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`UN TfiD STATj
`S PATLNT AND TRADEMARK Obi'Cfi
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`L
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` %fiEORZ
`THfi
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`PATflNT TRHAL AND APB
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` fiAL %OARD
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`ARGENTUM RHARMKC?UTWCALS LLC,
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` ?etitioner
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`V.
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`ALCON RfiSfiARCH, LTD.
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`Paoen- Owner
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`Case :RRZOl7—01053
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`Paten: 8, 268, 299
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` %UYS
`DtPOS T
`M.
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` ON Ob DR. YVONNt
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`November 20, 2017
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`Chicago, Illinois
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`8:56 a.m.
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`Reported By:
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`
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`Sheri ? Hiss, CSR, RPR, CRR
`Job No. 52740
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`Argentum Pharm. LLC V. Alcon Research, Ltd.
`CaseIRR2017-01053
`
`ALCON 2127
`
`
`
`2
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` The deposition of DR. YVONNE B. BUYS, called
`by the Patent Owner for examination, taken pursuant
`to the Code of Civil Procedure and the Rules of the
`Supreme Court of the State of Illinois pertaining to
`the taking of depositions for the purposes of
`evidence, taken before Sheri E. Liss, CSR NO.
`084-002600, a Certified Shorthand Reporter within
`and for the State of Illinois, Registered
`Professional Reporter, Certified Realtime Reporter,
`at the offices of Foley & Lardner, 321 North Clark
`Street, Chicago, Illinois, on November 20, 2017 at
`the hour 8:56 o'clock a.m.
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`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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`APPEARANCES:
` Appeared on behalf of the Petitioner:
` FOLEY & LARDNER, LLP
` 321 North Clark Street
` Suite 2800
` Chicago, Illinois 60654-5313
` BY: MICHAEL R. HOUSTON, Ph.D., ESQ.
` mhouston@foley.com
`
` Appeared on behalf of the Patent Owner:
` WILLIAMS & CONNOLLY, LLP
` 725 Twelfth Street, N.W.
` Washington, D.C. 20005
` BY: ALEXANDER S. ZOLAN, ESQ.
` azolan@wc.com
`
`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 500, New York, NY 10123 1.800.642.1099
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` I N D E X
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` Page
`By Mr. Zolan 5
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` E X H I B I T S
`Exhibit Description Page
` 1021 (Previously marked) 5
` 1026 (Previously marked) 8
` 2004 (Previously marked) 16
` 1025 (Previously marked) 21
` 1024 (Previously marked) 29
` 1001 (Previously marked) 37
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` (Whereupon, the witness was
` duly sworn.)
` DR. YVONNE B. BUYS,
`having been first duly sworn, was examined and
`testified as follows:
` EXAMINATION
` BY MR. ZOLAN:
` Q. Could you please state and spell your
`name?
` A. My name is Yvonne Buys, Y-v-o-n-n-e,
`last name Buys, B-u-y-s.
` Q. Dr. Buys, I'm Alexander Zolan, and I'll
`be asking you some questions today. I'm going to
`hand you an exhibit that's already been marked
`Exhibit 1021.
` (Whereupon, the document was
` tendered.)
`BY MR. ZOLAN:
` Q. Do you recognize Exhibit 1021?
` A. Yes, I do.
` Q. What is it?
` A. This is my declaration.
` Q. And when was the last time you reviewed
`the declaration?
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` A. This morning.
` Q. And if you go to the last page of the
`declaration, it's Page 8, at the bottom, 9 in the
`small numbers at the bottom.
` Is that your signature?
` A. Yes, that is my signature.
` Q. And is there anything in this
`declaration you want to correct or fix?
` A. No.
` Q. Dr. Buys, if we could go to Paragraph 12
`of your declaration.
` In the first sentence there in
`Paragraph 12, you write that "First, unlike Dr.
`Parrish," and let's stop there.
` Who is Dr. Parrish?
` A. Dr. Parrish is a Ophthalmologist from
`Bascom Palmer, a glaucoma specialist.
` Q. And why do you mention Dr. Parrish
`there?
` A. Because he has written a declaration
`that I'm responding to.
` Q. Okay. So in this first sentence, you
`say, "First, unlike Dr. Parrish, I prescribe
`Travatan Z in my clinical practice as a first line
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`treatment only for patients I know to be allergic to
`BAK."
` Did I read that right?
` A. Yes, you did.
` Q. So let's talk about what you mean by
`"allergic to BAK." You mean, I think by "allergic
`to BAK," that a patient experiences an irritant
`toxic reaction to BAK; is that right?
` A. Correct.
` Q. So you don't mean that the patient
`experiences some other sort of allergy?
` A. I don't mean that the patient has ocular
`surface disease that could be from sources other
`than BAK.
` Q. But you're not talking about a true
`allergic response, are you?
` A. Yes, I am.
` Q. You're talking about a -- are you aware
`of any finding in the literature that BAK in
`ophthalmic formulation causes an immunoglobin
`E-mediated process?
` A. I'm aware of literature that states that
`BAK in ophthalmology causes allergies.
` Q. What literature is that?
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` A. One of the cited papers in this
`declaration, which is the third from the end,
`Bagnis. And they report an eight percent incidence
`in the literature of BAK allergies.
` Q. So the eight percent figure you referred
`to in the first sentence of -- sorry -- the second
`sentence of Paragraph 12 is supported solely by the
`Bagnis reference; is that right?
` A. Correct.
` Q. When was the last time you reviewed the
`Bagnis reference?
` A. Within this past week.
` Q. I'm going to hand you what's already
`been marked as Exhibit 1026.
` (Whereupon, the document was
` tendered.)
`BY MR. ZOLAN:
` Q. Do you recognize this document?
` A. Yes, I do.
` Q. Is this the Bagnis reference you're
`referring to?
` A. Yes, it is.
` Q. And if you go to Page 3 at the bottom,
`391 at the top, and you look at the right-hand
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`column, down in the lower right underneath the
`heading 5, "Antiglaucoma Drugs and Preservative" are
`you with me?
` A. Yes.
` Q. "As a quaternary ammonium, BAK, is most
`commonly associated with irritant toxic reactions
`(8 percent in OVID and PubMED based researches.)"
` Do you see that?
` A. Yes, I do.
` Q. And the Bagnis reference distinguishes
`those irritant toxic reactions from allergic
`responses, doesn't it?
` A. I believe the terms are used relatively
`equivalently.
` Q. In the Bagnis reference?
` A. Correct. I don't see a strong
`distinction between allergy and toxic.
` Q. Well, the Bagnis reference itself
`distinguishes the two, doesn't it?
` A. I find it sometimes uses the terms
`interchangeably.
` Q. Now, here in this sentence it says, that
`the -- the first sentence I read continues, "Whereas
`the organomercurials, such as thimerosal, and the
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`alcohols, such as chlorobutanol, have the highest
`associations with allergic responses."
` Did I read that right?
` A. Correct.
` Q. So is it your testimony that Bagnis
`supports the premise that BAK in ophthalmic
`formulations causes allergic responses in eight
`percent of patients?
` A. Yes. Because the next sentence says,
`"Such reactions appear mainly like an irritant
`effect for alcohols, whereas organomercurials appear
`to truly interact with the immune system as
`neoantigens," which does not to me reflect there is
`a big difference between an irritant toxic reaction
`and an allergic response.
` Q. Have you reviewed the Hong and Bielory
`reference that's cited at the end of the sentence
`you just read?
` A. No, I have not.
` Q. Are you aware of the methodology that
`they used in order to come up with the statistic
`eight percent?
` A. No, I am not aware. I don't believe the
`eight percent however came from that reference.
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` Q. Where did the eight percent come from?
` A. It says in OVID and PubMED based
`researches. So that means several papers are broad
`based on databases.
` Q. So are you aware of a specific finding
`in any literature, any reference that BAK causes a
`true allergic response as distinguished from a toxic
`irritant reaction?
` A. I would not have a reference for that.
` Q. And you don't know how the Bagnis
`reference supports its eight percent figure either,
`do you?
` A. By what they have in the quotation mark.
` Q. And what do they have in the quotation
`mark?
` A. Eight percent in OVID and PubMED based
`researches.
` Q. And do you have any knowledge of how
`they did those searches?
` A. I do not.
` Q. Going back to the first sentence of
`Paragraph 12, you write that you again prescribe
`Travatan Z in your clinical practice as a first line
`treatment only for patients you know to be allergic
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` DR. YVONNE B. BUYS
`to BAK.
` Now, you can't know that a patient
`is allergic to BAK before they're treated with a
`ophthalmic formulation containing BAK; isn't that
`true?
` A. Unless they had symptoms of ocular
`surface disease prior to being on antiglaucoma
`medications, then I think you could assume that the
`BAK did not cause those symptoms because they were
`preexisting.
` Q. So, you're saying that if a patient
`presents with ocular surface disease, which I'll
`call OSD, you don't know whether that patient is
`going to be allergic, as you've used the term
`"allergic," also to BAK; is that right?
` A. Correct.
` Q. Now, when a patient presents with OSD,
`it's your practice to prescribe which medication for
`a glaucoma patient?
` A. My usual, first-line medication, as long
`as they have no other contraindications, would be
`Latanoprost.
` Q. And if a patient presents with OSD, you
`would prescribe that patient Latanoprost?
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` A. Correct.
` Q. And you would only prescribe Travatan Z
`if the patient was allergic to BAK?
` A. Correct.
` Q. And how do you determine that a patient
`is allergic to BAK?
` A. It would be in retrospect that you would
`be able to determine that. So if their systems of
`ocular surface disease got significantly worse with
`Latanoprost, then I might consider switching to
`Travatan Z.
` Q. Do you have any reason to doubt the
`15 percent figure that Dr. Parrish -- that you refer
`to that Dr. Parrish says is the percentage of
`individuals over 65 years old who suffer from OSD
`symptoms?
` A. No.
` Q. And you don't know whether the
`percentage of patients who experience irritant toxic
`reactions to BAK, how that group fits within the
`15 percent presented with ocular surface disease?
` A. Correct. Because ocular surface disease
`is a term that describes a variety of conditions
`caused by a variety of etiologies, the most common
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`being a dry eye.
` Q. So do you have an opinion one way or the
`other whether a patient who presents with ocular
`surface disease is going to be more likely to have
`an allergy to BAK?
` A. No.
` Q. You have no opinion one way or the
`other?
` A. I don't think that you can predict who
`would be more likely to be allergic to BAK.
` Q. The last sentence of Paragraph 12 on
`Page 6 of exhibit 1021, you write, "Therefore my
`prescribing practices in this regard are different
`than Dr. Parrish's and highlight a more modest need,
`approximately half of that described by Dr.
`Parrish."
` What do you mean by "need"?
` A. I don't recognize that Travatan Z
`necessarily will solve the problem in these patients
`who have ocular surface disease. And that's borne
`out by the literature that Dr. Parrish also
`presented.
` Q. What do you mean by "solve the problem"?
` A. I mean that their ocular surface disease
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`symptoms would be less by using Travatan Z, a BAK
`premedication as compared to a medication that had
`benzalkonium chloride.
` Q. Do you have an opinion one way or the
`other whether there was a need for a BAK-free
`ophthalmic formulation to treat glaucoma because
`that medication wouldn't make the OSD systems worse?
` A. But there were BAK-free medications
`available in 2006. So I don't know -- are you
`asking was there a need for an additional one?
`Because there were several BAK-free medications
`available prior to Travatan Z. So I'm not sure if
`you're asking was there need for more.
` Q. None of those that were available before
`Travatan Z were multi use medications, were they?
` A. One was. Alphagan P.
` Q. And is Alphagan P a PAG, prostaglandin
`analog?
` A. No, none were prostaglandin analogs.
` Q. So as of the time Travatan Z came on the
`market, there were no prostaglandin analogs
`available in a BAK-free formulation?
` A. Correct.
` Q. In Paragraph 13 of your declaration, the
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`first sentence you refer to an "alleged need" again.
`Is that the same need you're talking about?
` A. Correct.
` Q. Then the next sentence says,
`"Approximately 10 percent of patients do not respond
`to Travatan Z."
` Do you see that?
` A. Yes.
` Q. And that 10 percent figure comes solely
`from the Mizoue study, correct?
` A. Correct.
` Q. And the Mizoue study involved patients
`with normal tension glaucoma, didn't it?
` A. Correct.
` Q. And Travatan Z was not indicated at its
`approval to treat patients with normal tension
`glaucoma, was it?
` A. I would not know.
` (Whereupon, the document was
` tendered.)
` Q. I'm handing you what's been marked as
`Exhibit 2004.
` Do you recognize this document?
` A. Yes.
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` Q. What is this?
` MR. HOUSTON: Wait. I'm sorry. I'm
`going to put an objection on the record. Alex,
`is -- this isn't from --
` MR. ZOLAN: I'm serving the exhibit now.
` MR. HOUSTON: You're serving the exhibit
`now. I was trying to get an understanding what this
`exhibit number was.
` For the record, authenticity
`objection, hearsay.
`BY MR. ZOLAN:
` Q. So what is this document?
` A. I believe this was the patent
`application for Travatan Z.
` Q. I'll represent to you that this is the
`medical review that's part of the drug approval
`package that is located on the FDA website.
` A. Okay.
` Q. And if you turn to Page 47 at the bottom
`here -- let me strike that.
` Are you familiar with the FDA's
`website?
` A. I have heard of it, yes.
` Q. Have you ever visited the FDA website?
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` DR. YVONNE B. BUYS
` A. No.
` Q. Have you ever looked at a drug approval
`package on the FDA's website?
` A. No.
` Q. Have you ever seen a document like
`you're looking at right now, 2004?
` A. Yes.
` Q. What context have you seen the document
`like the one we're looking at now?
` A. They have sometimes been provided by
`drug representatives of companies.
` Q. At Page 43 of Exhibit 2004, do you see
`an X next to draft labeling?
` A. Correct.
` Q. Do you know what the labeling for a
`marketed pharmaceutical product is?
` A. This would be, I would assume, in the
`drug insert with the product.
` Q. And if you turn to Page 47 of
`Exhibit 2004, do you see a heading "Indications and
`Usage"?
` A. Correct.
` Q. And could you read the first sentence of
`that paragraph?
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` DR. YVONNE B. BUYS
` A. "Travatan Z ophthalmic solution is
`indicated for the reduction of elevated intraocular
`pressure in patients with open-angle glaucoma or
`ocular hypertension who are intolerant of other
`intraocular pressure lowering medications or
`insufficiently responsive (failed to achieve target
`IOP determined after multiple measurements over
`time) to another intraocular pressure lowering
`medication."
` Q. Have you ever reviewed the package
`insert to Travatan Z?
` A. I believe I've read that before.
` Q. And did patients with normal tension
`glaucoma have elevated intraocular pressure?
` A. Patients with normal tension glaucoma
`have elevated pressure for themselves as an
`individual.
` Q. Is there some consensus about in the
`clinical community about what a normal intraocular
`pressure is?
` MR. HOUSTON: Objection. Form.
`BY THE WITNESS:
` A. So the average intraocular pressure, the
`consensus is around 15 millimeters mercury with a
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` DR. YVONNE B. BUYS
`standard deviation of 2-1/2; however, it is skewed
`to the right, meaning that population doesn't have a
`bell-shaped curve for intraocular pressures. They
`tend to run a little bit higher than the 2.5 on
`average.
` Q. Is it your testimony that patients with
`normal tension glaucoma have elevated intraocular
`pressure?
` A. They are on average above the mean of
`15, so they don't have low pressures per se, they do
`have typically pressures in the higher teens, which
`are slightly above normal.
` Q. Today is Travatan Z indicated to treat
`normal level glaucoma, normal tension glaucoma?
` A. I think you're asking is Travatan Z used
`to treat normal tension glaucoma. Absolutely.
` Q. What I'm asking is whether it's
`indicated to treat patients with normal tension
`glaucoma?
` A. I would believe it is from here, because
`it says fail to achieve a targeted intraocular
`pressure, so elevated intraocular pressure means
`it's higher than your target, so in normal tension
`glaucoma, still the treatment is to lowering
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` DR. YVONNE B. BUYS
`intraocular pressure to target.
` Q. I'm going to hand you what's been marked
`as Exhibit 1025.
` (Whereupon, the document was
` tendered.)
`BY MR. ZOLAN:
` Q. Do you recognize Exhibit 1025.
` A. Yes.
` Q. What is the 1025?
` A. A paper by Mizoue, a Japanese paper
`looking at the efficacy of Travatan Z in normal
`tension glaucoma.
` Q. In the first page of this Exhibit, 347
`at the bottom, it's got a "Methods" section at the
`top of that page. And in the "Methods" section it
`says, "In this prospective, multicenter, open-label
`study, Japanese NTG," which I take it to mean normal
`tension glaucoma?
` A. Correct:
` Q. "Patients with baseline IOPs less than
`20 millimeters of mercury were enrolled after three
`consecutive time measurements taken at screening and
`baseline visits."
` Did I read that right?
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` DR. YVONNE B. BUYS
` A. Yes.
` Q. Are you aware of the data the FDA relied
`on to approve Travatan Z as a marketed drug?
` A. No.
` Q. You're unfamiliar with the study that
`the FDA relied upon to approve Travatan Z?
` A. I would not know what the specific study
`was.
` Q. Are you aware of the characteristics, in
`particular the intraocular pressure of the patients
`who were used in that study?
` A. In the study that I said I didn't know
`the specific study?
` Q. That's right.
` A. No, I would not know what the specific
`intraocular pressure was.
` Q. On Page 4 of your declaration, this is
`back to Exhibit 1021, you said you reviewed the
`Lewis reference. That's at the bottom of the page.
` A. Yes.
` Q. Can you describe what the Lewis
`reference is?
` A. So the Lewis reference was a study where
`they involved about 690 patients and compared the
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` DR. YVONNE B. BUYS
`safety and efficacy of Travatan Z with BAK to
`Travatan Z, which is travoprost without BAK, looking
`at both the outcomes in terms of intraocular
`pressure and safety.
` Q. And do you know one way or the other
`whether the Lewis study summarized the data that was
`submitted to the FDA for the approval of Travatan Z?
` A. I am assuming by the question that it
`could have.
` Q. Do you know what the mean IOP level for
`the patients who were in that study was?
` A. I would need to reread the study to know
`what the specific number was, but typically these
`papers are around 24 millimeters mercury.
` Q. If you look at Page 19 of
`Exhibit 1026 -- sorry, 2004, my apologies.
`Exhibit 2004.
` A. Which page?
` Q. Page 19 at the bottom.
` A. There's two numbers.
` Q. 19 is all the way at the bottom there.
`Do you see a heading "Inclusion Criteria"?
` A. Yes.
` Q. And No. 2 there, "Patients must have met
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` DR. YVONNE B. BUYS
`the following IOP entry criteria in at least one
`eye."
` Do you see that?
` A. Correct, yes.
` Q. And it says, "For each qualifying eye,
`the mean IOP must have been 24 to 36 millimeters of
`mercury at 8:00 a.m. on both eligibility visits one
`and two."
` Do you see that?
` A. Yes, I do.
` Q. Is that higher than the IOP readings in
`the patients in the Mizoue study?
` A. Yes, it is.
` Q. And below that there's another bullet
`that says, "For each qualifying eye, the mean
`IOP must have been 21 to 36 millimeters of mercury
`at 10:00 a.m. and 4:00 p.m. on both eligibility
`visits one and two."
` Did I read that right?
` A. Yes.
` Q. And are those readings of IOP higher
`than the readings of the patients in the Mizoue
`study?
` A. Yes, they are.
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` DR. YVONNE B. BUYS
` Q. Now, I know you said you're unfamiliar
`with Exhibit 2004 or you weren't -- I think you said
`you were familiar with it but you described it as a
`patent application.
` I'll represent to you it's not a
`patent application. It is a portion of the new drug
`approval package that is submitted to the FDA. But
`assuming that this is a portion of the NDA
`submitted for the approval of Travatan Z, are the
`patients studied in the Mizoue study representative
`of the patients whose data was submitted for the
`approval of Travatan Z?
` MR. HOUSTON: Objection. Beyond the
`scope.
`BY THE WITNESS:
` A. They are a different cohort.
`BY MR. ZOLAN:
` Q. What do you mean by "a different
`cohort"?
` A. They all have open-angle glaucoma, but
`one is a higher pressure open-angle glaucoma, than
`the Mizoue paper, however they're all treated the
`same by lowering intraocular pressure.
` Q. And the 10 percent figure that you cite
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`in Paragraph 13 of your declaration, that refers to
`the nonresponsive patients in the Mizoue study,
`right?
` A. That's correct. But they also mention
`high pressure intraocular pressure, which is their
`reference 15, and they report a non-responder rate
`for prostaglandins in general of 20 percent for high
`pressures.
` Q. And -- but you --
` A. So they reported a lower rate in their
`study.
` Q. For the 10 percent figure, you're solely
`relying on the Mizoue study?
` A. Correct.
` Q. And then in your declaration at
`Exhibit 1021, after you site the Mizoue study, you
`say, "In addition to this group of non-responders,
`in my experience, an even larger percentage of
`patients show an insufficient response to Travatan Z
`and require the addition of at least one more
`medication to lower their intraocular pressure."
` Do you see that?
` A. Yes.
` Q. Now, for that sentence, you're just
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` DR. YVONNE B. BUYS
`relying on your experience as a practicing
`physician, right?
` A. No, I'm not. I'm also looking at the
`literature.
` Q. And what literature are you looking at?
` A. Well, there are several papers that show
`demographics of people treated with glaucoma,
`treated with medications to lower their pressure and
`show the number of medications that are required in
`order to achieve a target pressure.
` Q. And can you cite to me a study that
`studies Travatan Z with an effective rate of higher
`than 10 percent?
` A. I don't know what study that would
`specifically highlight only Travatan Z, but there
`are many studies that look at how people are really
`treated in practice that would include Travatan Z in
`the patients that are managed.
` Q. But your declaration says, in your
`experience, an even larger percentage of patients
`show an insufficient response to Travatan Z.
` Did I read that right?
` A. As compared to the -- I agree that
`non-responder rate is one cohort, but then you also
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`want to know will the drop bring your pressure to
`your target pressure and that would be larger than a
`non-responder rate.
` Q. I'm not sure if that answered my
`question. My question is, this sentence of yours,
`you're referring to a non-responder rate of Travatan
`Z treated patients that's larger than 10 percent,
`right?
` A. No. I'm referring to an insufficient
`response being higher than a non-responder rate.
` Q. And the insufficient response is
`particular to Travatan Z in this sentence, isn't it?
` A. It mentions Travatan Z, but it also
`would apply for virtually all eyedrops.
` Q. So my question was, are you relying on
`anything other than just your experience to say that
`an even larger percentage of patients show an
`insufficient response to Travatan Z and require the
`addition of at least one more medication?
` MR. HOUSTON: Objection. Asked and
`answered.
`BY THE WITNESS:
` A. Again, I would say I looked at the
`literature which helps to support that.
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`BY MR. ZOLAN:
` Q. And what literature have you looked at?
` A. So I cite one paper here, the paper by
`Kass, et al., and that was a large trial for ocular
`hypertensives where they were trying to reduce their
`pressures 20 percent or to get to a target below 24.
`And in the over 800 patients that were put in the
`medication treatment arm, they found that
`39.7 percent would require more than one medication
`in order to achieve that target.
` Q. I'm going to give you Exhibit 1024.
` (Whereupon, the document was
` tendered.)
`BY MR. ZOLAN:
` Q. Do you recognize Exhibit 1024?
` A. This is the paper I just mentioned.
` Q. This is the Kass study you say is
`consistent with your experience?
` A. Yes.
` Q. And at the bottom of Page 704 of
`Exhibit 1024, in the left-hand column below IOP
`reduction and medication, about four lines up from
`the bottom there's a sentence that begins, "At 60
`months."
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` Are you with me?
` A. Yes.
` Q. That sentence says, "At 60 months, two
`or more topical medications were prescribed for
`39.7 percent (259 of 653) of the medication
`participants."
` Did I read that right?
` A. Correct.
` Q. Kass does not break down that
`39.7 percent by drug class, does it?
` A. I don't believe it does.
` Q. So you can't tell whether that
`39.7 percent are patients who are taking PGAs or any
`other type of glaucoma therapy, can you
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