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`TfiD STATLS PATjNT AND TRADEMARK Obi'Cfi
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`UN
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`L
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`TH
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` fl PATflNT TRHAL AND APB
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` fiEORZ
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` fiAL %OARD
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`ARG
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`ENTUM ?HARMKC?UTWCALS LLC,
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` ?etitioner
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`V.
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`ALCON QfiSfiARCH, LTD.,
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`Paoen- Owner
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`Case :?R2017—01053
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`Paten: 8, 268, 299
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`DflPO
`S i ON Ob
`flRN NG X A,
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`Ph.i.
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`November 29, 2017
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`Chicago, Illinois
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`8:56 a.m.
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`-—.
`3y:
`Reporte
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`il
`Sheri
`Hiss,
`Job No. 52741
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`CSR, RPR, CRR
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`Argentum Pharm. LLC V. Alcon Research, Ltd.
`CaseIPR2017-01053
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`ALCON 2 1 2 1
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` DEPOSITION OF ERNING XIA, Ph.D.
` The deposition of ERNING XIA, Ph.D., 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 29, 2017 at
` the hour 8:56 o'clock a.m.
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`DAVID FELDMAN WORLDWIDE, INC.
`450 Seventh Avenue - Ste 502, 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 M. KRINSKY, ESQ.
` dkrinsky@wc.com
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` DEPOSITION OF ERNING XIA, Ph.D.
` I N D E X
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` ERNING XIA, Ph.D.,
` EXAMINATION PAGE
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` Mr. Houston 180
` Mr. Zolan 189
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` E X H I B I T S
` NO. DESCRIPTION MARKED/REFERRED TO
` Exhibit 1007 Previously marked 19
` Exhibit 1003 Previously marked 28
` Exhibit 1004 Previously marked 83
` Exhibit 1001 Previously marked 89
` Exhibit 1005 Previously marked 110
` Exhibit 1002 Previously marked 152
` Exhibit 1018 Previously marked 152
` Exhibit 1039 Previously marked 165
` Exhibit 2005 Patent Application 171
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` DEPOSITION OF ERNING XIA, Ph.D.
` (Whereupon, the witness was
` sworn.)
` ERNING XIA,
` having been first duly sworn, was examined and
` testified as follows:
` EXAMINATION
` BY MR. ZOLAN:
` Q. Doctor, it's good to meet you. I'm Alex
` Zolan.
` A. Good to meet you too.
` Q. Could you please state your name and
` spell your name?
` A. My last name X-i-a, first name
` E-r-n-i-n-g.
` Q. And Dr. Xia, what was the problem that
` the person of ordinary skill in the art was trying
` to solve as of September of 2006?
` MR. HOUSTON: Objection. Form.
` BY THE WITNESS:
` A. You talking about Travatan?
` BY MR. ZOLAN:
` Q. Well, it's my understanding you're here
` to give some opinions about the obviousness of the
` '299 patent; is that right?
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` DEPOSITION OF ERNING XIA, Ph.D.
` A. Yes.
` Q. That's U.S. Patent No. 8,268,299; is
` that correct?
` A. Yes.
` Q. And your opinion is that the claims of
` the '299 patent were obvious to the person of
` ordinary skill in the art as of September 2006; is
` that right?
` A. Yes.
` Q. So what problem was the POSA, person of
` ordinary skill in the art, trying to solve as of
` September 2006?
` MR. HOUSTON: Objection. Form.
` BY THE WITNESS:
` A. To me, the issues can come from the
` technique respect and also can come from business
` decisions. When you work for a company like Bausch
` & Lomb or Alcon, sometimes they have a group of
` people sit together and discuss the goal or
` strategies for certain products, development work.
` And to me, I think that one of the
` issues and attention associated with Travatan is try
` to remove preservative to come out with
` preservative-free version of Travatan.
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` DEPOSITION OF ERNING XIA, Ph.D.
` BY MR. ZOLAN:
` Q. And so I think what you're saying is
` there was a need to develop a preservative-free or a
` self-preserved formulation of Travatan?
` A. I don't have a statistic in front of me,
` but I think that you can always find some patient
` their ocular tissues may be sensitive to certain
` preservatives such as BAK. And as a company, if you
` have preserved version and self-preserved version
` you may give a doctor more options to treat their
` patient, which is pharmaceutical companies'
` responsibility.
` Q. Was the need -- strike that.
` You were working in the ophthalmic
` formulation field in September 2006, right?
` A. Yes.
` Q. And was there a need greater than simply
` developing a self-preserved version of Travatan such
` as a need for developing a self-preserved ophthalmic
` formulation for the treatment of any number of eye
` conditions?
` A. The answer is yes. Especially when
` you're working for, for example, if you working for
` dry eye products, especially for OTC dry eye
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` products, you have to use the products many, many
` times a day. And for that case, you try to not
` preserve your formulation with some harsh
` preservatives such as BAK.
` And BAK, certain percentage of
` population are sensitive to BAK. Second, BAK could
` be toxic or irritant to the ocular tissues. And,
` for example, there's lots of evidence to support BAK
` can damage to integrity of tight junctions of
` epithelial cells.
` So there's a need for scientists
` from all over the place, from every single company
` to come out with new innovations for self-preserved
` formulations, sometimes we call gently preserved
` formulations.
` Q. And I think you mentioned in that answer
` sort of two reasons why the self-preserved
` formulations would be necessary, and let me try to
` review those. One was for the example of dry eye,
` it would -- this is a condition that would need to
` be treated multiple times a day, potentially for a
` long time; is that right?
` A. Yes.
` Q. And the need for glaucoma patients is
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` similar; is that right?
` A. I wouldn't say similar, because you
` using glaucoma drug one or two times a day, not like
` dry eye products used as needed. So that -- also
` that dry eyes OTC products is much less regulated,
` not like therapeutic.
` Therapeutic drugs, sometimes if I
` work on therapeutic drugs, there's always trade off.
` You want to make sure that your product is well
` preserved and you do not have secondary
` contaminations. Especially in the south part of
` this country, Texas, some people leave their
` eyedrops in the cars for certain amount of time.
` That could cause problem.
` So in that case, you do need
` products, special therapeutic drug to make sure that
` you do not have preservation issues.
` Q. I guess I wasn't trying to say that the
` need was the same. I meant similar in that you
` would agree with me that glaucoma patients need to
` put at least one drop of, say, a prostaglandin
` analog into their eye each day, right?
` A. Yes.
` Q. And these glaucoma patients take a
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` prostaglandin analog, as an example, each day
` chronically; is that right?
` A. Most of the time.
` Q. Other than dry eye and glaucoma,
` or -- strike that.
` Other than dry eye and elevated
` intraocular pressure, are there other eye conditions
` that you are aware of that require daily chronic use
` of an ophthalmic medication?
` A. Depends. If you do have dry eye, really
` dry eye issues, there's two ways to treat you. One
` way is using OTC dry eye, just make you feel
` comfortable for the next couple of hours. By end of
` day, we do use drug products to treat your dry eye.
` Dry eye patients could use product for long time.
` Q. I'm sorry, maybe you misunderstood my
` question or maybe I didn't ask it right. I'm saying
` putting to the side dry eye and glaucoma, are there
` any other eye conditions that might require daily
` chronic use of an ophthalmic medication?
` A. I tried to answer that. I said if you
` have severe dry eye disease.
` Q. And that's something different from the
` dry eye I put to one side?
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` DEPOSITION OF ERNING XIA, Ph.D.
` A. Yes. Dry eye can be caused by 20 or 50
` different reasons. So most of the time with dry
` eye, we're talking about -- we talking about
` unstable tear films and overproduction of tears. By
` end of day, some inflammation inside the lacrimal
` glands could be the key target issues for us to
` focus on.
` So we do have certain companies
` such as Shine Pharmaceuticals that come out with new
` drugs target certain ocular tissues. So that type
` of drug could take a long time to eliminate the
` inflammation.
` Q. So I think what you're saying is there
` are -- there's dry eye, there's glaucoma and then
` there are the root causes of dry eye?
` A. Yes.
` Q. And -- is that right?
` A. Yes.
` Q. And it's those root causes of dry eye
` that are those other conditions other than dry eye
` and glaucoma that would necessitate potentially
` daily chronic use of an ophthalmic medication?
` A. Yes.
` Q. We've used the term "self-preserved" so
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` DEPOSITION OF ERNING XIA, Ph.D.
` far today; is that right?
` A. Yes.
` Q. And can we agree that self-
` preserved -- strike that.
` Can we agree that a self-preserved
` ophthalmic composition is an ophthalmic composition
` that does not contain a conventional antimicrobial
` preservative?
` A. Yes and no, because people have
` different definitions about the tradition of
` preservatives. Sometimes I agree, sometimes I
` disagree, which is okay, which okay. I don't
` believe it's -- for example, if you're using
` stabilizer hydrogen peroxide to preserve your
` medications, then when peroxide hits your eyes it
` become water and oxygen so we call them a
` disappearing preservative system. And Alcon has
` such products as well.
` And I will -- I would say this kind
` of preservative could be qualified as gentle
` preservative. It is not traditional preservative.
` So --
` Q. In this case, for your opinions in this
` case, when you use the term "self-preserved
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` DEPOSITION OF ERNING XIA, Ph.D.
` ophthalmic composition," are you referring to a
` ophthalmic composition that does not contain a
` traditional -- a conventional preservative?
` A. Yes.
` Q. And the conventional preservatives you
` mean when you use that term in this case include
` benzalkonium chloride, right?
` A. That's No. 1.
` Q. And it would include polyquaternium-1,
` right?
` A. Yes.
` Q. And that's also known by the trade name
` Polyquad; is that right?
` A. Yes. Polyquaternium-1, yes.
` Q. Chlorite is another conventional
` preservative for the purpose of your opinions in
` this case?
` A. I disagree. I still believe that
` compared with BAK, I would say sodium chlorite,
` chlorite, this is a gentle preservative. It's not a
` traditional conventional preservative.
` Q. Let me ask a slightly different question
` then. Your opinions in this case are from the
` perspective of a person of ordinary skill in the
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` DEPOSITION OF ERNING XIA, Ph.D.
` art, right?
` A. Yes.
` Q. Would a person of ordinary skill as of
` September 2006 have considered chlorite to be a
` conventional preservative?
` A. Sodium chlorite, c-h-l-o-r-i-t-e.
` Q. Are you asking me a question?
` A. Yes. Is it chlorite?
` Q. Well, I don't know. I'm looking at your
` declaration and you use the term "chlorite."
` Is sodium chlorite what you meant
` when you used the term "chlorite"?
` A. Correct.
` Q. And the POSA, as of September 2006,
` would have considered sodium chlorite to be a
` conventional preservative; is that right?
` A. I disagree. Chlorite is much more
` gentle than BAK or polyquaternium-1.
` Q. Are you changing your opinions in this
` case, because you disagree with what the POSA would
` have considered to be a conventional preservative as
` of 2006?
` MR. HOUSTON: Objection. Form.
` BY THE WITNESS:
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` DEPOSITION OF ERNING XIA, Ph.D.
` A. I don't change my position. I just have
` different understanding about what's exact
` definition of traditional/conventional. And I
` believe traditional and conventional preservative,
` most of the time, is cationic compound.
` BY MR. ZOLAN:
` Q. Let me make this a little bit easier.
` The '299 patent defines conventional antimicrobial
` preservative, doesn't it?
` A. Yes.
` Q. And it defines, it identifies
` benzalkonium chloride, polyquaternium-1, chlorite
` and hydrogen peroxide to be conventional
` preservatives; is that right?
` A. Yes.
` Q. So it's your understanding that a POSA
` as of September 2006 reviewing the '299 patent would
` understand it to be defining conventional
` preservatives as BAK, Polyquad, chlorite and
` hydrogen peroxide; is that fair?
` A. It's fair. The reason I was hesitating
` to answer your questions, I went to so many
` ophthalmic meetings around the United States. I saw
` many, many publications, posters from Alcon. They
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` DEPOSITION OF ERNING XIA, Ph.D.
` promote certain preservatives not as conventional,
` such as polyquat-1. Polyquat-1 is totally different
` from BAK, as well as gentle. Does not hurt the
` tissues. You can use as high as 10 PPM.
` So I have no problem. I believe
` that people can have disagreement. And especially
` Alcon products preserved with chlorite and as
` oxidative preservative system. A traditional
` preservative system is chemical preservative system.
` So we can have different position
` for that. I do not believe -- that's what I did
` not. And if Alcon wants to define Polyquad as not a
` gentle preservative, it's fine with me. I don't
` object, I can respect their position. I have no
` problem.
` Do you know what I'm talking about?
` Q. I think I do understand what you're
` talking about. I want to be clear. You're not
` relying on any of the posters or presentations that
` you discussed in that last answer for your opinions
` in this case, are you?
` A. I respect science. When I read
` publications, I see certain argument from Alcon's
` publications. There is a point, they demonstrate a
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` DEPOSITION OF ERNING XIA, Ph.D.
` lot of scientific studies, results, and over and
` over you demonstrate that polyquat-1 is not as harsh
` as traditional preservatives such as BAK.
` Q. Is this something that the person of
` ordinary skill in the art would have known as of
` September 2006?
` A. Yes.
` Q. And we agree that for all purposes,
` benzalkonium chloride is a conventional
` preservative?
` A. Yes.
` Q. Your opinion is that the person of
` ordinary skill, as of September 2006, would have
` been motivated to combine the Schneider reference
` with other references in order to solve the problem
` we spoke about a few minutes ago, right?
` A. Can you repeat it one more time.
` Q. A few minutes ago we talked about the
` problems facing the POSA as of September 2006.
` Do you remember that conversation?
` A. Yes.
` Q. And the problem I think we landed upon
` was for daily chronically used ophthalmic
` medications there was the need for a gentler
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` DEPOSITION OF ERNING XIA, Ph.D.
` formulation of those ophthalmic medications; is that
` right?
` A. It mitigate the problems, but still the
` having the products for the patient.
` Q. And so your opinion is that the POSA in
` September of 2006 would have looked to Schneider and
` combined the formulations disclosed in that patent
` with other references in order to solve that
` problem; is that right?
` A. Yes.
` Q. What would have motivated the POSA to
` choose Schneider to combine the other references?
` A. Because Schneider's formulations is
` already in the marketplace and demonstrate both
` safety and effectiveness.
` Q. There may have been other patents that
` covered products that were already in the
` marketplace, for example, patents that covered
` latanoprost, right?
` A. Yes.
` Q. And the POSA could have looked to the
` formulations disclosed in those patents in order to
` formulate a BAK-free, for example, glaucoma
` medication?
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` DEPOSITION OF ERNING XIA, Ph.D.
` A. Yes. I agree with you.
` Q. Schneider does not teach self-preserved
` ophthalmic compositions, right?
` A. Yes.
` Q. I'm going to hand you what's already
` been marked as Exhibit 1007.
` (Whereupon, the document was
` tendered.)
` BY MR. ZOLAN:
` Q. And do you recognize this document?
` A. Yes.
` Q. Is this in fact the Schneider patent you
` refer to in your declaration?
` A. Yes.
` Q. Each of the example formulations
` disclosed in Schneider contains benzalkonium
` chloride, right?
` A. Yes.
` Q. And each of the formulations disclosed
` in Schneider contains EDTA, right?
` A. Yes.
` Q. And EDTA has antimicrobial activity?
` A. Yes.
` Q. The concentration of BAK in the examples
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` DEPOSITION OF ERNING XIA, Ph.D.
` disclosed in Schneider is between .01 percent by
` weight and .015 percent by weight; is that right?
` A. Yes.
` Q. Would you agree with me that that's
` toward the upper end of the concentration of BAK
` found in marketed ophthalmic formulations?
` A. My understanding, this is average
` concentrations most of the companies use.
` Q. Are you aware of any marketed ophthalmic
` formulations to be used as an eyedrop that contain
` greater than .15 (sic) percent by weight
` benzalkonium chloride?
` A. Before I answer your question. BAK raw
` materials, most of the time you buy BAK materials
` it's not a hundred percent pure. I use in Bausch &
` Lomb 50 percent, and lots of people use 25 percent.
` So that the concentration here looks like maybe
` we're just assuming it's a hundred percent.
` In the specification it did not say
` my BAK is 50 percent, but if you look at the
` publication, people always say 50 percent, I add
` this much. Actually, the concentration could have
` been less, and people have a hundred percent BAK.
` May not have anything to do, but I
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` DEPOSITION OF ERNING XIA, Ph.D.
` just want to clarify that.
` Here it's a hundred percent. You
` can assume it's a hundred percent.
` Q. So the POSA would assume this was a
` hundred percent BAK?
` A. Yes.
` Q. And my question was, are you aware of
` any marketed ophthalmic formulation to be used as an
` eye drop that contains the concentration of BAK of
` greater than .015 by weight?
` A. I don't recall that product. I did not
` see that before. I do not recall this product.
` Q. Did that product that you don't quite
` recall contain a concentration of benzalkonium
` chloride greater than .02 percent by weight?
` A. I don't remember. I don't remember. I
` don't have piece of paper in front of me. I don't
` want to speculate.
` Q. Schneider does not teach the use of
` borate-polyol complexes as an antimicrobial agent,
` does it?
` A. Yes and no. If I say yes, because I am
` very familiar with the formulation work, and when
` you add boric acid or borate with mannitol and
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` DEPOSITION OF ERNING XIA, Ph.D.
` sorbitol, so there you can see the significant
` decrease of pH in the system from 7 to 5. So that's
` the sign of the complex form.
` Q. But that's not a teaching that's in
` Schneider, is it?
` A. I think he may teach there. The No. 1
` goal of teaching is to how do you stabilize your
` active waste, HCO-40. And I think it's No. 1 goal
` for every single product to benefit. If you cannot
` stabilize your actives, then you don't have a
` product.
` Q. And there aren't, in fact, any
` antimicrobial data contained in Schneider, are
` there?
` A. No.
` Q. And the POSA wouldn't understand
` the -- strike that.
` The POSA would understand the
` function of benzalkonium chloride to be the
` antimicrobial agent in the formulations disclosed in
` Schneider, wouldn't it?
` A. POSA would understand the majority of
` preservative efficacy is from BAK.
` Q. I think I know why you answered that way
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` DEPOSITION OF ERNING XIA, Ph.D.
` but let me try this: At that concentration of BAK,
` the .015 percent by weight, which earlier you said
` was the average, I think, in ophthalmic
` formulations. That's going to -- a formulation
` containing that concentration of BAK, the POSA would
` expect to pass preservative efficacy standards;
` isn't that right?
` A. If they do not have anything else, if
` it's just API actives with BAK and the boric buffer
` there, I will agree with you.
` But if sometimes we do add high
` concentration of surfactant, and this surfactant
` might do certain things to -- and could decrease
` your efficacy a little bit, could enhance your
` efficacy a little bit, so there's a way we published
` articles there.
` But that's what I -- I do not have
` that preservative efficacy there in front of me. I
` cannot say that the 150 PPM here will cure
` everything by four, five logs. I do not have that
` in front of me. So I just come out and say yes to
` you. But that's the average concentration, I agree
` with you, people use for that.
` Q. And the one example you brought up of an
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` DEPOSITION OF ERNING XIA, Ph.D.
` excipient that might affect the efficacy of BAK was
` a surfactant; is that right?
` A. Yes, because so many people --
` surfactant, you could pick and choose.
` Q. Would the POSA -- I'm sorry, are you
` finished?
` A. Yes.
` Q. Would the POSA as of September 2006 have
` known that .5 percent by weight of HCO-40 would
` interfere with the antimicrobial effectiveness of
` benzalkonium chloride?
` MR. HOUSTON: Objection. Form.
` BY THE WITNESS:
` A. I don't know that answer but I would
` have to run an experiment. For example, if I do the
` studies, if I pick a .5 percent HCO and with this
` formulation I were to -- there is some dose response
` for BAKs, right? You say a hundred PPM, I do 50 PPM
` to 150 PMM. I could do 25 to 200 PPM. I want to
` make sure that why I pick 150.
` If I could pick less, I do not pick
` less because today, if you submit your paperwork to
` FDA, they ask you those questions. Why you want to
` put something more than you need it? So if I do not
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` DEPOSITION OF ERNING XIA, Ph.D.
` have -- you're a hundred percent right. You don't
` have that data in front of me, I cannot readily
` answer those questions. But that's the routine
` exercise we do in the lab.
` BY MR. ZOLAN:
` Q. I think your answer was, you don't know
` one way or another whether that concentration of
` HC0-40, and by "that concentration" I mean the
` concentrations that are disclosed in Schneider,
` would have -- would impede the effectiveness of the
` concentration of benzalkonium chloride in those same
` examples?
` A. Yes.
` Q. And I want to go back to the question I
` asked a few minutes ago, and I'm not sure I got an
` answer really to this question, and it is -- just
` looking at the -- at Schneider itself, which we
` already covered, does not contain any antimicrobial
` data; is that right?
` A. Yes.
` Q. So the POSA looking at Schneider would
` not understand Schneider to teach anything about the
` antimicrobial efficacy of borate-polyol complexes;
` is that fair?
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` DEPOSITION OF ERNING XIA, Ph.D.
` A. If I read it, if I read these
` publications I would ask myself besides borate-
` polyol complex there, some people may not be aware
` of that, which is okay. What is the purpose of
` putting a trace as another ingredient in the
` formulation? What is the purpose to add .1 percent
` EDTA in there? Both of those ingredients can
` enhance preservative efficacy.
` Q. I understand that when you look at the
` patent, you see excipients that may have
` antimicrobial activity, that's what you're
` explaining to me?
` A. Yes.
` Q. I understand that. What I'm asking you
` is, does Schneider itself teach the POSA that
` borate-polyol complexes have antimicrobial activity?
` A. Did not have any description in this
` patent, yes, you're right.
` Q. The only polyol that is present in an
` example in Schneider is mannitol; that's right,
` right?
` A. That's right.
` Q. And Schneider itself describes mannitol
` as a tonicity or osmolality adjusting agent, right?
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` DEPOSITION OF ERNING XIA, Ph.D.
` A. Right.
` Q. Schneider doesn't have anything to do
` with zinc, does it?
` A. Does not.
` Q. An
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