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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`Case IPR 2017-01053
`Patent 8,268,299
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner
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`v.
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`ALCON RESEARCH, LTD,
`Patent Owner
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`Case IPR2017-01053
`Patent 8,268,299
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`ALCON RESEARCH, LTD.’S MOTION FOR OBSERVATIONS ON THE
`SECOND DEPOSITION OF PETITIONER’S EXPERT
`ERNING XIA, PH.D.
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`Case IPR 2017-01053
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`Patent 8,268,299
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`Pursuant to 77 Fed. Reg. 48,767-68, Paper 7 at 6, and Paper 34 at 2, Patent
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`Owner Alcon Research, Ltd. (“Alcon”) submits this motion for observations
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`regarding cross-examination of Petitioner’s reply declarant Erning Xia, Ph.D.,
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`following his deposition on May 11, 2018 (Exhibit 2166).
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`
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`Observation 1. Dr. Xia testified:
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`Q. Can you point me toward any data that would have led
`the POSA to a zinc-sorbitol-borate-propylene glycol
`ionic buffering system as of September 2006?
`
`A. At this point, I left – I used to collect all dry eye
`products. I have this product [Systane® Free] in my
`office. So in United States, when you want to introduce a
`product like this, you have to put all ingredients on the
`box. I can clearly remember that propylene glycol is in
`this product. It is in this product, propylene glycol.
`
`Q. . . . Are those the data in your opinion the POSA
`would rely upon to be led to the zinc-propylene glycol-
`sorbitol-borate combination that’s claimed in the ’299
`patent?
`
`A. They may. They may. Some POSA will move
`forward with that. But if there’s not patent – blocking
`patent there. If you have blocking patent, you cannot do
`anything.
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`Q. You said that the POSA may get there. Is that the
`only place the POSA may have ended up or could the
`POSA have ended up at –
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`A. Different formulation?
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`Q. – different formulation?
`
`A. Oh, yeah, yes.
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`1
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`Ex. 2166 at 106:10-107:12. This testimony is relevant to Petitioner’s argument
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`Case IPR 2017-01053
`Patent 8,268,299
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`that “[b]y 2006, a POSA was well-motivated to improve a host of ophthalmic
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`products to avoid BAK, including the well-known travoprost formulation of
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`Travatan®, via inclusion of zinc and borate-polyol complexes to achieve PE, and
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`would have arrived at the claims of the ’299 Patent via routine optimization . . . .”
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`Paper 35 at 1 (emphasis added). The testimony is relevant because it is contradicts
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`Petitioner’s argument.
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`Observation 2. Dr. Xia testified:
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`Q. What is a micronutrient?
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`A. Micronutrient, I’m not expert of microbiologist, . . .
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`Ex. 2166 at 12:20-22 (emphasis added).
`
`Q. So, the complete lack of zinc in a solution causes
`microorganisms in that solution to die because they don’t
`have the zinc they need to survive; is that fair?
`
`A. Again, I’m not a microbiologist. . . .
`
`Ex. 2166 at 14:7-11 (emphasis added).
`
`Q. Would the person of ordinary skill in the art have
`considered whether zinc was a micronutrient when using
`zinc as an antimicrobial agent?
`
`A. Using zinc as a preservative at the same time you
`believe zinc is food source of bacteria, that’s what you
`say, right? That’s your question? Same time you think
`this is food source for bacteria also can kill bacteria
`because they go both or different ways.
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`Case IPR 2017-01053
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`Patent 8,268,299
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`Q. Well, at particular concentrations, they might only go
`one way, right?
`
`A. Because in order to have bacteria grow, I don’t know
`what kind of nutrients they need for bacteria to grow.
`That’s why I cannot answer that question. I’m not a
`microbiologist.
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`Ex. 2166 at 41:14-42:7 (emphasis added; Argentum’s objections omitted).
`
`Q. Just to be clear, your opinions in this case are all
`based on the premise that zinc is not a micronutrient, is
`not a source of food for bacteria?
`
`
`
`A. I told you that before. I say I don’t know the answer
`for that. . . .
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`Ex. 2166 at 49:16-20. This testimony is relevant to Alcon’s argument that “the
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`POSA would affirmatively be concerned that zinc compositions with less zinc than
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`the 0.48 mM in Xia’s Example 18 would fail PET,” Paper 22 at 19, and to
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`Petitioner’s argument that the “POSA would not have relied on any of the
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`references [cited by Alcon’s microbiology expert Dr. Zhanel] to assess the
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`potential of zinc to pass PET in an ophthalmic composition,” Paper 35 at 5. The
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`testimony is relevant because it demonstrates that Dr. Xia cannot provide credible
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`testimony in response to the testimony of Alcon’s Dr. Zhanel (a microbiologist)
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`regarding (i) zinc’s properties as a micronutrient and (ii) the POSA’s associated
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`concern about using concentrations of zinc lower than the 0.48 mM in Xia’s
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`Example 18.
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`Case IPR 2017-01053
`Patent 8,268,299
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`Observation 3. Dr. Xia testified:
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`Q. When you are referring to high zinc concentrations in
`that sentence, you are not talking about the
`concentrations of zinc, the range of which is referred to
`in Xia, is that fair?
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`A. It should not.
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`Ex. 2166 at 53:21-25. This testimony is relevant to Petitioner’s argument that the
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`“POSA would have been concerned with using too high a level of zinc, and would
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`therefore have engaged in optimization to find the lowest suitable zinc
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`concentration,” Paper 35 at 5, and Dr. Xia’s statements regarding the same, Ex.
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`1093 ¶ 24. This testimony is also relevant to Alcon’s argument that “[n]o
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`reference Argentum cites suggests, for example, that the levels of zinc in Xia’s
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`examples would cause ocular irritation” and that “the POSA would have known
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`that zinc salts have been used as ophthalmic astringents at concentrations of around
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`0.25% w/v; that is, concentrations many times higher than the highest
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`concentration of zinc chloride used in any of Xia’s examples.” Paper 22 at 15.
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`The testimony is relevant because it is consistent with Alcon’s argument and
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`contradicts Petitioner’s argument.
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`Observation 4. Dr. Xia testified:
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`Q. I want you to focus on the words “are useful” in
`Paragraph 11 of your declaration. By using those words,
`you are not stating an opinion that Xia teaches that zinc
`ions alone without a primary preservative agent as
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`defined in Xia in the concentrations in Paragraph 11
`[0.001 wt% and 0.005 wt%] would pass PET, right?
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`Case IPR 2017-01053
`Patent 8,268,299
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`A. In my application, it does not have the concentration
`in this range alone to pass PET.
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`Q. And the POSA wouldn’t understand Xia to teach that
`those concentrations in Paragraph 11 in your declaration
`alone would pass PET, right?
`
`A. “Are useful” words could be means it may need some
`help from other ingredients.
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`Ex. 2166 at 72:17-73:5. This testimony is relevant to Alcon’s argument that
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`“nothing in Xia would suggest to the POSA that these lower amounts of zinc alone
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`provide sufficient preservative efficacy.” Paper 22 at 16. The testimony is
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`relevant because it is consistent with Alcon’s argument.
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`Observation 5. Dr. Xia testified regarding the last paragraph on page 9 of
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`Exhibit 1003:
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`Q. So, one of the characteristics that’s shared by the
`primary preservative agents in this paragraph is that it’s
`possible to use them alone in an ophthalmic composition
`and achieve preservative efficacy; is that fair?
`
`A. It’s fair, yes.
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`. . .
`
`Q. And where in Chowhan would the POSA get the
`understanding that borate-polyol complexes could be
`used as a sole preservative in ophthalmic composition to
`achieve preservative efficacy?
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`Patent 8,268,299
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`A. If a POSA reads column 2, line 21, it says that borate-
`polyol complex of the present invention are also useful in
`unpreserved saline solutions.
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`Q. So is it your testimony that those unpreserved saline
`solutions would pass preservative efficacy testing?
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`A. This is the way I understand, this POSA understand,
`yeah.
`
`Q. Is there any data to support that statement?
`
`A. I’m not challenging his teaching. If you make
`statement, you know, in patent applications, you must
`have some data to support it in order to make that
`statement. So, at least POSA will – this application will
`provide POSA enough information to explore.
`
`Q. Just to be clear, Chowhan does not say that borate-
`polyol complexes in unpreserved saline solutions caused
`the unpreserved saline solutions to pass preservative
`efficacy testing, Chowhan doesn’t use those words, right?
`
`A. Chowhan didn’t use those words, yeah.
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`Ex. 2166 at 75:11-77:25 (emphasis added). This testimony is relevant to
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`Petitioner’s argument that “borate-polyols’ antimicrobial properties qualify them
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`as a ‘primary preservative agent’ in Xia.” Paper 35 at 9. This testimony is also
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`relevant to Dr. Xia’s statement that the “POSA would reasonably consider a
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`borate-polyol complex a primary preservative agent under Xia’s definition.” Ex.
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`1093 ¶ 30. The testimony is relevant because it demonstrates that the POSA would
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`not have considered borate-polyol complexes to fall within Xia’s (Ex. 1003)
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`Patent 8,268,299
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`definition of “primary preservative agent” because borate-polyol complexes were
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`not known to be effective as the sole preservative in an ophthalmic composition.
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`Observation 6. Dr. Xia testified:
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`Q. . . . Schneider formulation A includes a polyol, right?
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`A. Yes
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`Q. That polyol is mannitol, right?
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`A. Yes. Yes, in the example A, yes. Mannitol, yes.
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`. . .
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`Q. And the POSA would know that it both passed
`preservative efficacy testing and was stable, right?
`
`A. Yes.
`
` .
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` . .
`
`Q. . . . Your opinion is that the POSA would take the zinc
`ions from Xia and take out the BAK from Schneider
`Formulation A and replace the BAK with –
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`A. Maybe take EDTA as well, right.
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`Q. Sure. But mannitol is still there in Schneider
`Formulation A?
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`A. At this point.
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` .
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` . .
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`Q. [T]here’s no evidence in Schneider showing that
`mannitol is causing problems, right?
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`A. That’s right.
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`Case IPR 2017-01053
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`Patent 8,268,299
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`Q. There’s nothing in Xia that teaches Mannitol being a
`problem in its formulations, right?
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`A. Yes.
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`Ex. 2166 at 62:19-66:2. This testimony is relevant to Alcon’s arguments that
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`“Chowhan’s clear preference for mannitol above all other polyols simply would
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`not motivate the POSA to select a different polyol—particularly if, as Argentum
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`posits, the POSA would be starting from a formulation derived from Schneider that
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`contains mannitol and not other polyols.” Paper 22 at 13. The testimony is
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`relevant because it is consistent with Alcon’s argument.
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`Observation 7. Dr. Xia testified:
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`Q. There’s nothing in Chowhan that’s teaching how
`antimicrobial activity is related to the choice of a polyol,
`right?
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`A. He teaches – he does teach that if you have the
`following three polyols such as glycerin, propylene
`glycol, and mannitol, mannitol is preferred. So he’s
`implying that mannitol will perform better.
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`Ex. 2166 at 86:18-25. This testimony is relevant to Petitioner’s argument that
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`“flawed is Alcon’s demand that a POSA would need a particular reason to select
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`‘propylene glycol and sorbitol over other polyols’ and ‘instead of mannitol.’”
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`Paper 35 at 13. This testimony is also relevant to Alcon’s argument that
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`“Chowhan’s clear preference for mannitol above all other polyols simply would
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`not motivate the POSA to select a different polyol—particularly if, as Argentum
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`Case IPR 2017-01053
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`Patent 8,268,299
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`posits, the POSA would be starting from a formulation derived from Schneider that
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`contains mannitol and not other polyols.” Paper 22 at 13. The testimony is
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`relevant because it is consistent with Alcon’s argument and contradicts Petitioner’s
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`argument.
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`Observation 8. Dr. Xia testified during examination by counsel for
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`Petitioner:
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`Q. . . . So you testified previously that when you
`increased the amount of borate-polyol complex, you
`would expect to see an increase in the preservative
`efficacy of your solution, right?
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`A. Yes.
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`Q. Okay. Is it your understanding that that increase –
`such an increase would apply across all concentration
`ranges of the borate-polyol complex?
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`A. I think that’s what I tried to clarify, that if we’re
`talking about a concentration in Chowhan’s application,
`there’s limits. But the question that was presented to me,
`I thought it was no limitations. So that’s what I was
`answered, slight different, I said, or if you go over, I
`think Chowhan’s limitation was polyol complex
`limitation is from .5 to 6 percent. 6 percent. Within that
`concentration range, if it increase, the complex will
`increase preservative efficacy.
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`Ex. 2166 at 118:9-119:1. This testimony is relevant to Alcon’s argument that “the
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`POSA following Chowhan’s teaching would be led to develop a composition
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`containing a high concentration of borate-polyol anions; Chowhan taught that
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`borate-polyol complexes are desirable.” Paper 22 at 31. This testimony is also
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`Patent 8,268,299
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`relevant to Petitioner’s argument that “the prior art motivated the POSA to
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`combine zinc and borate-polyol formulations having minimal or even no other
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`Anionics.” Paper 35 at 17. The testimony is relevant because it is consistent with
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`Alcon’s argument and contradicts Petitioner’s argument.
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`Observation 9. Dr. Xia testified during examination by counsel for Alcon:
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`Q. So let’s say you are testing under both [USP 27 and
`European] preservative effective criteria, and you test the
`solution in Xia, and the amount of pseudomonas goes
`down less than one log after one day, your opinion is that
`that’s not enough information to predict whether it will
`pass the USP PET at seven days?
`
`A. Yes.
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`Q. What if there is growth in pseudomonas after one day,
`does that allow you to predict the results at seven days?
`
`A. That formulation is gone.
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`Q. It’s gone?
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`A. Yeah.
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`Q. So if there’s growth, if after one day, it’s not going to
`be reduced by three logs at 7 days?
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`A. The formulation failed.
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`Ex. 2166 at 52:11-53:2. Dr. Xia later testified during examination by
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`counsel for Petitioner:
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`Q. If you measure your bacteria concentration after one
`day and it has gone up, do you know whether it will pass
`or fail the USP test measurement at 7 days, 14 days, 28
`days?
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`Case IPR 2017-01053
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`A. You cannot predict that.
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`Ex. 2166 at 115:20-24. This testimony is relevant to Petitioner’s argument that the
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`“POSA would not have relied on any of the references [cited by Alcon’s
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`microbiology expert Dr. Zhanel] to assess the potential of zinc to pass PET in an
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`ophthalmic composition” because “none of the references measure microorganism
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`concentrations after 48 hours, yet the ’299 patent shows measurements prior to 7
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`days do not predict the 7-day PET result.” Paper 35 at 5-6. The testimony elicited
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`by Alcon’s counsel is relevant because it contradicts Petitioner’s argument, and the
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`testimony elicited by Petitioner’s counsel undermines Dr. Xia’s credibility because
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`he testified to two inconsistent positions at two different points in his examination.
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`Observation 10. Dr. Xia testified:
`
`Q. . . . And my question is you can’t identify any art that
`shows a travoprost and HCO-40 containing ophthalmic
`solution with a pH between 5.5 and 5.7, can you?
`
`A. I cannot find any formulation with a pH between 5.5
`and 5.7, that’s your question? Yeah.
`
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`Ex. 2166 at 98:11-16. This testimony is relevant to Petitioner’s argument that
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`“without any optimization, the art already provides for a pH within 5.5-5.9 for a
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`travoprost solution,” Paper 35 at 20, and Dr. Xia’s statements that “[w]ithout any
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`optimization, the art already provides for a pH within 5.5-5.9 for a travoprost and
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`HCO-40 containing ophthalmic solution,” Ex. 1093 ¶ 57, and “the art already
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`provides for a pH within 5.5-5.9 for a travoprost and HCO-40 containing
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`11
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`Patent 8,268,299
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`ophthalmic solution absent any optimization,” Ex. 1093 ¶ 59. The testimony is
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`relevant because it contradicts Petitioner’s argument and undermines the credibility
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`of Dr. Xia.
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`Observation 11. Dr. Xia testified regarding Exhibits 1099 and 1100:
`
`Q. But these two papers aren’t papers at about
`ophthalmic formulating, right?
`
`A. No. But when you search publications, you searching
`publications by keywords, you put a complex, those
`things will come up. Those publications will come up.
`So you don’t want to limit yourself. Sometimes, I told
`you in the morning, I’m looking for bad publications, the
`publications will give me enough warnings don’t go
`there.
`
`Ex. 2166 at 92:24-93:8. This testimony is relevant to Petitioner’s argument the
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`“POSA would not have relied on any of the references [cited by Alcon’s
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`microbiology expert Dr. Zhanel]” because “none of the references tested an
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`ophthalmic composition,” Paper 35 at 5, and Dr. Xia’s statement regarding the
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`same, Ex. 1093 ¶ 19. The testimony is relevant because it is inconsistent with
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`Petitioner’s argument and undermines Dr. Xia’s credibility.
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`Observation 12. Dr. Xia testified regarding Exhibit 1042:
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`Q. AMP is part of the ionic buffer system in Systane
`Free, right?
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`A. Yes.
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`Ex. 2166 at 95:1-3. Dr. Xia testified regarding Exhibit 1110:
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`Q. And if you look at Exhibit 1110, on the second
`paragraph, it says: ‘Systane Free contains a novel system
`of proprietary ingredients including four that help form
`its gel structure and maintain its preservation.’ Do you
`see that?
`
`A. Yes.
`
`Q. The first ingredient listed there is AMP, right?
`
`A. Yes.
`
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`Ex. 2166 at 95:13-22. Dr. Xia testified regarding Exhibit 1111:
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`Q. Again, Exhibit 1111 reflects that AMP is an ingredient
`in the proprietary ionic buffer system of Systane Free,
`right?
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`A. Yes.
`
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`Ex. 2166 at 96:12-15 (emphasis added). This testimony is relevant to Petitioner’s
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`argument that Systane® Free “refutes Alcon’s assertions that a POSA would have
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`no reason to think that borate-polyol complexes work effectively with zinc to
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`provide preservation.” Paper 35 at 10. The testimony is relevant because it
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`demonstrates that Systane® Free’s ionic buffer system included another
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`ingredient—AMP—in addition to zinc, boric acid, and sorbitol.
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`Observation 13. Dr. Xia testified:
`
`Q. Is that person of ordinary skill in the art motivated by
`a desire to innovate, create something new, invent
`something that’s patentable?
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`A. Your question is is there motivation for POSA to
`invent some things?
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`Q. Yeah.
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`A. Yes.
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`Ex. 2166 at 12:5-11. This testimony is relevant to Petitioner’s argument that
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`“Alcon’s POSA is little more than an automaton,” Paper 35 at 13, and Dr. Xia’s
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`suggestion of the same, Ex. 1093 ¶ 41. This testimony is relevant because it
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`undermines Petitioner’s argument by revealing that Petitioner and Dr. Xia apply a
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`legally incorrect standard for the POSA.
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`Dated: May 18, 2018
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`Respectfully submitted,
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`/David M. Krinsky/
`David M. Krinsky
`Reg. No. 72,339
`Lead Counsel for
`Patent Owner
`
`Williams & Connolly LLP
`725 Twelfth Street NW
`Washington, D.C. 20005
`202-434-5338 (Telephone)
`202-434-5029 (Facsimile)
`dkrinsky@wc.com
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`Case IPR 2017-01053
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`CERTIFICATE OF SERVICE (37 C.F.R. § 42.6(e))
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`The undersigned hereby certifies that the foregoing “
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`ALCON RESEARCH, LTD.’S MOTION FOR OBSERVATIONS ON THE
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`SECOND DEPOSITION OF PETITIONER’S EXPERT ERNING XIA, PH.D.”
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`was served on May 18, 2018, via electronic mail upon the following attorneys of
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`record for the Petitioner:
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`Michael R. Houston
`Joseph P. Meara
`James P. McParland
`FOLEY & LARDNER LLP
`mhouston@foley.com
`jmeara-pgp@foley.com
`jmcparland@foley.com
`
`Tyler C. Liu
`ARGENTUM PHARMACEUTICALS LLC
`tliu@agpharm.com
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`
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`Dated: May 18, 2018
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`Respectfully submitted,
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`/David M. Krinsky/
`David M. Krinsky
`Reg. No. 72,339
`Lead Counsel for Patent Owner
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`15
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