct.
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` 6
`
`
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` 7 BY MS. SIMIC:
`
` 8 Q. Okay, and if you just look at the
`
` 9 right-hand side of the table, it says in the very
`
`10 far right-hand side, the top heading says:
`
`11 "...Phenylacetic acid fed percentage..."
`
`12 Do you see that?
`
`13 A. I do.
`
`14 Q. And does that refer to the amount of
`
`15 phenylacetic acid that was fed to the patient and
`
`16 then detoxicated? Is that right?
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`17 MR. SILVERSTEIN: Objection, foundation.
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`18 THE DEPONENT: I'm sorry. Say the
`
`19 question again.
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`20
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`
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`21 BY MS. SIMIC:
`
`22 Q. So let me ask it in a different
`
`23 way. Does the percentage of phenylacetic acid fed,
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`24 which is a heading in table 2...
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`25 A. Yes.
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` 1 Q. ...does that refer to the amount of
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` 2 phenylacetic acid that was detoxicated by that
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` 3 patient?
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` 4 MR. SILVERSTEIN: Same objection.
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` 5 THE DEPONENT: It's the percentage of
`
` 6 phenylacetic acid that was re-isolated from
`
` 7 the urine.
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` 8
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`
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` 9 BY MS. SIMIC:
`
`10 Q. Okay, and so for day 7 of the
`
`11 study, am I correct in saying that the percentage of
`
`12 phenylacetic acid that was recovered in the urine as
`
`13 PAGN amounted to 95 percent?
`
`14 A. No. No, that's not what it says.
`
`15 Q. And so...okay, so can you explain to
`
`16 me what the 95 number means at the bottom of table 2
`
`17 with respect to the subject that was dosed on day 7?
`
`18 A. It just refers to that being the
`
`19 amount of phenylacetic acid that was re-isolated.
`
`20 It doesn't say anything about the conjugation.
`
`21 Q. So when you say "the amount of
`
`22 phenylacetic acid that was re-isolated", what does
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`23 that mean?
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`24 A. It means the total amount of acid
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`25 that was re-isolated from the patient's urine.
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` 1 Q. So it's the total amount of
`
` 2 phenylacetic acid that was excreted in the urine by
`
` 3 the patient after the administration of phenylacetic
`
` 4 acid on day 7?
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` 5 MR. SILVERSTEIN: Objection, form.
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` 6
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`
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` 7 BY MS. SIMIC:
`
` 8 Q. Is that right?
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` 9 A. That's correct. It's the total
`
`10 amount of phenylacetic acid.
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`11 Q. And in what form would that
`
`12 phenylacetic acid have been recovered from the
`
`13 urine?
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`14 MR. SILVERSTEIN: Objection, foundation.
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`15 THE DEPONENT: That's not described in
`
`16 Shiple.
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`17
`
`
`
`18 BY MS. SIMIC:
`
`19 Q. Okay. So it doesn't state whether
`
`20 or not the phenylacetic acid was recovered as its
`
`21 conjugation product, PAGN. Is that right?
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`22 MR. SILVERSTEIN: Objection, form,
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`23 foundation.
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`24 THE DEPONENT: So that column doesn't
`
`25 describe glutamine.
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` 1 BY MS. SIMIC:
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` 2 Q. But it does state that it's the
`
` 3 amount of acid that was detoxicated, correct?
`
` 4 That's the heading of that column.
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` 5 A. So detoxicated doesn't mean that it
`
` 6 was re-isolated in any particular form. It just
`
` 7 means it was the amount that the body processed and
`
` 8 was excreted. It doesn't refer to whether it's
`
` 9 conjugated or not.
`
`10 Q. Okay, and so what other forms could
`
`11 phenylacetic acid have appeared in in the urine,
`
`12 other than PAGN?
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`13 MR. SILVERSTEIN: Objection, form.
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`14 THE DEPONENT: It could have appeared as
`
`15 the free compound, but I don't want to
`
`16 speculate on other things it could have
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`17 appeared as. I'm only reading the
`
`18 manuscript. I'm not...I can only assess
`
`19 the data that was actually provided.
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`20
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`
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`21 BY MS. SIMIC:
`
`22 Q. Okay. So let me just make sure I
`
`23 understand that this...your explanation works with
`
`24 the text here. So if you turn to page 623 of
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`25 Shiple, the end of the first paragraph, the last
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` 1 three...the last four lines?
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` 2 A. M'hm.
`
` 3 Q. It states:
`
` 4 "...Again, in the fourth sub-period (four
`
` 5 hours) of the seventh day after the
`
` 6 ingestion of 10 grams of phenylacetic acid,
`
` 7 52 percent of the entire nitrogen output of
`
` 8 the sub-period appeared in the urine as
`
` 9 glutamine nitrogen..."
`
`10 Correct?
`
`11 A. Yes.
`
`12 Q. Okay. Can you show me where that
`
`13 amount is noted in table 2?
`
`14 A. It's in table 2. It's period 7.
`
`15 It's the fourth segment of period 7. If you go
`
`16 across to the column that says:
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`17 "...Percentage of total nitrogen [under
`
`18 which is 'Glutamine']..."
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`19 You'll find the 52 percent there, which is what he
`
`20 describes on page 623.
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`21 Q. "...Percentage of total nitrogen...
`
`22 glutamine..."
`
`23 Oh, I see. Okay. Okay, so prior to August of 2008,
`
`24 would a person of ordinary skill in the art have
`
`25 expected urea cycle disorder patients to exhibit
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` 1 higher PAA to PAGN conversion than in healthy
`
` 2 subjects?
`
` 3 A. So that...it's possible that that
`
` 4 may have occurred, and I explained that in the
`
` 5 report in the section where I describe Shiple, and
`
` 6 that reason has to do with an underlying feature of
`
` 7 urea cycle defects, which is that the patients'
`
` 8 glutamine levels are higher than the glutamine
`
` 9 levels of healthy individuals.
`
`10 Q. Okay, and what would the higher
`
`11 glutamine level...what would that result in with
`
`12 respect to PAA to PAGN conversion?
`
`13 MR. SILVERSTEIN: Objection, form.
`
`14 THE DEPONENT: So the chemical reaction
`
`15 for acylation is written on page 22, and it
`
`16 has three reactants which are...sorry, two
`
`17 reactants and one product, and glutamine is
`
`18 one of the reactants.
`
`19 Under the rules of equilibrium for
`
`20 this reaction, if the glutamine level is
`
`21 elevated, then the relative ratio between
`
`22 PAA and PAGN will also be elevated.
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`23
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`
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`24 BY MS. SIMIC:
`
`25 Q. Okay. In your declaration you
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` 1 don't state how much higher the conversion a POSA
`
` 2 would expect for a urea cycle disorder patient
`
` 3 compared to a healthy subject, correct?
`
` 4 A. No, a POSA would understand it would
`
` 5 depend exactly on the glutamine. It's a defined
`
` 6 relationship.
`
` 7 Q. And would a POSA know how much
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` 8 glutamine a UCD patient had in terms of availability
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` 9 of the conjugation with PAA?
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`10 MR. SILVERSTEIN: Objection, form.
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`11 THE DEPONENT: Yes, a person of ordinary
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`12 skill in the art would be very familiar
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`13 with the fact that glutamine was elevated
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`14 in urea cycle defects.
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`15
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`16 BY MS. SIMIC:
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`17 Q. Okay, but again, you haven't
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`18 expressed an opinion in your declaration with
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`19 respect to how much more conversion a POSA would
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`20 expect in a urea cycle disorder patient compared to
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`21 a normal patient?
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`22 MR. SILVERSTEIN: Objection, form.
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`23 THE DEPONENT: No, I think I did. I
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`24 said because UCD patients typically have
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`25 elevated glutamine levels.
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` 1 BY MS. SIMIC:
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` 2 Q. Okay, but you're not saying how
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` 3 much higher the percentage conversion would be in a
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` 4 UCD patient compared to a normal subject, correct?
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` 5 MR. SILVERSTEIN: Objection, form.
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` 6 THE DEPONENT: I didn't. I mean, I'm
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` 7 well aware of the normal ranges of
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` 8 glutamine and the ranges of glutamine that
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` 9 are expected in UCD patients on treatment,
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`10 as any POSA would be.
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`11
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`
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`12 BY MS. SIMIC:
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`13 Q. Okay, well, I'm not asking about
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`14 levels of glutamine. With respect to the percentage
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`15 conversion of PAA to PAGN, that's what I'm referring
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`16 to. So you, in your expert declaration, you do not
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`17 provide an opinion concerning how much more
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`18 conjugation of PAA to PAGN would be expected in a
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`19 UCD patient compared to a healthy subject, correct?
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`20 MR. SILVERSTEIN: Objection, form.
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`21 THE DEPONENT: I realistically provide
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`22 no exact figure for that, but a person of
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`23 ordinary skill in the art is well aware of
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`24 the relationship of glutamine to the
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`25 outcome of this reaction, and is also well
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` 1 aware of the normal values for glutamine
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` 2 and the values for glutamine that would be
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` 3 expected in a UCD patient.
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` 4
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`
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` 5 BY MS. SIMIC:
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` 6 Q. So your answer is no, that you
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` 7 haven't provided a specific number with respect to
`
` 8 how much higher PAA to PAGN conversion would be in a
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` 9 UCD patient compared to a healthy subject, correct?
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`10 MR. SILVERSTEIN: Objection, form.
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`11 THE DEPONENT: No, there is no exact
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`12 number. It's merely that a person of
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`13 ordinary skill in the art would know how to
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`14 use that relationship in the determination
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`15 of their patients.
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`16
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`
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`17 BY MS. SIMIC:
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`18 Q. And so you mentioned that UCD
`
`19 patients have higher circulating glutamine than
`
`20 healthy subjects, correct?
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`21 MR. SILVERSTEIN: Objection, form.
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`22 THE DEPONENT: Yes.
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`23
`
`
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`24 BY MS. SIMIC:
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`25 Q. And is there any danger for UCD
`