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`Page 1
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________
`
`LUPIN LTD. AND LUPIN PHARMACEUTICALS INC.,
`
`Petitioner
`
`v.
`
`HORIZON THERAPEUTICS, LLC,
`
`Patent Owner
`
`_______________________
`
`Case IPR2017-01160
`
`Patent 9,326,966
`
`________________________
`
`620 Eighth Avenue
`
`New York, New York
`
`February 7, 2018
`
`9:00 a.m.
`
`DEPOSITION of KEITH KENNETH VAUX, M.D.
`
`taken pursuant to Notice, held at the offices
`
`of Goodwin Proctor, LLP, before Fran Insley, a
`
`Notary Public of the States of New York and
`
`New Jersey.
`
`www.veritext.com
`
`Veritext Legal Solutions
`
`888-391-3376
`
`Page 1 of 64
`
`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`Page 1
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________________
`
`LUPIN LTD. AND LUPIN PHARMACEUTICALS INC.,
`
`Petitioner
`
`v.
`
`HORIZON THERAPEUTICS, LLC,
`
`Patent Owner
`
`_______________________
`
`Case IPR2017-01160
`
`Patent 9,326,966
`
`________________________
`
`620 Eighth Avenue
`
`New York, New York
`
`February 7, 2018
`
`9:00 a.m.
`
`DEPOSITION of KEITH KENNETH VAUX, M.D.
`
`taken pursuant to Notice, held at the offices
`
`of Goodwin Proctor, LLP, before Fran Insley, a
`
`Notary Public of the States of New York and
`
`New Jersey.
`
`www.veritext.com
`
`Veritext Legal Solutions
`
`888-391-3376
`
`Page 1 of 64
`
`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
`
`
`
`Page 2
`
`A P P E A R A N C E S :
`
` G O O D W I N P R O C T O R L L P
`
` A t t o r n e y s f o r L U P I N a n d W i t n e s s
`
` T h e N e w Y o r k T i m e s B u i l d i n g
`
` 6 2 0 E i g h t h A v e n u e
`
` N e w Y o r k , N e w Y o r k 1 0 0 1 8
`
` B Y : C Y N T H I A L A M B E R T H A R D M A N , E S Q .
`
` P h o n e : ( 2 1 2 ) 4 5 9 - 7 2 9 5
`
` F a x : ( 2 1 2 ) 2 0 8 - 4 6 3 9
`
` c h a r d m a n @ g o o d w i n l a w . c o m
`
` G R E E N , G R I F F I T H & B O R G - B R E E N , L L P
`
` A t t o r n e y s f o r H O R I Z O N T H E R A P E U T I C S
`
` 6 7 6 N . M i c h i g a n A v e n u e , S u i t e 3 9 0 0
`
` C h i c a g o , I l l i n o i s 6 0 6 1 1
`
` B Y : P E T E R F . G R E E N , E S Q .
`
` P h o n e : ( 3 1 2 ) 8 8 3 - 8 0 8 0
`
` r g r e e n @ g r e e n g r i f f i t h . c o m
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` o O o
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`1 7
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`1 8
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`2 0
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`2 1
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`2 2
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`Veritext Legal Solutions
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`Page 2 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
`
`
`
`Page 3
`
`----------------- I N D E X -------------------
`
`WITNESS EXAMINATION BY PAGE
`
`KEITH VAUX MR. GREEN 4, 44
`
` MS. LAMBERT HARDMAN 42
`
` oOo
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`Page 3 of 64
`
`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
`
`
`
`Page 4
`
`K E I T H V A U X ,
`
` having been first duly sworn by the
`
` Notary Public, was examined and
`
` testified as follows:
`
`EXAMINATION BY
`
`MR. GREEN:
`
` Q. Good morning, Dr. Vaux.
`
` A. Good morning.
`
` Q. Can you state your full name for the
`
`record, please?
`
` A. Keith Kenneth Vaux. V-A-U-X is the
`
`spelling.
`
` Q. And again, just for the record,
`
`Doctor, I did offer to depose you in
`
`California, so that's why you are here today on
`
`this snowy day in New York.
`
` A. Thanks for the offer.
`
` Q. A general question first, Dr. Vaux.
`
`You're familiar with the composition known as
`
`Buphenyl, right?
`
` A. I am.
`
` Q. And you're familiar with the
`
`composition that's known as Ravicti currently
`
`under the trademark or I think you used IPN-100
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`Page 4 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`
`
`as a nomenclature for that as well, correct?
`
`Page 5
`
` A. HPN.
`
` Q. HPN, yes.
`
` And in your years of dealing with
`
`patients that have UCD, have you had patients
`
`that were being treated with Buphenyl?
`
` A. Yes, I have.
`
` Q. Have you had patients that have been
`
`treated with, if it's okay with you, I'm going
`
`to refer to it as Ravicti?
`
` A. Okay. I was thinking back over
`
`this. There's -- I am not familiar with
`
`treating with that. We use sodium benzoate a
`
`lot.
`
` Q. And sodium benzoate is equivalent
`
`to?
`
` A. It's another one of the nitrogen
`
`scavenging drugs.
`
` Q. So, based upon your review of the
`
`prior art and your interaction with other
`
`doctors that have UCD patients that they are
`
`treating, are you aware of any difference in
`
`the efficacy between Buphenyl and Ravicti when
`
`administered to a UCD patient?
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`Page 5 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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` MS. LAMBERT HARDMAN: Objection to
`
` the extent it calls for hearsay.
`
` A. I haven't heard nor am I aware of
`
`any significant differences.
`
` Q. So sitting here today as an expert
`
`on behalf of Lupin, is it your opinion that
`
`there is no significant difference between
`
`Buphenyl and Ravicti from the standpoint of
`
`efficacy in treating UCD patients?
`
` MS. LAMBERT HARDMAN: Objection,
`
` outside the scope.
`
` A. Again, I'm not aware that there's a
`
`significant difference. We determine the
`
`treatment based on a variety of clinical
`
`variations. There may be some differences that
`
`would arise with a single patient.
`
` Q. So if a patient, UCD patient again,
`
`and I'm asking you as an expert, is treated
`
`with Buphenyl in a specified amount and later
`
`treated with Ravicti at the same amount when
`
`determined based upon the PAA conversion, would
`
`you expect any difference in the results
`
`between using Ravicti and Buphenyl for that
`
`patient?
`
`www.veritext.com
`
`Veritext Legal Solutions
`
`888-391-3376
`
`Page 6 of 64
`
`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
`
`
`
`Page 7
`
` MS. LAMBERT HARDMAN: Objection,
`
` form and outside the scope.
`
` A. Again, the circumstances would be so
`
`different it would be very difficult to compare
`
`the two without a head-to-head study which
`
`would be quite hard to do.
`
` Q. What do you mean by the
`
`circumstances would be different?
`
` A. The circumstances of each occurrence
`
`of treatment varies so much. So if it were an
`
`induced flu crisis, that would be very
`
`different than if it was an induced pneumonia
`
`crisis. So the treatment protocol is usually
`
`based on an additional factor in addition to
`
`just the hyperammonemia.
`
` Q. So if we assume that we're talking
`
`about a patient who is undergoing long-term
`
`treatment with the nitrogen scavenging agent
`
`and starts off with Buphenyl, and that patient
`
`is then transferred, and let's assume there is
`
`no other change in condition with respect to,
`
`the patient's transferred over to Ravicti,
`
`using an equivalent dosage based on PAA, would
`
`you expect any significant difference in the
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`Page 7 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`
`
`Page 8
`
`treatment outcome of that patient?
`
` MS. LAMBERT HARDMAN: Same
`
` objections.
`
` A. Well, there would be a reason it
`
`would be switching if one medication wasn't
`
`working. So I guess I could expect some -- I
`
`would hope to get some difference between the
`
`two.
`
` Q. And when you're referring to a
`
`difference, what degree of difference would you
`
`be expecting?
`
` MS. LAMBERT HARDMAN: Objection to
`
` form.
`
` A. Perhaps, you know, a change in the
`
`level of ammonia, a decrease in some of the
`
`other symptoms. It would be -- there would be
`
`a reason to change the treatment, that the
`
`prior treatment hadn't been as effective.
`
` Q. Well, if we assume that the reason
`
`for the change is simply to determine if in
`
`fact there is a difference in the response by
`
`the patient, would you expect any significant
`
`difference in the treatment outcome between
`
`using those two?
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`Page 8 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`
`
`Page 9
`
` MS. LAMBERT HARDMAN: Objection,
`
` form and outside the scope.
`
` A. If we were doing a study, again that
`
`would probably be one of my measures, if we
`
`were doing a study to compare the two. It's
`
`not something we would normally do in clinical
`
`practice just to kind of see.
`
` Q. So without the clinical results do
`
`you have an opinion as to whether there would
`
`be a significant outcome, let's say, with
`
`respect to the amount of ammonia found in the
`
`patient's bloodstream?
`
` MS. LAMBERT HARDMAN: Same
`
` objections.
`
` A. There's just so many other
`
`variables. I mean we haven't even talked about
`
`which kind of UCD. I mean there are just too
`
`many variables for me to comment on that.
`
` Q. So, again, just to make sure I'm
`
`clear, you don't have an opinion as to whether
`
`a patient being treated with Buphenyl versus
`
`being treated with Ravicti under the same
`
`conditions would have any significant
`
`difference in the amount of, let's say, ammonia
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`Page 9 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`
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`Page 10
`
`that results in the bloodstream after that?
`
` MS. LAMBERT HARDMAN: Same
`
` objections.
`
` A. I would not have an opinion on that,
`
`no. There are just too many variables to make
`
`a scientific statement on it.
`
` Q. And variables, again, would be what?
`
` A. They're numerous. The age of the
`
`patient, race of the patient, the type of
`
`condition. The diet that the patient is
`
`undergoing, the amount of exercise. Whether
`
`they are in school. I mean I could go on
`
`forever. There are a lot of variables involved
`
`in treating a patient with UCD.
`
` Q. And if those variables don't change
`
`between the dosage of administration between
`
`Ravicti and Buphenyl, does that change your
`
`view?
`
` MS. LAMBERT HARDMAN: Same
`
` objections.
`
` A. I would have no way of knowing that
`
`because that situation would not arise.
`
` Q. So if there is a change between a
`
`patient who was previously given Buphenyl and
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`Page 10 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`
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`Page 11
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`later Ravicti with respect to the plasma
`
`ammonia content, would you know whether it was
`
`due to a difference in the drug?
`
` MS. LAMBERT HARDMAN: Same
`
` objections.
`
` A. I would not -- again, I would have
`
`to such tightly controlled situations that it
`
`would fall under a clinical trial type of setup
`
`rather than my personal observation of an
`
`individual.
`
` Q. And what parameters would exist in
`
`that clinical trial that would allow you to
`
`make that determination?
`
` MS. LAMBERT HARDMAN: Objection,
`
` outside the scope.
`
` A. I've mentioned some of them. It
`
`would depend, again, primarily on what the UCD
`
`was. We would have to have, you know, just the
`
`basic ones are variation in diet over time
`
`which, as you know, varies significantly by
`
`age, by time, by whether or not they're in
`
`school. I mean, again, I could go on forever.
`
`And I'm not doing a clinical trial so I haven't
`
`really spent a ton of time thinking about what
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`Page 11 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`
`
`Page 12
`
`variables I would have to make sure were solid.
`
` Q. I'm going to hand you Lupin Exhibit
`
`1007. It's a publication of an application
`
`filed by Bruce Scharschmidt. Publication
`
`Number US 2010/008859.
`
` That's a publication you're well of
`
`of, correct, Dr. Vaux?
`
` A. That is correct.
`
` Q. I would like to direct your
`
`attention to page 17 in this publication, 17 at
`
`the top. It says page 33 of 39 at the bottom.
`
`On the right side of page 17 there is a table
`
`that is captioned "Venous Ammonia
`
`Pharmacodynamics Following Seven Days of Dosing
`
`With Either Sodium PBA or HPN-100 (Steady
`
`State)." Do you see that?
`
` A. I do.
`
` Q. Let's focus on Subject 1007. It's
`
`under the left column. It has the numbers
`
`1006. Do you see that?
`
` MS. LAMBERT HARDMAN: Objection.
`
` MR. GREEN: Yes?
`
` MS. LAMBERT HARDMAN: You started
`
` out saying subject 1007 and then switched
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`Page 12 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`Page 13
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` to 1006.
`
` MR. GREEN: Thank you for the
`
` correction.
`
` Q. It's 1006.
`
` A. Okay, good. I do see that one, yes.
`
` Q. From this table, it's indicated that
`
`the patient received 17.5. Do you see that,
`
`under the "PBA Equivalent Dose"?
`
` A. I do.
`
` Q. What does that 17.5 mean?
`
` A. I would have to review where the --
`
`so it's the equivalent dose. Let's see here.
`
`Let me just make sure I'm going to read this
`
`correct to you.
`
` Q. I think, Dr. Vaux, if you look at
`
`page 20, in the right column, there's a table
`
`and then there's a footnote on that table.
`
`That might help you. So it's page 20 at the
`
`top, page 36 at the bottom.
`
` A. Okay. Yeah, usually when there's a
`
`footnote reference it's right below it.
`
` Q. Yes, it took me 30 minutes the other
`
`day to chase this one down.
`
` A. I'm sorry. I'm sorry, Mr. Green,
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`Page 13 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`Page 14
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`what page was that?
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` Q. So it's page 20 at the top.
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` A. Thank you.
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` Q. Does that help?
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` A. If one assumes that those are
`
`attached to each other. So, yes. So, the 17.5
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`would be the actual PBA dose minus the sodium,
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`assuming that those footnotes apply to the
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`table that is four pages away. It says
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`20 grams sodium PBA contains 17.6 grams of PBA,
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`which means that the sodium accounts for the
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`rest of the weight. So it's a delivery method.
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` Q. And for that same patient, when we
`
`look over to the right in the column that's
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`captioned "PBA Equivalent Dose," that's under
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`the "HPN-100 heading," it says "17.7." Do you
`
`see that?
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` A. Yes, I do, again with the same
`
`assumptions.
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` Q. So the 17.7 for the HPN-100, that's
`
`a dose of approximately equivalent, when viewed
`
`on the PBA basis, to the dose of the PBA being
`
`administered to the patient; is that correct?
`
` A. It's numerically quite close, yes.
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`Page 14 of 64
`
`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
`
`
`
`Page 15
`
` Q. And for this patient, if we look
`
`back to the column "Cmax," Cmax in that column
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`represents the highest amount of plasma ammonia
`
`that was found in that patient during the time
`
`the patient's blood level was determined,
`
`correct?
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` A. Yes, that's -- I am aware that
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`that's what that means.
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` Q. And the same thing under the HPN-100
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`column where there is a Cmax value of 13 that's
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`shown; do you see that?
`
` A. That is correct.
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` Q. So for this patient, when given
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`sodium PBA, that patient had a maximum ammonia
`
`level of 150 micromoles per liter and when
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`given the HPN-100 demonstrated a Cmax with
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`respect to the plasma ammonia level of 13,
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`correct?
`
` A. Yes. According to this chart,
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`that's exactly what those numbers are.
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` Q. So that's a reduction of what,
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`90 percent or so?
`
` A. In that particular patient, at that
`
`particular time, yes.
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`Page 15 of 64
`
`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`
`
`Page 16
`
` Q. And from this set of data with
`
`respect to Patient 1006, do you know whether
`
`the reduction from 150 to 13 was due to the
`
`fact that the patient was simply switched from
`
`sodium PBA to HPN-100?
`
` A. Obviously, I don't. I can't
`
`attribute it all to that because I know no
`
`other situations that are going on with this
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`patient. That is a significant drop, but again
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`I don't know when those were drawn, I'm not
`
`aware of other features within the patient. I
`
`don't recall if they had controlled for when
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`the time was done or not. So I can't with
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`scientific certainty say that that was what's
`
`happening. This is also not a published study.
`
`This is just an observational statement.
`
` Q. Do you know if the Cmax that
`
`resulted for the Patient 1006 that is indicated
`
`to be 150 was taken under the same fasting or
`
`fed conditions as the value of 13 that's shown
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`for the HPN-100 Cmax?
`
` A. I don't know that.
`
` Q. Do you know if the patient's protein
`
`intake was different in the period prior to the
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`Page 16 of 64
`
`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`
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`determination of the Cmax?
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` A. I don't know that either.
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` Q. I would like to turn your attention
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`Page 17
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`down to Patient 3002.
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` A. Okay.
`
` Q. Now, the Cmax shown for the sodium
`
`PBA for Patient 3002 is 108 micromoles per
`
`liter, correct?
`
` A. Correct.
`
` Q. And then the Cmax that's shown for
`
`the HPN-100 is 36 micromoles per liter?
`
` A. Correct.
`
` Q. And the PBA equivalent in this
`
`situation was 16.5, or the sodium PBA, and 17.7
`
`for the HPN-100, correct?
`
` A. That is correct.
`
` Q. So in this instance, the patient had
`
`a reduction in blood ammonia level from 108
`
`micromoles per liter to 36 micromoles per
`
`liter, correct?
`
` A. Correct.
`
` Q. And the dosing amount for the
`
`HPN-100 is the same for Patient 1006 versus
`
`Patient 3002, correct?
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`Page 17 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`
`
`Page 18
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` MS. LAMBERT HARDMAN: Objection to
`
` form.
`
` A. The HPN-100 dosing is the same, but
`
`the dosing between sodium PBA and HPN-100 is
`
`significantly different.
`
` Q. Yes. In fact the amount of HPN-100
`
`given on a PBA equivalent amount is actually
`
`higher than that given for the sodium PBA,
`
`correct?
`
` A. That is correct.
`
` Q. Just while we are looking at this
`
`table, Dr. Vaux, under Subject 1004 there's a
`
`PBA equivalent dose that says 99.2.
`
` A. Yes.
`
` Q. Yet at the bottom the maximum dose
`
`given is indicated for all patients to be 17.5.
`
`Do you see that?
`
` A. Yes.
`
` Q. In your view, is that 99.2 an error?
`
` MS. LAMBERT HARDMAN: Objection to
`
` form.
`
` A. It's strikingly different than the
`
`others.
`
` Q. Also with respect to the same
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`Page 18 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`exhibit, could you turn to the bottom? It says
`
`Page 19
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`page 15 of 39.
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` A. Yes.
`
` Q. In this figure the Patient 1006,
`
`which is identified in the chart on page 17
`
`that we were just discussing, is illustrated
`
`with an X; is that correct?
`
` A. That is correct.
`
` Q. And for this particular patient, it
`
`shows graphically the drop with respect to the
`
`administration of the Buphenyl in comparison to
`
`the HPN with respect to the TN-AUC, correct?
`
` A. That is correct.
`
` Q. And for the record, what is TN-AUC?
`
` A. That's the area under the curve and
`
`it's a predicted dosing based on a calculation
`
`of the amount of time that the dose spends
`
`under the curve which is known as the time
`
`under the curve.
`
` Q. Do you know whether that reduction
`
`in the TN-AUC when the patient was changed from
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`Buphenyl to HPN-100 was simply due to the
`
`change in the nitrogen scavenging agent that
`
`was used?
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`Page 19 of 64
`
`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
`
`
`
`Page 20
`
` M S . L A M B E R T H A R D M A N : O b j e c t i o n ,
`
` f o r m .
`
` A . I d o n ' t k n o w t h a t .
`
` Q . D r . V a u x , y o u ' v e t e s t i f i e d b e f o r e
`
`y o u w o r k w i t h c e r t a i n p a t i e n t s t h a t h a v e U C D ,
`
`c o r r e c t ?
`
` A . C o r r e c t .
`
` Q . A n d y o u t r e a t t h o s e p a t i e n t s ,
`
`c o r r e c t ?
`
` A . T h a t i s o n e e l e m e n t i n t h e i r c a r e ,
`
`y e s .
`
` Q . T h e p a t i e n t s t h a t y o u s e e t h a t h a v e
`
`U C D , t h e y a r e a l s o g i v e n c a r e b y o t h e r
`
`p h y s i c i a n s c o n c e r n i n g t h e U C D c o n d i t i o n ,
`
`c o r r e c t ?
`
` A . I ' m s o r r y - -
`
` M S . L A M B E R T H A R D M A N : O b j e c t t o
`
` f o r m .
`
` A . I d i d n ' t h e a r t h e q u e s t i o n .
`
` Q . F o r t h e p a t i e n t s t h a t h a v e U C D t h a t
`
`y o u t r e a t , t h o s e p a t i e n t s a l s o s e e o t h e r
`
`p h y s i c i a n s f o r t r e a t m e n t w i t h r e s p e c t t o t h a t
`
`c o n d i t i o n , c o r r e c t ?
`
` A . Y e s .
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`1 8
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`2 3
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`www.veritext.com
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`Page 20 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
`
`
`
`Page 21
`
` Q . A n d t h o s e p h y s i c i a n s i n c l u d e
`
`p h y s i c i a n s t h a t h a v e b o a r d c e r t i f i c a t i o n i n
`
`d e a l i n g w i t h s u c h c o n d i t i o n s , c o r r e c t ?
`
` M S . L A M B E R T H A R D M A N : O b j e c t i o n ,
`
` f o u n d a t i o n .
`
` A . Y o u ' l l h a v e t o b e a l i t t l e m o r e
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`s p e c i f i c . B o a r d c e r t i f i c a t i o n i n w h i c h ?
`
` Q . O k a y , t h a t ' s a g o o d q u e s t i o n . S o
`
`f o r t h e c l i n i c i a n s t h a t a l s o s e e t h e p a t i e n t s
`
`t h a t y o u t r e a t t h a t h a v e U C D , w h a t b o a r d
`
`c e r t i f i c a t i o n s d o t h o s e o t h e r p h y s i c i a n s h a v e ?
`
` M S . L A M B E R T H A R D M A N : O b j e c t i o n ,
`
` f o u n d a t i o n .
`
` A . I n m y e x p e r i e n c e t h e y ' v e h a d
`
`c e r t i f i c a t i o n s i n a n e s t h e s i o l o g y , i n p e d i a t r i c
`
`i n t e n s i v e c a r e , i n p u l m o n o l o g y , e n d o c r i n o l o g y .
`
`A n d t h e r e i s o n e b i o c h e m i c a l g e n e t i c i s t ,
`
`a l t h o u g h t h e y a r e n o t i n v o l v e d i n t h e a c t i v e
`
`i n p a t i e n t c a r e o f t h e p a t i e n t .
`
` Q . S o t h e b i o c h e m i c a l g e n e t i c i s t , i s
`
`t h a t i n d i v i d u a l i n v o l v e d w i t h a l l o f t h e
`
`p a t i e n t s t h a t y o u t r e a t t h a t h a v e U C D ?
`
` M S . L A M B E R T H A R D M A N : O b j e c t i o n ,
`
` f o u n d a t i o n .
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`1 8
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`2 2
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`2 3
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`2 4
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`Page 21 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
`
`
`
`Page 22
`
` A. There is a non-board-certified
`
`biochemical geneticist who also cares for those
`
`patients. There are two, primarily; there's
`
`one that is board certified and one that's not.
`
`He also wrote most of the text on the
`
`condition.
`
` Q. When it comes to making adjustments
`
`to the dose that is administered to your
`
`patients, do you consult with one or the other
`
`of those two individuals that are biochemical
`
`geneticists?
`
` A. Not in every circumstance, and in
`
`fact rarely.
`
` Q. Do you make dosing changes for your
`
`patients without consultation with a
`
`biochemical geneticist; is that correct?
`
` A. Correct. As I mentioned, there's
`
`only one available board-certified biochemical
`
`geneticist in San Diego County. I'm focusing
`
`on available. There is one other who does not
`
`work for my institution.
`
` Q. If you have patients for whom you
`
`have difficulty in maintaining, let's say,
`
`their quality of life, do you reach out to such
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`Page 22 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
`
`
`
`Page 23
`
`a g e n e t i c i s t f o r c o n s u l t a t i o n ?
`
` M S . L A M B E R T H A R D M A N : O b j e c t t o
`
` f o r m .
`
` A . I n d i f f i c u l t p a t i e n t s , y e s . W e
`
`a t t e m p t t o o b t a i n i n f o r m a t i o n f r o m j u s t a b o u t
`
`a n y w h e r e w e c a n g e t i t .
`
` Q . T u r n i n g b a c k f o r a m o m e n t t o t h e
`
`' 8 5 9 p u b l i c a t i o n . W i t h r e s p e c t t o t h e
`
`i n f o r m a t i o n t h a t ' s c o n t a i n e d i n t h e t a b l e w e
`
`w e r e j u s t d i s c u s s i n g , t h e r e i s n o i n d i c a t i o n
`
`t h a t t h e d e t e r m i n a t i o n o f t h e p l a s m a a m m o n i a
`
`l e v e l i n a n y o f t h o s e i n s t a n c e s w a s d o n e u n d e r
`
`f a s t i n g c o n d i t i o n s ?
`
` A . I ' m s o r r y . C o u l d y o u r e p e a t t h a t
`
`a g a i n ?
`
` Q . S u r e . S o , t u r n i n g b a c k t o t h e ' 8 5 9
`
`p u b l i c a t i o n a n d t h e t a b l e w e h a d j u s t
`
`d i s c u s s e d .
`
` A . Y e s .
`
` Q . T h e r e i s n o i n d i c a t i o n t h a t a n y o f
`
`t h o s e a m m o n i a l e v e l s t h a t a r e l i s t e d i n t h a t
`
`t a b l e w e r e o b t a i n e d u n d e r f a s t i n g c o n d i t i o n s ,
`
`c o r r e c t ?
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` A . I w o u l d h a v e t o r e v i e w i t . I t i s
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`Page 23 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`
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`Page 24
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`generally considered to be standard of care to
`
`obtain them under fasting conditions, but I'm
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`not 100 percent sure that that was done on here
`
`since the parameters are not clearly laid out
`
`with the table.
`
` Q. Let's step back for a second. I'm
`
`going to hand you a copy of Lupin Exhibit 1002,
`
`which is a document that's captioned
`
`"Declaration of Keith Vaux."
`
` So, Lupin Exhibit 1002 in front of
`
`you is your declaration, correct?
`
` A. Correct.
`
` Q. Now, Dr. Vaux, in this declaration
`
`you don't identify any piece of prior art that
`
`specifically states that patients with a
`
`fasting blood ammonia level that's below the
`
`upper limit of normal but above half the upper
`
`limit of normal should be given an increased
`
`dose with nitrogen scavenging agent, correct?
`
` MS. LAMBERT HARDMAN: Objection to
`
` form.
`
` A. That is not correct. I actually
`
`mention on several occasions that the fasting
`
`ammonia level can be at or below normal, which
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`Veritext Legal Solutions
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`888-391-3376
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`Page 24 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`
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`Page 25
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`would include half.
`
` Q. So I'll try to ask my question
`
`again. I'm sorry if I'm a little difficult to
`
`understand. I have a little congestion today.
`
` A. No problem.
`
` Q. You have no single reference in your
`
`declaration that specifically says that if a
`
`patient's fasting blood ammonia level is below
`
`the upper limit of normal but still above half
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`the upper limit of normal that that patient
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`should be given an increased dose, correct?
`
` MS. LAMBERT HARDMAN: Objection,
`
` asked and answered.
`
` A. Again, I read the references that I
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`have included in here to say that it's at or
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`below. Nitrogen really doesn't have a good
`
`function -- I mean ammonia doesn't have a good
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`function, so it would make sense that below
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`means including normal and anywhere down to
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`zero including a half.
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` Q. Setting aside your interpretation
`
`that it can be read that way, is there any
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`specific -- there is no reference that you cite
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`to that specifically says that if a patient's
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`Page 25 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
`
`
`
`Page 26
`
`fasting blood ammonia level is below the upper
`
`limit of normal but above half the upper limit
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`of normal that that patient should be given an
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`increased dose?
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` MS. LAMBERT HARDMAN: Same
`
` objection.
`
` A. Again, I don't really know how I can
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`say it any differently. It includes that
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`amount. It doesn't say a lot, it doesn't say a
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`third, it doesn't say a quarter. It says at or
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`below, which includes half in my mind.
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` Q. So is it your view, Dr. Vaux, then,
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`that after a fasting blood ammonia level is
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`taken that's below the upper limit of normal, a
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`patient should just continue to be treated with
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`increased doses of the hydrogen scavenging
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`agent until it gets down to zero?
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` A. I think the goal -- again, there's
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`so many factors at play here. It depends what
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`age they are. You're in a fine balance with
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`trying to maximize your protein intake, you
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`know, especially in growing pediatric patients.
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`So the goal would be to get the level in a
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`place where development can continue normally
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`Page 26 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`
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`Page 27
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`and the interference on day-to-day living would
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`be minimized. So it's always a balance between
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`side effects of the medication and health of
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`the patient, so -- what your treatment goal is,
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`that's always the balance. If I could get it
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`to zero without any side effects that would be
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`spectacular. Unfortunately, every medication
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`has some kind of side effect so at some point
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`you'll hit a point where the side effects will
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`outweigh the benefits of being able to take in
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`protein and allow the patient to grow and
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`develop.
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` Q. So when you say you'll hit a point
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`where there are side effects, what side effects
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`are you referencing?
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` MS. LAMBERT HARDMAN: Objection to
`
` form.
`
` A. The ones that have been described
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`are nausea, discomfort, just difficulty in
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`taking that dose of medication. Those are the
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`primary ones, nausea being a big one.
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` Q. So it's true, is it not, that a
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`patient who is given a nitrogen scavenging drug
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`such as HPN-100 can be dosed to the point where
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`Page 27 of 64
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`Horizon Exhibit 2051
`Lupin v. Horizon
`IPR2017-01159
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`Page 28
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`there is actually saturation that occurs?
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` MS. LAMBERT HARDMAN: Objection,
`
` outside the scope.
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` A. I am familiar with there being
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`concern that there is a saturation point.
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`Again, it would vary from patient to patient.
`
` Q. What is meant by a
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