UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS, LLC
`
`Petitioner
`
`v.
`
`ALCON RESEARCH LIMITED
`
`Patent Owner
`
`U.S. Patent No. 8,268,299
`
`Inter Partes Review Case No. IPR 2017-01053
`
`SECOND DECLARATION OF ERNING XIA, Ph.D.
`
`Exhibit 1093
`ARGENTUM
`IPR2017-01053
`
`000001
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS, LLC
`
`Petitioner
`
`v.
`
`ALCON RESEARCH LIMITED
`
`Patent Owner
`
`U.S. Patent No. 8,268,299
`
`Inter Partes Review Case No. IPR 2017-01053
`
`SECOND DECLARATION OF ERNING XIA, Ph.D.
`
`Exhibit 1093
`ARGENTUM
`IPR2017-01053
`
`000001
`
`
`
`
`
`TABLE OF CONTENTS
`
`
`Introduction ......................................................................................................................... 4
`
`My Background and Qualifications .................................................................................... 5
`
`List of Documents I Considered in Formulating My Opinion ............................................ 5
`
`Person of Ordinary Skill in the Art ..................................................................................... 5
`
`The Basis of My Analysis With Respect to Obviousness................................................... 6
`
`It Would Have Been Obvious to a POSA to Combine Xia, Schneider, and
`Chowhan ............................................................................................................................. 7
`
`A.
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`B.
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`C.
`
`D.
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`A POSA would look to all of Xia’s disclosure and would not be
`constrained solely to the examples ......................................................................... 8
`
`A POSA would not rely on Winslow, McCarthy, or Zeelie to assess the
`potential of zinc to pass preservative efficacy (“PE”) in an ophthalmic
`composition ............................................................................................................. 9
`
`A POSA would have omitted EDTA from an ophthalmic composition with
`zinc ........................................................................................................................ 15
`
`Borate-polyol complexes were in Xia, Schneider Formulation A, were
`known to have antimicrobial activity, and were known to increase the
`antimicrobial efficacy of other antimicrobial agents ............................................ 17
`
`
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`I.
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`II.
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`III.
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`IV.
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`V.
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`VI.
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`000002
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`VII. The Recited Concentrations of Propylene Glycol and Sorbitol Would Have Been
`Obvious to a POSA ........................................................................................................... 22
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`VIII. A pH within 5.5-5.9 was taught by the art to provide a stable, comfortable
`travoprost solution. ........................................................................................................... 36
`
`Formulations Meeting the Claimed Anionic Species and Buffering Ion
`Limitations Would Have Been Obvious in View of the Prior Art .................................... 42
`
`Formulations Meeting the Claimed Anionic Species, Buffering Ion and
`Multivalent Cation Limitations Would Have Been Obvious in View of the Prior
`Art ..................................................................................................................................... 50
`
`Chowhan, Schneider and a Related Patent Would Have Prevented a POSA From
`Commercializing a Zinc/Borate-Polyol Preserved Ophthalmic Before 2014 ................... 56
`
`IX.
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`X.
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`XI.
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`3
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`000003
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`I, Erning Xia, Ph.D., hereby declare as follows.
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`I.
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`Introduction
`1.
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`I am over the age of eighteen (18) and otherwise competent to
`
`make this declaration.
`
`2.
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`I have been retained as an expert witness on behalf of
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`ARGENTUM PHARMACEUTICALS, LLC., (“ARGENTUM”) for the above-
`
`captioned inter partes review (“IPR”). I am being compensated for my time by
`
`the hour in preparing this declaration, but my compensation is not tied to the
`
`outcome of this matter.
`
`3.
`
`I understand that this Declaration accompanies Petitioner’s Reply
`
`to Patent Owner’s Response for IPR2017-01053, an IPR involving U.S. Patent
`
`No. 8,268,299 (“the ’299 patent”), Ex. 1001, which resulted from U.S.
`
`Application No. 11/858,781 (“the ’781 application”), filed on September 20,
`
`2007, and alleging an earliest priority date of September 21, 2006. I further
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`understand that, according to the United States Patent and Trademark Office
`
`(“USPTO”) records, the ’299 patent is currently assigned to Alcon Research
`
`Limited (“Alcon” or “the patentee”).
`
`4.
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`In preparing this Declaration, I have reviewed the ’299 patent and
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`considered each of the documents cited herein, in light of general knowledge in
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`the art. In formulating my opinions, I have relied upon my experience, education
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`4
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`000004
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`and knowledge in the relevant art. In formulating my opinions, I have also
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`considered the viewpoint of a person of ordinary skill in the art (“POSA”), i.e., a
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`person of ordinary skill in the field of ophthalmic drug formulations and
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`antimicrobial preservation of such compositions. Throughout this declaration, in
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`rendering my opinion, I have considered what the viewpoint of a POSA would
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`have been prior to September 21, 2006, the filing date of U.S. Provisional Patent
`
`Application No. 60/826,529, to which the challenged ’299 patent claims priority.
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`II. My Background and Qualifications
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`5. My background and qualifications are essentially the same as set
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`forth in my first Declaration: EX1002 ¶¶6-13.
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`III. List of Documents I Considered in Formulating My Opinion
`
`6.
`
`In formulating my opinion, I have considered Dr. Majumdar’s and
`
`Dr. Zhanel’s declarations, relevant documents cited therein, and the documents
`
`cited herein.
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`IV. Person of Ordinary Skill in the Art
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`8. My understanding of a person of ordinary skill in the art (“POSA”)
`
`remains unchanged from my first declaration. EX1002 15-18. A POSA is
`
`presumed aware of all pertinent art and is a person of ordinary creativity. Id. I
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`further understand that a POSA would consider a reference for all it discloses or
`
`suggests, whether expressly spelled out or not, and would not look only to
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`5
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`000005
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`
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`examples and preferred embodiments. Also, I understand a POSA would
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`consider what the combined references would suggest, and not just the individual
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`references. These precepts comport with my own experience of how a POSA
`
`would understand prior art patents and other references pertinent to ophthalmic
`
`formulation.
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`V.
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`The Basis of My Analysis With Respect to Obviousness
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`9. My understanding of the obviousness analysis is set forth in my first
`
`declaration. EX1002 ¶¶42-44. A fundamental difference in my obvious analysis
`
`from Alcon’s experts is in the skill attributed to a POSA. While Alcon’s experts
`
`list similar (though slightly lower) educational and experiential levels of a POSA
`
`than I do, their description in practice assumes a much lower skill level.
`
`ALCON2023 ¶¶16-19; ALCON2025 ¶¶16-18. As described by Dr. Majumdar
`
`and Dr. Zhanel, a POSA focuses solely on a reference’s examples or most
`
`preferred embodiment (e.g., of Xia and Chowhan), ignoring other pertinent
`
`information in that reference. See, e.g., ALCON2025 ¶¶30-34; ALCON2023
`
`¶¶57-64. Worse, according to Dr. Zhanel, a POSA relies on irrelevant art, not
`
`predictive of preservative efficacy in ophthalmic formulations. ALCON2025
`
`¶¶35-44. He would be unaware of the art-recognized equivalence of mannitol
`
`and sorbitol, and the well-known ionization behavior of complexes of boric acid
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`and mannitol, sorbitol, and propylene glycol. ALCON2023 ¶¶82-97. He would
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`6
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`000006
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`
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`be unable to recognize polyols as result-effective variables or routinely optimize
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`preservative efficacy of ophthalmic formulations containing them, despite
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`Chowhan’s explicit disclosure to do so. Id. And he would require express
`
`directions to avoid particular levels of anions and cations in a zinc-borate polyol
`
`formulation even though the obvious combination and optimization of such
`
`formulations meet the claimed anion and cation concentrations. Id. ¶¶69-81. For
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`the reasons given in my previous declaration and below, each of the references in
`
`the proposed grounds of invalidity provides specific guidance concerning self-
`
`preserved ophthalmic formulations and travoprost formulations that would have
`
`led a POSA to the claimed formulations with a reasonable expectation of success.
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`VI.
`
`It Would Have Been Obvious to a POSA to Combine Xia, Schneider, and
`Chowhan
`10.
`
`In my first declaration I explained that multi-dose ophthalmic
`
`formulations must be protected from contamination by bacteria and fungi, and
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`prior to 2006 it was well known to use preservative agents such as BAC to do so.
`
`EX1002, ¶33. Formula A1 of Schneider (EX1007) provides an example of a
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`glaucoma medication (travoprost) which incorporates BAC. EX1002, ¶46. I
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`agree with Dr. Zhanel that for an ophthalmic composition “used in a chronic
`
`fashion, a person of ordinary skill in the art would [have seen] the advantage of
`
`
`1 Formula A is the same as the formula in the TRAVATAN® Label.
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`7
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`000007
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`
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`not having BAK and potentially preserving using other preservatives.”2 EX1048,
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`11:19-23. A POSA looking to improve Schneider Formulation A to make it
`
`BAC-free, would have looked for a self-preserved formulation that could be used
`
`for a variety of products. Xia (EX1003) fills this need with its self-preserved
`
`ophthalmic compositions that pass a standard preservative efficacy test (“PET”).
`
`EX1002, ¶¶46-87.
`
`A. A POSA would look to all of Xia’s disclosure and would not be
`constrained solely to the examples
`
`11.
`
`I agree with Dr. Zhanel that nowhere does Xia teach or suggest that
`
`zinc concentrations below those in the examples are unsuitable for use in
`
`combination with Schneider. EX1048, 123:12-124:14. As I discussed in my first
`
`declaration, Xia expressly teaches zinc ion concentrations of 0.074 mM (“about
`
`0.001 wt.%”) and 0.37 mM (“about 0.005 wt.%”) are useful, which fall squarely
`
`within the zinc concentration range claimed in the ’299 patent. EX1002, ¶50;
`
`EX1003, 5.
`
`12. A POSA would use the lowest preservative concentration that passes
`
`PET and would avoid zinc at high concentrations. I agree with Dr. Majumdar
`
`that all else being equal, a POSA would opt for the lowest preservative
`
`concentration that passes PET. EX1045, 51:24-52:10. I also agree with Dr.
`
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`2 “BAK” and “BAC” are both accepted abbreviations for benzalkonium chloride.
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`8
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`000008
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`
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`Majumdar that a POSA would avoid zinc concentrations that cause astringency
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`(i.e., 0.25 w/v%). EX1045, 79:9-16; ALCON2023, ¶56; ALCON2032, 7089.
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`With this knowledge, a POSA would optimize the zinc concentration in an
`
`ophthalmic composition to avoid astringency (i.e.., zinc concentrations below
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`0.25 w/v%) and opt for the lowest zinc concentration that passes PET.
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`B. A POSA would not rely on Winslow, McCarthy, or Zeelie to assess
`the potential of zinc to pass preservative efficacy (“PE”) in an
`ophthalmic composition
`
`13.
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`I agree with Dr. Zhanel that minimum inhibitory concentration
`
`(“MIC”), minimum bactericidal concentration (“MBC”), and minimum lethal
`
`concentration are not the same as standard PE tests and cannot be relied on to
`
`predict PET outcome. EX1048, 46: 8-23, 50:8-10. I also agree with Dr. Zhanel
`
`that a preservative “is an agent with antimicrobial activity that inhibits the growth
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`of microorganisms” and in the context of ophthalmic formulations a preservative
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`has “antimicrobial activity and [] inhibits the growth of microorganisms
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`potentially allowing it to pass preservative efficacy testing or fail preservative
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`efficacy testing.” Id., 43:15-17; 44:9-11, 19-25 (emphasis added).
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`14. Standardized PETs like FDA/ISO 14730 and USP 27 have testing
`
`criteria that must be followed including specific types of microorganisms tested
`
`and
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`their starting concentrations,
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`temperatures, media/medium, and pH.
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`EX1048, 50:17-56:3. For example, FDA/ISO 14730 and USP 27 test PE against
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`9
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`000009
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`
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`the microorganisms S. aureus, E. coli, P. aeruginosa, C. albicans, and A. niger.
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`EX1001, 10:46-55; EX1003, 14. As exemplified by Xia and the ’299 patent, the
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`microorganism concentrations used to inoculate test formulas are commonly 1 x
`
`105 - 1 x 106 colony forming units/mL (“CFU/mL”). EX1001, 11:17-21;
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`EX1003, 14. An example of an acceptable media for bacteria is Tryptic Soy
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`Agar and Sabouraud Dextrose Agar for fungi. EX1003, 14.
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`15. The time points for measuring viable microorganisms are a
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`particularly important requirement of a standardized PET. For example, to pass
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`FDA/ISO 14730 requires at least a 3 log reduction of the inoculated bacteria by
`
`day 14 and after the rechallenge at day 14, the concentration of bacteria must be
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`reduced by at least 3.0 logs by day 28. EX1003, 15; EX1001, 7:46-50.
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`Similarly, to pass USP 27 requires a 1 log reduction of the inoculated bacteria by
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`day 7, a 3 log reduction by day 14, and no increase after day 14. EX1001, 7:33-
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`38; 11:17-37. For fungi, USP 27 standards require that no growth of the fungi
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`occurs relative to the population in the initial inoculum over a 28 day test period.
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`Id. I agree with Dr. Zhanel that these time points were set by experts who
`
`determined they “are the most relevant to assessing whether [an] ophthalmic
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`composition supports or doesn’t support growth [of a microorganism].” EX1048,
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`55:17-22. The importance of time points is exemplified in the ’299 patent.
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`Examples R-W illustrate that formulas may pass PET according USP 27
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`10
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`000010
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`
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`standards by having a 1 log bacteria reduction at day 7 and a 3 log reduction at
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`day 14, yet do not achieve a similar log reduction by 24 hours. EX1001, 8:1-
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`22:46. For instance, Example V has a 0.2 log reduction of S. aureus at 24 hours,
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`but still passes PET with a 4.2 log reduction at 7 days. Id., 21:31-38.
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`16. MIC differs from standard PET and cannot be used to predict PET
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`outcome.
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` Unlike a standardized PET
`
`that measures microorganism
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`concentrations at 7, 14, and/or 28 days, an MIC test measures microorganism
`
`concentrations typically 24 hours after inoculation. EX1048, 48:19-24. I agree
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`with Dr. Zhanel that a “person of ordinary skill would say that by simply viewing
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`the MIC, you cannot form a direct correlation to what the PET test result may
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`be.” Id., 49:6-9; 50:8-10; see also the ’299 patent Example V (S. aureus).
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`17. MBC and minimum lethal concentration tests also differ from
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`standard PETs and cannot be used to predict PET outcome. MBC and minimum
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`lethal concentration tests measure microorganism killing and growth inhibition.
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`Id., 46:16-23. Unlike standardized PETs, these tests typically measure
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`microorganism concentrations 48 hours after inoculation. I agree with Dr.
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`Zhanel that a 48 hour kill test such as MBC cannot be used to predict the
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`outcome of PET. Id., 50:13-16.
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`
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`Time point(s)
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`Time point(s)
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`11
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`000011
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`USP 27 (standard
`PET)
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`(bacteria concentration)
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`(fungi concentration)
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`7 days (1 log reduction)
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`14 days (3 log reduction)
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`After day 14 (no increase)
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`28 days (no growth
`compared to initial
`inoculum)
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`FDA/ISO 14730
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`(standard PET)
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`14 days (3.0 log reduction
`compared to initial
`inoculum)
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`14 days (no growth
`compared to initial
`inoculum)
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`28 days (3.0 log reduction
`compared to rechallenge at
`day 14)
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`28 days (no growth
`compared to rechallenge
`at day 14)
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`24 hours
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`48 hours
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`Minimum inhibitory
`concentration (“MIC”)
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`24 hours
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`Minimum bactericidal
`concentration
`(“MBC”)
`
`48 hours
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`or
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`Minimum lethal
`concentration
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`
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`18. A POSA would not have relied on any of the references cited by Dr.
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`12
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`000012
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`
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`Zhanel to assess the potential of zinc to pass PET in an ophthalmic composition.
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`Nor would a POSA interpret the references as suggesting “using zinc
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`concentrations lower than those in Xia’s working examples would be likely to
`
`lead to a loss of preservative efficacy testing, and would even stimulate bacterial
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`growth” as asserted by Dr. Zhanel. ALCON2025, ¶¶33-44; citing Winslow
`
`(ALCON2122), McCarthy (ALCON2123); Zeelie (ALCON2124).
`
`19. First, unlike Xia, none of the references cited by Dr. Zhanel
`
`(Winslow, McCarthy, and Zeelie) tested an ophthalmic composition. I agree
`
`with Dr. Zhanel that ophthalmic compositions include a variety of ingredients
`
`that may affect preservative efficacy and therefore non-ophthalmic compositions
`
`cannot predict PET outcome for ophthalmic compositions. EX1048: 114:15-21.
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`20. Second, the tests performed by Winslow, McCarthy, and Zeelie are
`
`all very different from a standard PET. In contrast to the 7, 14, and/or 28 day
`
`microorganism measurements in a standard PET, none of Winslow, McCarthy, or
`
`Zeelie measured microorganism concentrations after 48 hours. ALCON2122,
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`54; ALCON2123, 51-52; ALCON2124, 505. Additionally, Winslow also used a
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`non-standard medium (Dolloff medium) and admitted the testing was affected by
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`the medium. ALCON2122, 51.
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`21. McCarthy and Zeelie performed microorganism “kill” tests, not
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`13
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`000013
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`
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`microorganism “inhibition” tests. ALCON2123, 51-52; ALCON2124, 505. As I
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`discussed above, killing tests (e.g., MBC or minimum lethal concentration)
`
`cannot predict the outcome of PET. Supra, ¶17.
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`22. Third, Xia’s Example 18 demonstrates that zinc (without Polymer
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`JR3) at 0.48 mM passed PET rebutting Dr. Zhanel’s conclusions that higher zinc
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`concentrations of 0.5 mM and 0.76 mM are not effective against E. coli or P.
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`aeruginosa, respectively. ALCON2025, ¶¶37-38. Dr. Zhanel concluded that
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`Winslow suggests to a POSA that microorganisms such as E. coli can adapt to
`
`zinc and beginning at 48 hours zinc has reduced antibacterial activity.
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`ALCON2025, ¶36. Dr. Zhanel came to his conclusion by relying on Winslow
`
`for using a zinc concentration of 0.5 mM and failing to reduce the bacteria
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`concentration even 1 log (bacterial counts were 57% of the control) after 48
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`hours. Id., ¶36 (citing ALCON2122, 54). However, Xia Example 18 has a lower
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`zinc concentration (0.48 mM) and no Polymer JR, yet reduced the bacteria
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`concentrations (including E. coli) at least 3.0 logs by day 14. EX1003, 14-15, 23.
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`23. McCarthy lacks any support for the statement relied on by Dr.
`
`
`3 Alcon and Alcon’s experts assert Xia teaches “preservation using zinc and ‘less
`than a preservative-effect amount of a primary preservative agent,’ such as a
`cationic polymer like Polymer JR.” POR, 9; ALCON2023, ¶29; ALCON2025,
`¶22.
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`14
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`000014
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`
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`Zhanel and Xia Example 18 rebuts the statement. Dr. Zhanel asserts a POSA
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`would understand McCarthy reported zinc at a concentration of 0.76 mM has
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`“little effect against the troublesome Pseudomonas aeruginosa.” ALCON2025,
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`¶38 (citing ALCON2123, 52). Although McCarthy makes this statement, the
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`reference fails to provide any data or cite to any reference to support the
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`statement. EX1048, 112:1-21. In fact, the reference lists the microorganisms
`
`tested were E. coli, S. aureus, and C. albicans—not P. aeruginosa.
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`ALCON2123, 51. Furthermore, Xia Example 18 has a lower zinc concentration
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`(0.48 mM) and no Polymer JR, yet passed PET and therefore was effective
`
`against P. aeruginosa. EX1003, 23.
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`24. Accordingly, I do not believe a POSA would rely on any of Dr.
`
`Zhanel’s proffered references to assess the potential of zinc to pass PET in an
`
`ophthalmic composition. Instead, I believe a POSA would avoid high zinc
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`concentrations knowing zinc at 0.25 w/v% is an astringent and use Xia’s express
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`teaching of zinc concentrations as low as 0.074 mM to determine an optimum
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`zinc concentration in an ophthalmic solution that passes standard PET.
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`C. A POSA would have omitted EDTA from an ophthalmic composition
`with zinc
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`25.
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`It would have been obvious to a POSA to omit EDTA from an
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`ophthalmic composition using zinc for preservation. As I discussed in my first
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`15
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`000015
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`declaration, EDTA was well-known to chelate zinc. EX1002, ¶55. Drs. Zhanel
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`and Majumdar also admitted a “POSA would expect [EDTA] to potentially have
`
`a deleterious effect on the antimicrobial activity of zinc.” ALCON2023, ¶28;
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`ALCON2025, ¶31. Xia itself demonstrates that EDTA does interfere with the
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`antimicrobial activity of zinc. Both Examples 15 and 18 had 0.48 mM zinc but
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`only Example 15 had EDTA. EX1003, 22-23. Example 15 with EDTA failed
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`PET, while Example 18 without EDTA passed PET. Id. Similarly, Examples 13
`
`and 14 with EDTA and higher levels of zinc, still failed PET, as did Examples 11
`
`and 12, which also included Polymer JR. Id.
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`26. Additionally, Dr. Majumdar explained a POSA would understand
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`EDTA boosts antimicrobial activity of BAC, which is likely the reason for its
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`inclusion in Schneider Formulation A. EX1045, 33:2-10. With this knowledge,
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`a POSA would be motivated to exclude EDTA, since BAC is not in the
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`formulation.
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`27. Because EDTA has a deleterious effect on the antimicrobial activity
`
`of zinc and is not needed to boost the antimicrobial activity of another
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`preservative such as BAC, it would have been obvious to a POSA to omit EDTA
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`from a zinc preserved formulation in order to attain highest efficacy of zinc.
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`16
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`000016
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`
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`D. Borate-polyol complexes were in Xia, Schneider Formulation A, were
`known to have antimicrobial activity, and were known to increase the
`antimicrobial efficacy of other antimicrobial agents
`
`28. Although I do not agree with Drs. Majumdar and Zhanel that
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`another preservative (“primary preservative agent”) is necessary for zinc below
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`the concentrations in Xia’s examples (i.e., 0.48 mM), I do agree that ophthalmic
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`compositions with zinc concentrations expressly taught by Xia of 0.74 mM and
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`0.37 mM may include a primary preservative agent. ALCON2023, ¶¶29-32;
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`ALCON2025, ¶26.
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`29.
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`It would have been obvious to a POSA to use a borate-polyol
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`complex as the primary preservative agent, because (1) Xia teaches the inclusion
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`of borate and polyols (EX1003, 14, 16-23 (Examples 1-20)), (2) Schneider
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`Formulation A teaches the inclusion of borate and polyols (EX1007, 9:24-42),
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`(3) polyols are a common ingredient in ophthalmic compositions and a borate
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`and polyol present in the same composition naturally form a borate-polyol
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`complex (EX1045, 102:5-12, 169:18-170:23; EX1048, 66:18-19), and (4)
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`Chowan
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`teaches
`
`that borate-polyol complexes are effective, yet gentle
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`antimicrobial agents that also “increase the antimicrobial efficacy of other
`
`antimicrobial agents when used in combination” in ophthalmic compositions
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`(EX1004, 1:49-2:12).
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`30. A POSA would reasonably consider a borate-polyol complex a
`
`17
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`000017
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`primary preservative agent under Xia’s definition. Xia states “[p]rimary
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`preservative agents are defined as non-zinc containing compounds that derive
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`their preservative efficacy through a chemical or physiochemical interaction with
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`the microbial organism.” EX1003, 4. A borate-polyol is a non-zinc containing
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`compound
`
`that
`
`interacts with microorganism
`
`either
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`chemically or
`
`physiochemically. EX1045, 203:21-204:8.
`
`31. Xia does not limit the primary preservative agents to traditional or
`
`conventional preservatives. Drs. Majumdar and Zhanel state Polymer JR is an
`
`example of a primary preservative agent taught by Xia. ALCON2023, ¶29;
`
`ALCON2025, ¶22. Dr. Majumdar admitted Polymer JR is not a traditional or
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`conventional preservative. EX1045, 114:19-115:19. Like Polymer JR, borate-
`
`polyol complexes are not traditional or conventional preservatives. Because Xia
`
`does not limit the primary preservative agents to traditional or conventional
`
`preservatives, and because a borate-polyol complex meets Xia’s definition of a
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`primary preservative agent, a POSA would understand borate-polyol complexes
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`may be used as the primary preservative agent in Xia.
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`32. Xia and Schneider Formulation A both include or may include a
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`borate-polyol complex. Xia teaches sodium borate and/or boric acid in all of its
`
`example formulations and states polyols (e.g., propylene glycol) can be added as
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`
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`a comfort agent. EX1003, 14 and 16-23. As admitted by Dr. Majumdar, polyols
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`are a common ingredient in ophthalmic compositions (EX1045, 102:5-12), so it
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`would be expected that a POSA may add a polyol to Xia’s formulations.
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`Schneider Formulation A also includes boric acid and a polyol (i.e., mannitol).
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`EX1007, 9:24-42.
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` Because both Xia and Schneider teach ophthalmic
`
`compositions that may/do have boric acid/borate and a polyol, the compositions
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`inherently have borate-polyol complexes present. EX1045, 169:18-170:23;
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`EX1048, 66:18-19.
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`33. A POSA would know that it is common in self-preserved
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`ophthalmic compositions to combine multiple PE boosting excipients to ensure
`
`passing PET. A POSA would also know that borate-polyols are effective, yet
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`gentle antimicrobial agents that also “increase the antimicrobial efficacy of other
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`antimicrobial agents when used in combination” in ophthalmic compositions.
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`EX1004, 1:49-2:12; see also EX1095, ¶9. It therefore would have been obvious
`
`to a POSA to add a borate-polyol complex to boost PE in a zinc self-preserved
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`ophthalmic composition.
`
`34. Drs. Zhanel and Majumdar assert a “POSA would not have
`
`understood Chowhan to teach that borate-polyol complexes are effective against
`
`bacteria.” ALCON2023, ¶65; ALCON2025, ¶49. I disagree. Chowhan
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`19
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`explicitly states “[t]he ophthalmic compositions of the present invention
`
`comprise borate-polyol complexes which have surprisingly been found to have
`
`increased antimicrobial activity...” EX1004, 2:5-9 (emphasis added). Drs.
`
`Majumdar and Zhanel admit that antimicrobial agents inhibit the growth of
`
`microorganism and the term microorganism refers to both bacteria and fungi.
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`EX1045, 23:5-10; EX1048, 41:8-42:25. Accordingly, a POSA would understand
`
`Chowhan to teach borate-polyol complexes have increased growth inhibition of
`
`bacteria and fungi.
`
`35. Chowan provides only one example that tests bacteria and a POSA
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`would understand that the design of this example does not allow a borate-polyol
`
`complex’s bacterial PET to be assessed, because (1) the bacteria levels were
`
`measured after 1 hour (EX1004, 9:13-14) and (2) as admitted by Dr. Zhanel,
`
`there is a limit below which bacteria log reduction cannot be measured (EX1048,
`
`59:8-16), and this limit is already met by BAC without the borate-polyol
`
`complex. EX1004, Example 10.
`
`36. As I discussed above, time points other than those in a standard PET
`
`cannot be relied on to predict PET outcome. Supra, ¶15. For instance, Example
`
`V of the ’299 patent illustrates that a microorganism reduction after 24 hours
`
`cannot accurately predict PET outcome. Id. With this in mind, a POSA would
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`20
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`
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`not rely on a bacteria reduction measured after 1 hour to predict PET outcome.
`
`37. A POSA would know it is not possible to achieve a measurable
`
`improvement by the addition of a borate-polyol complex in Chowan’s Example
`
`10, because BAC without borate-polyol is so effective at lowering bacteria
`
`levels. A POSA would understand that the limit of detection for microorganism
`
`log reduction is based upon the starting microorganism concentration. EX1048,
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`59:8-16. Commonly PET and other inhibition tests start with a microorganism
`
`concentration from about 1 x 105 - 1 x 106 CFU/mL. Supra, ¶14. Starting at this
`
`concentration correlates to detecting up to a maximum 5-6 log reduction.
`
`Chowan Example 10 shows that Formula A with BAC (no borate-polyol
`
`complex) almost completely reduced the bacteria P. aeruginosa, S. aureus, and
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`E. coli (log reductions of 5.3, 5.5, and 5.5, respectively4). EX1004, 8:48-9:25. In
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`comparison, Formula A had a fungi log reduction of 2.1 and 4.0 (A. niger and C.
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`albicans, respectively). Id. From these results, it is clear that BAC alone was far
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`more effective at reducing bacteria than fungi concentrations. Because BAC
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`alone (Formula A) was so effective at reducing the bacteria concentrations,
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`Formulation B (with a borate-polyol complex) had a very similar bacteria log
`
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`4 This almost complete bacteria reduction is higher than the bacteria reduction in
`most examples of the ‘299 patent after 7 days and is significantly higher than the
`bacteria reduction after 6 hours. EX1001, 18:1-22:46.
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`21
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`reduction. Id. In contrast, BAC was not nearly as effective at reducing fungi, so
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`reduction of fungi concentrations upon the addition of the borate-polyol complex
`
`in Formulation B could still be detected. Because BAC alone was so effective at
`
`reducing the bacteria concentrations, a POSA would understand that it precluded
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`measuring the efficacy of the borate-polyol complex against bacteria from
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`Chowhan’s Example 10.
`
`38. Furthermore, even if Drs. Zhanel and Majumdar are correct (which
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`they are not) that a POSA would understood Chowhan to teach that borate-polyol
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`complexes are effective against fungi and not bacteria, a POSA would still be
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`motivated to combine an antifungal preservative with the known antibacterial
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`activity of zinc to ensure comprehensive preservation of the formulation against
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`both bacteria and fungi.
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`VII. The Recited Concentrations of Propylene Glycol and Sorbitol Would Have
`Been Obvious to a POSA
`39.
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`Chowhan teaches the use of borate-polyol complexes where
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`preferred polyols are “mannitol, glycerin, propylene glycol, and sorbitol” and
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`mixtures of these polyols5 may be used to adjust the buffering and antimicrobial
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`5 “The water-soluble borate-polyol complexes of the present invention may be
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`formed by mixing borate with polyol(s) of choice in an aqueous solution.”
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`EX1004, 3:10-13 (emphasis added).
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`properties of the borate-polyol complexes in an ophthalmic composition.
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`EX1004, 2:5-12, 3:4-6, 10-13, 43-52; 9:32-64. Chowhan explicitly states “[t]he
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`ophthalmic compositions of the present invention comprise borate-polyol
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`complexes which have surprisingly been found to have increased antimicrobial
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`activity as compared to boric acid or its salts” and further that “these complexes
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`unexpectedly increase the antimicrobial efficacy of other antimicrobial agents.”
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`Ex. 1004, 2:5-12.6 Included in this disclosure are preferred ranges for the borate-
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`polyol complexes in order to affect such antimicrobial activity and buffering
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`properties. EX1004, 3:43-46. Based on Chowhan’s extensive disclosure, a
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`POSA would understand the buffering and/or antimicrobial activity of such
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`complexes may be manipulated and optimized via the selection of any of
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`Chowhan’s preferred polyols within the preferred concentrations disclosed. Thus
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`a POSA would understand that the choice and concentration of these polyols were
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`result-effective variables known to affect the antimicrobial properties and
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`buffering properties of the composition. EX1002 ¶¶47-48, 51, 54, 60-62, 94, 117.
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`As Chowhan is Alcon’s own patent, they cannot deny that optimization of the
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`6 As noted previously in this declaration, Drs. Majumdar and Zhanel admit that
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`antimicrobial agents inhibit the growth of microorganism and the term
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`microorganism refers to both bacteria and fungi. EX1045, 23:5-10; EX1048, 41:8-
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`42:25.
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`preservative efficacy and buffering imparted by borate-polyol complexes to a
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`formulation was well-understood to depend on the particular components used
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`(e.g., the amounts and types of polyols, etc.), and that such optimization was
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`readily performed by a POSA. EX1004, 3:43-52; infra ¶¶42-49.
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`40.
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`Instead of acknowledging these teachings, Alcon appears to ignore
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`them to focus only on “most preferred” embodiments and on particular working
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`examples of Chowhan. For example, Alcon and Dr. Majumdar claim a POSA
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`“would have selected mannitol – not propylene glycol or sorbitol – as a starting
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`point for a proposed composition” because Chowhan described mannitol as “most
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`preferred” and used mannitol in working examples. POR at 37; EX2023, ¶ 85.
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`Alcon also requires 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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